Influence of Inflammation on Cytochromes P450 Activity in Adults: A Systematic Review of the Literature

Background: Available in-vitro and animal studies indicate that inflammation impacts cytochromes P450 (CYP) activity via multiple and complex transcriptional and post-transcriptional mechanisms, depending on the specific CYP isoforms and the nature of inflammation mediators. It is essential to review the current published data on the impact of inflammation on CYP activities in adults to support drug individualization based on comorbidities and diseases in clinical practice. Methods: This systematic review was conducted in PubMed through 7th January 2021 looking for articles that investigated the consequences of inflammation on CYP activities in adults. Information on the source of inflammation, victim drugs (and CYPs involved), effect of disease-drug interaction, number of subjects, and study design were extracted. Results: The search strategy identified 218 studies and case reports that met our inclusion criteria. These articles were divided into fourteen different sources of inflammation (such as infection, autoimmune diseases, cancer, therapies with immunomodulator…). The impact of inflammation on CYP activities appeared to be isoform-specific and dependent on the nature and severity of the underlying disease causing the inflammation. Some of these drug-disease interactions had a significant influence on drug pharmacokinetic parameters and on clinical management. For example, clozapine levels doubled with signs of toxicity during infections and the concentration ratio between clopidogrel’s active metabolite and clopidogrel is 48-fold lower in critically ill patients. Infection and CYP3A were the most cited perpetrator of inflammation and the most studied CYP, respectively. Moreover, some data suggest that resolution of inflammation results in a return to baseline CYP activities. Conclusion: Convincing evidence shows that inflammation is a major factor to be taken into account in drug development and in clinical practice to avoid any efficacy or safety issues because inflammation modulates CYP activities and thus drug pharmacokinetics. The impact is different depending on the CYP isoform and the inflammatory disease considered. Moreover, resolution of inflammation appears to result in a normalization of CYP activity. However, some results are still equivocal and further investigations are thus needed.


INTRODUCTION
Cytochromes P450 (CYP) are the major drug-metabolizing enzymes (DME) responsible for 75% of drug metabolism, making them decisive in the efficacy and safety of drugs (Wienkers and Heath, 2005). The interindividual variability in CYP activity is influenced by genetic factors, environmental factors and comorbidities (Lynch and Price, 2007). CYP genetic polymorphisms are well described, resulting in major functional differences (Zhou et al., 2017). CYP are also impacted by drug-drug interactions (DDIs) and several widely used drugs were removed from the market because of serious adverse drug reactions (ADRs) due to DDIs via the CYPs (Wilkinson, 2005). Therefore, the Food and Drug Administration (FDA) requires invitro evaluation of potential DDIs during the course of drug development (Kato, 2020; Food and Drug Administration).
A less well described but increasingly studied source of modulation of CYP activity and recently reviewed is that of endogenous inflammatory markers (de Jong et al., 2020;Stanke-Labesque et al., 2020). Inflammation is a response to endogenous or exogenous aggression that can be acute or chronic. It is prominent in many diseases, such as infection, trauma, surgery, arthritis, asthma, atherosclerosis, autoimmune disease, various immunologically mediated and crystal-induced inflammatory conditions, diabetes and cancer, to name a few (Gabay and Kushner, 1999;Germolec et al., 2018;Stavropoulou et al., 2018). This universal protective response involves innate and adaptative immunity and is present in virtually all tissues. Acute changes can be associated with variation in the concentrations of several plasma proteins, the acute-phase proteins (APP), and numerous behavioral, physiological, biochemical and nutritional changes (Gabay and Kushner, 1999). Cytokines are the main stimulators of APP production, and interleukin-6 (IL-6) is the key stimulator of APP while other cytokines (IL-1β, Tumor Necrosis Factor α, interferon-γ, transforming growth factor β and possible IL-8) influence APP subgroups (Gabay and Kushner, 1999). Thus, inflammation is a complex and well-orchestrated process involving many cell types and molecules that function as a cascade network, some of which initiate, amplify or sustain the process and others attenuate or resolve it (Gabay and Kushner, 1999;Stanke-Labesque et al., 2020).
Inflammation can impact drug PK through multiple mechanisms which typically occur in the liver, kidney, or intestinal epithelial cells (Stavropoulou et al., 2018;de Jong et al., 2020;Stanke-Labesque et al., 2020). The metabolic activities of CYPs are suppressed by inflammation in most cases, but some CYPs may be induced or remain unaffected (Morgan, 2001;de Jong et al., 2020;Stanke-Labesque et al., 2020). The positive and negative control of gene transcription is generally achieved by the interaction of regulatory proteins with specific DNA sequences on the regulated genes (Morgan, 1997). The impact of inflammation on the metabolic activity of CYPs has been studied in various in-vitro and animal models of inflammation, including trauma, infection and administration of endotoxin or cytokines (de Jong et al., 2020;Stanke-Labesque et al., 2020). Information available in the literature suggests that this impact on PK is triggered by cytokines and their intracellular signaling, directly or via interaction with the nuclear receptor pathway, on drug transporters and metabolizing enzymes (Liptrott and Owen, 2011;de Jong et al., 2020;Stanke-Labesque et al., 2020). Importantly, no single common pathway has been identified to explain the changes in the entire CYP family and involves different mediators but also different transcription factors (Renton, 2005;de Jong et al., 2020;Stanke-Labesque et al., 2020). Different effects of cytokines are observed in different cell types, which could be explained by a difference in the way intracellular signals from cytokine receptors are generated (Liptrott and Owen, 2011). Different cytokines exhibit a widely different spectrum of activity trough individual CYP isoforms and many different transcription factors (Morgan, 1997;Ruminy et al., 2001;Renton, 2005;Liptrott and Owen, 2011). Their activation by cytokines have been implicated in the downregulation and transcriptional regulation of different CYP isoforms (Morgan, 1997;Ruminy et al., 2001;Renton, 2005;Liptrott and Owen, 2011). Regulation of CYP during inflammation can occur trough pre-and post-transcriptional mechanisms that are cytokine and CYP specific (de Jong et al., 2020;Stanke-Labesque et al., 2020). Pre-transcriptional mechanisms currently described in the literature include transcriptional downregulation of transcription factors, interference with dimerization/ translocation of (nuclear) transcription factors, altered liverenriched C/EBP signaling, and direct regulation by NF-κB (de Jong et al., 2020). Overall, three main mechanisms have been described to explain the downregulation of inflammation in drug metabolizing enzyme and transporters expression and activity, namely inhibition of drug metabolizing enzyme transcription, epigenetic modifications in genes as a result of DNA methylation, modification of histone patterns, release of microRNA and NOdependent proteasome degradation, which is a posttranscriptional mechanism (Stanke-Labesque et al., 2020).
Therefore, the aim of this systemic review is to evaluate the impact of inflammation on CYP activity in the adult population. condition, caused by disease, treatment or a medical or surgical procedure. The outcomes of interest were the effect of potential inflammation (suggested or provided) on metabolic ratios (MR) of CYP isoforms, the PK/PD and the safety profile of CYP substrates.
Successive steps in article selection included reading the title, abstract and full text according to the predefined eligibility criteria to screen for potentially relevant records. The selected articles were classified into literature reviews and in-vitro, animal, in-silico and human studies. Then, only studies involving adults (defined as over 18 years old) were kept, classified into studies or case reports/series. The same procedure was applied to assess the inclusion of additional articles identified by the manual search. The study selection process was summarized in a flowchart created according to the PRISMA statement requirements ( Figure 1) (Moher et al., 2009).

Data Extraction and Management
Articles selected from the search results were collected and exported to the reference management software Zotero (version 5.0.85, © 2006(version 5.0.85, © -2018 and merged to remove duplicates. Data from the included articles were extracted and synthetized. The authors extracted the following data according to the PICOS framework discussed above. These included study design, sample size, source of inflammation and comparators, victim drugs and CYP involved, and outcomes of interests (potential effect of interaction). When a CYP substrate was used in the article to determine whether or not inflammation or concomitant drugs altered its PK/PD profile, a verification of its metabolic pathway was performed. The verification process was performed using the Summary of Product Characteristics (SmPCs), the Lexi-Interact drug interaction checker and the Geneva table of CYP substrates, inhibitors, and inducers (Uptodate,; Samer et al., 2013).

Identification and Selection of the Studies
The primary search, performed in PubMed, yielded a total of 2′283 articles that were screened according to their title and abstract. Of the remaining 523 articles, an additional 366 articles were identified by cross-referencing and handsearching of the reference list of the relevant articles (n 889). Of these, 352 records were removed because the full text was not available (n 128) or because they were considered irrelevant or not translated into English (n 224). The remaining 537 articles were classified into review articles (n 55), in-vitro (n 77) or in-silico (n 8) studies, and animal (n 152) or human (n 245) studies. The articles and case reports concerning the pediatric population (n 27) are the subject of another systematic review and were excluded from this work (Lenoir et al., 2021). Finally, 218 articles conducted in adults were included and classified into studies (n 180) and case reports/series (n 38) for analysis ( Figure 1).
CYP3A5, because the probe drugs used to assess the activity of CYP3A4 are metabolized by these two isoenzymes and no distinction can be made between them. Distribution in percent of all the references in the different categories are illustrated in Figure 2.

Infection
Several studies have assessed the association between infection, represented by elevated levels of CRP, and PK variations of voriconazole. This is of particular interest and voriconazole therapeutic drug monitoring should thus be used to optimize clinical success and safety in these settings (Luong et al., 2016). Increased levels of CRP were correlated with increased voriconazole concentrations or decreased metabolic ratio of voriconazole/N-oxide and this could be explained by CYP2C19 and/or CYP3A downregulation, as voriconazole is mainly metabolized by these two CYPs (van Wanrooy et al., 2014;Encalada Ventura et al., 2015;Dote et al., 2016;Niioka et al., 2017;Vreugdenhil et al., 2018;Schulz et al., 2019). A positive correlation between inflammatory markers and voriconazole concentration was seen in adults, as well as with the severity of infection (van Wanrooy et al., 2014;Dote et al., 2016;Veringa et al., 2017;Gautier-Veyret et al., 2019). Drug metabolism appears to be influenced by the degree of inflammation and standardization of the classification of inflammatory markers elevation seems necessary (van Wanrooy et al., 2014;Niioka et al., 2017;Veringa et al., 2017;Gautier-Veyret et al., 2019). Indeed, voriconazole through concentration increased by 0.015 mg/L every 1 mg/L increase in CRP, and a recent metaanalysis showed that an increase in voriconazole through concentration of 6, 35 and 82% was associated with an increase in the CRP level of 10, 50 and 100 mg/L, respectively (van Wanrooy et al., 2014;Bolcato et al., 2021). As a final evidence to support of a correlation between inflammation and CYP downregulation, inflammation, and its resolution, decreased, and increased voriconazole clearance respectively, suggesting that the improvement of the inflammation allows a return to the baseline (Dote et al., 2016). However, no studies have investigated the duration of the resolution of inflammationinduced metabolic phenoconversion (Stanke-Labesque et al., 2020). This is an important limitation to allow individualization of treatment without therapeutic drug monitoring (TDM), as under-exposure to drug remains a risk (Stanke-Labesque et al., 2020).
Early works assessed the effect of an infection induced intentionally by lipopolysaccharides (LPS) injection on antipyrine pharmacokinetics, and several studies have assessed the impact of infection on psychotropic agents (clozapine, risperidone). The increase of clozapine levels, a CYP1A2 substrate, due to inflammation has been well studied and demonstrated (Raaska et al., 2002;Haack et al., 2003;de Leon and Diaz, 2003;Jecel et al., 2005;Pfuhlmann et al., 2009;Darling and Huthwaite, 2011;Espnes et al., 2012;Abou Farha et al., 2012;Leung et al., 2014;Kwak et al., 2014;Takahashi et al., 2015;ten  1 | Impact of unspecified source inflammation on CYP substrates, explained totally or partially by modulation of CYP activity.

Inflammation characterized by
Victim drugs (CYPs concerned)

18
-mean oxprenolol AUC 2-fold greater in inflammation group Zhou et al. (2017) Cohort study CRP serum levels tacrolimus (CYP3A4) 31-year-old man -tacrolimus C/D increased during two inflammation episodes by 54% (cholestasis) and 141% (infection following surgery), and strongly correlated with CRP (r2 0.78, p 0.079) Wilkinson (2005)    56-year-old man 5-fold higher risperidone dose requirement during pneumonia Ruminy et al. (2001) Case report Elevated serum levels of CRP (>5 mg/L) clozapine (CYP1A2), quetiapine (CYP3A4 and CYP2D6) and risperidone (CYP3A4 and CYP2D6) 33 clozapine, 32 quetiapine 40 risperidone -C/D of clozapine was significantly higher (p < 0.01) and CYP1A2 MR (NCLZ/CLZ) significantly lower (p < 0.05) Moher et al. (2009) -positive and significant correlation between clozapine and CRP levels (r 0.313, p < 0.01) Cohort study -no difference in C/D or in MR of quetiapine -C/D of risperidone was significantly higher (p < 0.01) and MR decreased ( Hefner et al., 2016;Ruan et al., 2017;Clark et al., 2018;Ruan et al., 2018;Ruan et al., 2020). A positive and significant correlation between clozapine and CRP levels (r 0.313, p < 0.01) was found, with a 2-to 6-fold increase in serum levels and the development of toxic symptoms, as well as improvement after dose reduction or infection recovery (Raaska et al., 2002;Haack et al., 2003;de Leon and Diaz, 2003;Jecel et al., 2005;Pfuhlmann et al., 2009;Darling and Huthwaite, 2011;Espnes et al., 2012;Kwak et al., 2014;Leung et al., 2014;Takahashi et al., 2015;ten Bokum et al., 2015;Hefner et al., 2016;Abou Farha et al., 2012;Ruan et al., 2017;Clark et al., 2018;Ruan et al., 2018;Ruan et al., 2020). Further investigations are needed concerning anticoagulant therapy, as only one case of severe bleeding in the context of infection was reported in the literature (Blumenkopf and Lockhart, 1983). First observation of a return to baseline metabolic activity after the end of the disruption that caused inflammation dates from 1985, with the gradual improvement of antipyrine clearance in days after the resolution of pneumonia (Sonne et al., 1985). Later, other authors demonstrated metabolic recovery after improvement of a liver fluke infection following praziquantel treatment (Satarug et al., 1996). In hepatitis (Table 2B), a study suggested an overall downregulation of several hepatic CYPs and transporters with liver fibrosis progression, although the mechanisms of regulation differed and large inter-individual variation existed (Hanada et al., 2012). Indeed, this study assessed that the mRNA level was largely dependent on fibrosis stage and that the role of the different nuclear receptors tested is not the same in the hepatic expression of each CYP isoenzyme (Hanada et al., 2012). CYP3A4 downregulation during HCV infection has been welldescribed (McHorse et al., 1975;Tuncer et al., 2000;Latorre et al., 2002;Wolffenbüttel et al., 2004). Indeed, numerous studies have described a higher drug exposure of the two most commonly used immunosuppressants, tacrolimus and cyclosporine A, in patients with hepatitis and especially in those with viremia (Tuncer et al., 2000;Latorre et al., 2002;Wolffenbüttel et al., 2004). Moreover, when HCV is treated, CYP activities appear to return to baseline levels in several studies (McHorse et al., 1975;van den Berg et al., 2001;Kugelmas et al., 2003;Ueda et al., 2015;Kawaoka et al., 2016;Saab et al., 2016;Raschzok et al., 2016;Ueda and Uemoto, 2016;Smolders et al., 2017). Indeed, through concentration of tacrolimus decreased after initiation of HCV treatment, such as sofosbuvir, daclatasvir, asunaprevir, simeprivir, ribavirin and interferon, administered alone or in combination, and it required a dosage increase (Kawaoka et al., 2016;Raschzok et al., 2016;Saab et al., 2016;Smolders et al., 2017). Subgroups were identified, such as patients not responding to interferon with higher CYP3A downregulation related to higher levels of circulating cytokines, confirming that CYP modulation is proportional to intensity of inflammation (Morcos et al., 2013). However, conflicting results exist, and clinical recovery from acute liver disease was not accompanied by a corresponding recovery of drug-metabolizing capacity in a study (Breimer et al., 1975). This could be due to a lag between the return to baseline CYP levels and recovery, as clinical recovery from liver disease is not accompanied by a corresponding recovery of drug metabolizing capability (Breimer et al., 1975). Indeed, it is generally recognized that recovery half-lives are approximatively 20-50 h after mechanism-based inhibition and 40-60 h after enzyme induction (Imai et al., 2011).
Several studies have examined the impact of HIV on CYP metabolism (Table 2C) and have shown that several concomitant treatments and antiretroviral drugs metabolized by CYP3A have reduced metabolism in HIV-infected individuals, with an increased risk of ADRs. For instance, clindamycin clearance decreased from 0.27 in healthy volunteers to 0.21 L/h/kg in AIDS patients (p 0.014) and a negative correlation between TNF-α and midazolam clearance was found (Gatti et al., 1993;Jones et al., 2010). Moreover CYP3A inhibitor (ketoconazole or ritonavir) and inducer (rifampicin) effects were less pronounced on antiviral PK in HIV-patients (Gatti et al., 1993;Grub et al., 2001;Jetter et al., 2010; European medicines agency; Packageinserts). It is important to characterize CYP3A modulation in HIV, as many antiviral treatments are metabolized by this pathway, and this could lead to efficacy or safety concerns. However, the AUC of atazanavir was lower in HIV-infected patients than in healthy volunteers and this could  be explained by the absence of correlation between its oral clearance and inflammatory markers in a cohort study, the lack of identical study conditions (doses, sample schedule, meals . . . etc.) between the two groups and the fact that HIV infection was well-controlled (Packageinserts; Le Tiec et al., 2005;Venuto et al., 2018). Indeed, caffeine metabolism was not altered in HIV-infected patient compared with healthy volunteers, but was decreased in AIDS patients (Lee et al., 1993;Jones et al., 2010). Moreover, atazanavir was administered with the booster ritonavir to decrease its clearance, and the effect of inflammation could have been minimized.
More recently, some studies have shown increased plasma concentration of CYPs substrates (mostly CYP3A) during SARS-CoV-2 infection, which may have led to believe that there was a CYPs downregulation due to inflammation (Table 2D) (Cojutti et al., 2020;Cranshaw and Harikumar, 2020;Gregoire et al., 2020;  Cohort study -dose requirement increased by more than 50% in 2 patients treated with IFN-α/ribavirin HCV treated with anti-HCV therapy tacrolimus (CYP3A) and cyclosporine (CYP3A) 12 (7 cyclosporine and 5 tacrolimus) responders -cyclosporine and tacrolimus levels at baseline vs after HCV RNA negativation decreased significantly (p 0.018 for cyclosporine and p 0.044 for tacrolimus) Ueda et al. (2015) 18 (7 cyclosporine and 11 tacrolimus) nonresponders -cyclosporine and tacrolimus levels in nonresponders did not change between baseline and the end of anti-HCV therapy (p 0.24 for cyclosporine and p 0.32 for tacrolimus) Cohort study HCV treated with simeprevir tacrolimus (CYP3A) and cyclosporine 2 -C/D ratio of calcineurin inhibitors were elevated in the first 2 weeks in both cases, but decreased thereafter, necessitating an increase in the dose Morcos et al. (2013) Case report Frontiers in Pharmacology | www.frontiersin.org November 2021 | Volume 12 | Article 733935  Marzolini et al., 2020;Schoergenhofer et al., 2020;Testa et al., 2020). Indeed, the plasma concentrations of some CYP3A substrates (lopinavir, darunavir and direct oral anticoagulants) were significantly increased in patients with SARS-CoV-2 infection (Cojutti et al., 2020;Gregoire et al., 2020;Schoergenhofer et al., 2020;Testa et al., 2020). CRP and IL-6 were also associated with lopinavir concentrations and a trend toward a return to baseline was observed after treatment with tocilizumab (Marzolini et al., 2020;Schoergenhofer et al., 2020). Indeed, lopinavir through level in patients with SARS-CoV-2 infection was twice as high as in HIV patients but concentrations decreased when tocilizumab was administered (Marzolini et al., 2020;Schoergenhofer et al., 2020). However, the impact of inflammation induced by SARS-CoV-2 infection on lopinavir through concentration may be also due to increased orosomucoid levels (Boffito et al., 2021;Stanke-Labesque et al., 2021). Lopinavir is a highly protein-bound drug and the misinterpretation of its overexposure during inflammation could be explained by the fact that total and not unbound concentration was considered (Boffito et al., 2021;Stanke-Labesque et al., 2021). Furthermore, a case report described clozapine toxicity and increased clozapine level from 0.57 to 0.73 mg/L during SARS-CoV-2 infection (Cranshaw and Harikumar, 2020). However, no correlation was found between CRP and hydroxychloroquine plasma concentrations (Marzolini et al., 2020).

Vaccination
Regarding vaccination (Table 3), several reports and studies assessed variations of PK/PD parameters of drugs after vaccination, but data remain contradictory. Of the 31 articles included, 28 were exclusively about influenza vaccination while two were about concomitant vaccinations including influenza (pneumococcus, tetanus and hepatitis A). Only one article did not evaluate the influenza vaccination but reported on the impact of tuberculosis vaccination (BCG). No significant difference of CYP activity between before or after vaccination was shown in several studies (Britton and Ruben, 1982;Fischer et al., 1982;Goldstein et al., 1982;Patriarca et al., 1983;Stults and Hashisaki, 1983;Stults and Hashisaki, 1983;Hayney and Muller, 2003). In particular, the impact of vaccination on anticoagulants effects has been wellstudied but the majority of studies showed no variation of PT time or INR (Farrow and Nicholson, 1984;Kramer et al., 1984;Gomolin, 1986;Raj et al., 1995;Poli et al., 2002;Paliani et al., 2003;Iorio et al., 2006;Jackson et al., 2007;MacCallum et al., 2007;Casajuana et al., 2008). However, the occurrence of bleeding events a few days after vaccination, when the PT time was previously stable, has been described (Kramer et al., 1984;Weibert et al., 1986;Carroll and Carroll, 2009). Moreover, the case of a patient hospitalized because of serum CPK level of 93,000 U/L during treatment with cerivastatin and bezafibrate or the occurrence of tramadol toxicity has been reported (Plotkin et al., 2000;Pellegrino et al., 2013). The patient had been vaccinated 5 days earlier (Plotkin et al., 2000). Other studies, few in number, have found an effect of vaccination on the PK of CYP substrates (Renton et al., 1980;Kramer and McClain, 1981;Gray et al., 1983). However, no study has correlated the data with pro-inflammatory markers.

Organs Diseases
The influence of liver and kidney function on disposition of drugs excreted by the liver and kidney is widely recognized and used to derive dosing adaptations. However, there is now an increasing appreciation that kidney impairment can also reduce non-renal clearance and alter the bioavailability of drugs predominantly metabolized by the liver (Nolin, 2008). Indeed, uremic toxin has been implicated in transcriptional, translational and acute posttranslational modifications of CYP, and it has been recognized that inflammation is a common feature in endstage renal disease (ESRD) patients (Nolin, 2008;Stenvinkel and Alvestrand, 2002). For example, CYP3A activity increased post-dialysis, meaning that it is the presence of uremic toxin that is responsible for CYP downregulation and not the underlying disease (Nolin et al., 2006). An inverse relationship between hepatic CYP3A activity was found in this study, but it did not prove causality (Nolin et al., 2006). It indicates that uremia can be used as a surrogate for dialyzable toxins that contribute to alterations in CYP3A function (Nolin et al., 2006). Indeed, hemodialysis improved CYP3A activity with a 27% increase 2 h post-dialysis in uremic patients, suggesting that potential toxins responsible for this alteration were removed (Nolin et al., 2006). Authors suggested that this improvement occurred independently of transcriptional or translational modifications, contrary to what has been suggested previously (Nolin et al., 2006). However, as shown in Table 4, two studies found an association between the modification of CYP activity and inflammation in ESRD patients (Molanaei et al., 2012;Molanaei et al., 2018).
All studies in patients with liver disease described a decrease in CYP activity, compared to controls, as shown in Table 5. Indeed, several studies studied antipyrine, an old drug that is metabolized by multiple CYP (Branch et al., 1973;Farrell et al., 1979;Salmela et al., 1980;Teunissen et al., 1984;Schellens et al., 1989;Bauer et al., 1994;Grieco et al., 1998;Frye et al., 2006). They showed that CYP activity and antipyrine metabolism decreased only in severe disease compared to inactive cirrhosis, mild-moderate liver disease or healthy volunteers (Farrell et al., 1979;Bauer et al., 1994;Grieco et al., 1998). Moreover, chronic liver disease appeared to have a higher impact than an acute/reversible pathology (Branch et al., 1973). However, few studies have focused on a specific CYP substrate, and no studies found an association with inflammatory markers. One study demonstrated that CYP2C19, 2E1, 1A2 and 2D6 probe drugs concentrations were inversely correlated to the Child-Pugh score and another one demonstrated that phenacetin clearance decreased by 90% in patients with cirrhosis (Frye et al., 2006;Wang et al., 2010). Concerning CYP2C9, tolbutamide plasma levels increased by 10-20% and irbesartan AUC increased by 20-30% in cirrhotic patients (Ueda et al., 1963;Marino et al., 1998). The same results were found with CYP3A as diazepam clearance decreased in cirrhosis (Klotz et al., 1975). These variations may therefore be attributed to the loss of liver function due to tissue destruction. CYP metabolism appeared to be influenced by other organ's disease, such as clozapine serum levels that increased by 2-fold during chronic obstructive pulmonary disease (COPD) exacerbation and antipyrine clearance that was significantly lower in patient with COPD and antitrypsin deficiency than in healthy volunteers (Laybourn et al., 1986;Leung et al., 2014). In addition, one study showed that inflammatory markers were inversely correlated with CYP1A2 and CYP2C19 activity but not with CYP2D6 and CYP2E1 activity in patients with congestive heart failure .
Some studies conducted in critically ill patients ( Table 8), showed that CYP1A2 and 3A metabolic activity were downregulated, and that it may be proportional to the severity and reversibility of the illness (Shelly et al., 1987;Toft et al., 1991;Kruger et al., 2009). For instance, theophylline clearance decreased by 10-66%, atorvastatin AUC increased by 15-fold, and clopidogrel active metabolite decreased by 48-fold, raising concerns about   Stults and Hashisaki (1983) 3 controls Random Influenza vaccination theophylline (CYP1A2) 7 3 recovering from an acute exacerbation of COPD and 4 healthy volunteers -plasmatic concentration before and after influenza vaccination significantly increased Goldstein et al. (1982) Non-random Influenza vaccination theophylline (CYP1A2) 13 -no difference in the mean serum theophylline levels before influenza vaccination and 24h, 72h, 1 week and 2 weeks after vaccination Britton and Ruben (1982) Non-random Influenza vaccination theophylline (CYP1A2) 7 (chronic bronchitis and chronic airflow obstruction thus and 5 men were smokers (CYP1A2 inductor)) -

References and design
Influenza vaccination theophylline (CYP1A2) 5 -no significant variations in the serum levels before and 24 h after vaccination Farrow and Nicholson (1984) Non-random Influenza vaccination theophylline (CYP1A2) and chlordiazepoxide (CYP3A) 8 theophylline -an effect of vaccination has been shown on theophylline clearance at day 1 after vaccination (p 0.016) but not at day 7 MacCallum et al. (2007) 5 chlordiazepoxide -no effect on chlordiazepoxide metabolism Non-random -the effect seems to be greater when initial clearance is higher Influenza vaccination vs controls theophylline (CYP1A2) and warfarin (CYP2C9) 152 influenza vaccinated -no ADR occurred in patients on theophylline in both groups and only one reaction in each group of patients who were taking warfarin Raj et al. (1995)  treatment efficacy (Toft et al., 1991;Kruger et al., 2009;Schoergenhofer et al., 2018). However, a systematic review reported that 20-65% of critically patients had an increased renal clearance, defined as a creatinine clearance greater than 130 ml/min/1.73 m 2 (Bilbao-Meseguer et al., 2018). This underscores the fact that inflammation has a different effect on drug clearance through the different mechanisms of drug elimination.

Surgery
The impact of surgery on concomitant treatment and analgesia management has been assessed in several studies (Table 11). Surgery is associated with an inflammatory response due to muscle or tissue injury to induce repair, regeneration and growth and so inflammatory markers increase after surgery, but not equally (Tidball, 2005;Stavropoulou et al., 2018). IL-1β was only detected during the early perioperative period and for a very short time (Baigrie et al., 1992). IL-6 plasma level peaked 4-48 h after surgery and declined drastically by 48-72 h in all patients without any postoperative complication (Baigrie et al., 1992). CRP level rose more slowly postoperatively compared with the cytokine levels (IL-6, TNF-α and IL-1β) (Bergin et al., 2011). Acute inflammation after elective surgery was associated with a significant decrease in CYP3A metabolic activity (Haas et al., 2003). A recent study with a cocktail approach has concluded that there is an isoform specific impact of inflammation on CYP activities (Lenoir et al., 2020). Indeed, this study showed that CYP1A2, CYP2C19 and CYP3A activities decreased significantly by 53, 57 and 61%, whereas CYP2B6 and CYP2C9 activities increased significantly by 120 and 79% (Lenoir et al., 2020). However, surgery did not significantly impact CYP2D6 activity (Lenoir et al., 2020). These findings were confirmed by a case report that showed a toxic increase in clozapine levels 4 days after surgery and by authors who further showed that clopidogrel efficacy was reduced in patients undergoing percutaneous coronary intervention, because clopidogrel must be bioactivated by CYP2C19 to be effective (Bernlochner et al., 2010;Leung et al., 2014;Mostowik et al., 2015).

Cancer
Inflammation is linked to all stages of cancer (risk of development, initiation, invasion, metastasis and mortality) as highlighted in Table 12 (Harvey and Morgan, 2014). Certain immune-mediated diseases have been associated with cancer such as inflammatory bowel disease (IBD), chronic infection by Helicobacter pylori and chronic psoriasis associated with an increased risk of colorectal, gastric and skin cancer, respectively (Harvey and Morgan, 2014). The first pro-cancer immune signals are via tumor cells that successively produce cytokines and act to increase transcription factors, induce epigenetic changes and initiate angiogenesis (Harvey and Morgan, 2014). Cytokines are involved from neoplastic transformation of cells to tumor progression and metastasis, and are thus involved in several cellular events leading to cancer (Kacevska et al., 2008). These signals and others induced to respond to cancer are opposed by antigen-presentating cell-mediated anticancer immune responses (Harvey and Morgan, 2014). Moreover, the greater the antitumoral response is, the more the cancer outcome is improved whereas some T-cells subsets are associated with tumor promotion (Harvey and Morgan, 2014). Some cytokines have tumor-promoting, antitumor effects or both (Kacevska et al., 2008). Some cytokines could be produced by the tumor itself  12 liver metastasis, 12 controls -no significant difference between patients with liver metastases before cytostatic treatment and controls Williams et al. (2000), Case-control study Bone marrow transplantation for haematological malignancies (radiation and chemotherapy) CyA (CYP3A) 6 -concentration peak value occurred 15.8 days after bone marrow transplantation and it's corresponded to a 3-or 4-fold increase relative to the steady state day (p > 0.015), -CyA concentration peak and IL-6 peak levels are interdependent because there was a correlation between these two parameters (r 0.794, p 0.03) Burns et al. (2014), Cohort study Cancer ERMBT (CYP3A) 40 -patients with CRP >10 mg/L had an average 30% reduction in CYP3A4 metabolic activity (p 0.0062), -1/Tmax values were negatively correlated with both CRP (r −0.64, p < 0.00001) and α-glycoprotein (r -0.45, p < 0.005), -3 patients were treated by a CYP3A4 inhibitor while 4 patients were on long-term treatment with dexamethasone (inducer) but correlation with CRP remained significant (r −0.55, p 0.002) after removal of these patients  (Kacevska et al., 2008). Inflammation has therefore a pivotal role in cancer and the proliferation of malignant cells by a dynamic equilibrium in the tumor environment (Harvey and Morgan, 2014). Cytokines present in the tumor environment are also launched in the systemic circulation and have general effects on the function of distant organs such as the liver (Kacevska et al., 2008). Inflammatory markers levels are dependent on tumor types, but high level of CRP, IL-6, IL-1β have been associated with poor prognosis (Kacevska et al., 2008). Some results suggest that high IL-6 is associated with decreased CYP3A metabolic activity but can also nonspecifically downregulate CYP-dependent drug metabolism (Chen et al., 1994). CRP and α-glycoprotein were also negatively correlated with CYP3A activity and cancer patients with significant acute-phase response may have reduced CYP3A drug metabolism, which may have implications for the safety and efficacy of chemotherapy (Rivory et al., 2002;Charles et al., 2006;Alexandre et al., 2007). Inflammatory status and lymphocyte count should thus be included in the evaluation of the benefit/risk ratio before the initiation of a cytotoxic chemotherapy (Alexandre et al., 2007). Concerning CYP2C19, studies showed that CYP2C19 activity was not solely predicted by the genotype in cancer patients (Williams et al., 2000;Helsby et al., 2008;Burns et al., 2014). Indeed, CYP2C19 activity was reduced in cancer patients, with a discordance between the measured phenotype and the predicted phenotype from the genotype. However, no significant correlation was found between CYP2C19 activity and the levels of cytokine, whereas this was the case for voriconazole through concentration (Helsby et al., 2008;Burns et al., 2014;Yasu et al., 2017;Mafuru et al., 2019). The mechanism behind the decrease of CYP2C19 activity observed in cancer patients may be related to the inflammatory response even though it remains debated (Helsby et al., 2008;Burns et al., 2014;Yasu et al., 2017;Mafuru et al., 2019). Other authors showed that cancer has no impact on CYP1A2 metabolic activity as compared to liver disease or infection (Wang et al., 2010).

Therapies With Immunomodulator, anti-TNF-α and -Mabs
As biological therapies aim to decrease the underlying inflammation of the disease, interleukins (IL) injections are expected to have an impact on CYP activity, as underlined in Table 13. As an example, IL-2 doses of 9-12 × 10 6 units daily may downregulate CYP activities in patients with HIV infection and cancer in whom this treatment is administered to boost the immune system (Piscitelli et al., 1998;Elkahwaji et al., 1999). Conflicting results exist regarding IFN administration, with a discrepancy between acute and chronic treatment (Williams and Farrell, 1986;Williams et al., 1987;Jonkman et al., 1989;Israel et al., 1993;Hellman et al., 2003;Sulkowski et al., 2005;Gupta et al., 2007;Furlanut et al., 2010;Brennan et al., 2013). However, case reports and more specific studies assessing CYP metabolic activity lean toward CYP downregulation and care must be taken to avoid interactions and ADRs (Craig et al., 1993;Adachi et al., 1995;Serratrice et al., 1998;Hassan et al., 1999;Becquemont et al., 2002). The level of anticoagulation should be closely monitored when interferon is given together with warfarin, as it appears that CYP are downregulated (Adachi et al., 1995;Serratrice et al., 1998). Additionally, the timing of IFN-α administration relative to concomitant chemotherapy should be considered to avoid a decrease in CYP3A4 and 2B6 activity and thus to achieve better efficacy (Hassan et al., 1999). For example, interferonα-2b inhibits CYP1A2, 2D6 and 2C19 and these findings pose new challenges for patients on these therapies with respect to PK interaction with concomitant drugs commonly used (Islam et al., 2002). Further studies are needed to measure the impact of IFN and new cytokine therapies coming on the market on CYP activities. Cytokines act on CYP in an isoform-specific manner, and it is likely that IFN or IL modulate different CYP while they have no impact on others. Moreover, it is crucial to understand whether the modulation of CYP activity is due to this kind of therapy, to the underlying disease which may be inflammatory,  -in the HIV seropositive-patients, the mean concentration of indinavir was significantly increased on day 5 of IL-2 therapy, -in the nine HIV seropositivepatients, the mean indinavir AUC increased significantly by 88% between day 1 and day 5 of IL-2, -mean IL-6 concentrations during IL-2 therapy increased between day1 and day5 from 4-to 86-fold, -study combines observations made in one observational and one prospective (as part of a phase II trial) studies Williams and Farrell (1986) 7 -no significant difference in TNF-α, IL-1β, IL-6 and CRP activities after both acute (initiation) and chronic (2 weeks) IFN-α injections compared to baseline, except for TNF-α activity that significantly decreased after chronic therapy, -significant effects of acute IFN-α administration on the oral clearance of the three probe drugs were not detected, -chronic exposure to IFNα was associated with a significant lowering clearance (33% compared with baseline, p < 0.05) but no significant correlations were observed between the changes in theophylline clearance and changes in serum cytokines or acute phase proteins,chronic IFN-α therapy decreased antipyrine oral clearances by 20% but this did not reach statistical significance and it appeared to have no effect on the metabolism of racemic hexobarbitone Sulkowski et al. (2005), Cohort study

20
-MR before and after initiation of peginterferon-α-2b and ribavirin therapy go from 0.10 ± 0.40 to 0.04 ± 0.09 and that's mean that metabolite production of dextromethorphan increased after hepatitis C, but it is not significant (p 0.087), -mean serum concentrations of fluoxetine and its metabolite (norfluoxetine) at baseline and 2 months later during combined antiviral treatment didn't change significantly, -only the half-life of fluoxetine showed a significant reduction during combined antiviral therapy ( or to its resolution by these same therapies (reduction of inflammation caused by the disease). The impact of-mabs therapies are summarized in Table 14. Monoclonal antibodies have a high degree of specificity against an antigen or an epitope (National Center for Biotechnology Information, 2012). In 2018, more than sixty therapeutic monoclonal antibodies were approved and used in the United States for their action against specific immune cells such as lymphocytes and cytokines or against specific enzymes, cell surface transporters or signaling molecules (National Center for Biotechnology Information, 2012). Consequently, a number of studies have examined the impact of monoclonal antibodies on CYP metabolic activity, assuming that these drugs, by reducing inflammation, return CYP metabolic activity to baseline (Ling et al., 2009;Schmitt et al., 2011;Wu and Fleming, 2011;Zhuang et al., 2015;Tran et al., 2016;Lee et al., 2017;Wen et al., 2020) (Table 14).
A return to baseline level after treatment of inflammation was not always observed (Wollmann et al., 2017;Davis et al., 2018). A lag was observed in some cases, such as basiliximab coadministration, which increased tacrolimus through concentration on day 3 but decreased on day 30 (Sifontis et al., 2002). Moreover, OKT3 (also known as muromonab, a CD3 receptor antibody) treatment transiently increased CyA through concentration, and authors suggested that OKT3 inhibits CYP3A4 metabolic activity by inducing transient cytokine release (Vasquez and Pollak, 1997). No changes were observed in drugs PK parameters before and after monoclonal antibodies administration, possibly because CYP metabolic activity was similar in psoriasis disease and in healthy volunteers (Bruin et al., 2019;Khatri et al., 2019). However, these therapies are used for a variety of diseases, with different levels of proinflammatory markers. In addition, a recently published study assessed the impact of clazakizumab, an anti-IL-6 antibody, in kidney transplant recipients with antibodymediated rejection (ABMR) on CYP3A and CYP2C19 activity by pantoprazole and on tacrolimus and CyA concentrations (Mühlbacher et al., 2021). In contrast to earlier observations, prolonged blockade of IL-6 did not enhance CYP metabolism (Mühlbacher et al., 2021). This could be because the included patients did not have systemic inflammation before initiation of clazakizumab, with IL-6 and CRP levels in the normal range (Mühlbacher et al., 2021). Thus, clazakizumab did not increase CYP metabolism because the included patients had unaltered CYP expression, as ABMR may be different from other disease states, such as infection or autoimmune disease, where systemic inflammation is present (Mühlbacher et al., 2021).

DISCUSSION AND PERSPECTIVES
Our systematic review identified 218 publications that evaluated the impact of inflammation on CYP activities which we divided into 17 sources of inflammation. Indeed, current literature suggests that cytokine signalling pathways differ according to the trigger of inflammation, leading to heterogeneous effects on CYP activity, with different magnitude, potency and time-course (de Jong et al., 2020;Stanke-Labesque et al., 2020). This analysis allowed us to identify areas where the literature is abundant, such as infections like pulmonary infection, hepatitis or HIV and for some therapeutic agents like immunosuppressants or clozapine, and others where further research is needed, such as for autoimmune diseases, and other specific diseases such as diabetes or the anti-inflammation treatments.
Our analysis also identified that studies should be more specifically conducted to assess whether resolution of inflammatory episodes allows a return to baseline of CYP activities. Indeed, inflammatory diseases are chronic, but with a possibility of remission, and acute inflammatory events can punctuate life (infection, surgery, cancer. . .). A better understanding of the mechanisms of modulation and return to the initial state would make it possible to anticipate changes in the PK of concomitant treatments at different phases of the disease or of the patient's life. This could be done through the impact of anti-inflammatory treatments as well as monoclonal antibody therapies. These therapies are relatively new and much remains to be discovered, but they are highly targeted, and the impact of these different molecules could be isoform specific.
Our literature review highlighted the different effect of inflammation according to the CYP considered. Several studies have investigated the impact of infection on drugs of the nervous systems, mainly CYP2D6 substrates without always showing a significant impact. It now appears that CYP2D6 activity is not modulated by inflammation and this is confirmed in chronic hepatitis C patients where downregulation is linked to the presence of liver kidney microsomal type 1 (LKM-1) antibodies (Girardin et al., 2012). LKM-1 antibodies are often produced during chronic HCV infection and appear to be   -levels did not change after the onset of any of the three treatments, -a trend was observed that lowest baseline 4βOHC levels (higher inhibition of CYP3A4 metabolic activity) showed highest relative increase in at follow-up and thus a highest regain in metabolic activity of CYP3A4 after initiation of treatment, -authors suggest that the absence of variation in 4βOHC levels in this study could be explained by the low level of inflammation in these patients because 4βOHC level in the study population at baseline was only 30% lower than in control groups Girardin et al. (2012), Cohort study and casecontrol study TNF-α inhibitor 4βOHC (CYP3A) 31 -CRP values were lower than before 3 months treatment, but the difference was not statistically significant (p > 0.2) and 4βOHC levels were not significantly affected (p > 0.9) by the initiation of treatment, -significant negative correlations were observed between 4βOHC and IL-1ra and IL-6 (r -0.410, p 0.022) and CXCL8 (r −0.403, p 0.025) Chládek et al. (1999), Cohort study Same subject as in Girardin et al. (2012) (Continued on following page) proportional to liver disease severity (Girardin et al., 2012). Moreover, it is well-known that CYP2D6 has an important inter-and intra-individual variability, in accordance with the available literature (Chládek et al., 1999). All sources of inflammation combined, the most studied CYP was CYP3A, which is in fact the CYP that metabolizes nearly 50% of the drugs on the market. Patients with inflammation/infection are, however, prone to receiving multiple drugs, and the impact on other CYPs should be carefully evaluated, in particular in critically ill patients or patients at different stages of HIV, where data is scarce. Studies should also be careful to exclude the impact of co-medications (CYP inhibitor and inducer) as a confounding factor. In organ diseases, current studies in liver diseases have not been able to determine whether CYP downregulation is caused by a decrease of CYP content or not, and in renal diseases it was not possible to identify whether the modulation of CYP activity was rather due to elimination issues (Farrell et al., 1979;Yang et al., 2003). Therefore, it is challenging to study inflammation as an independent factor in PK variability and not as a consequences of organ damage.
Our literature review also found that inflammation is a complex process, which is expressed differently depending on the disease and conditions and therefore, extrapolation between different types of inflammation should be avoided. Indeed, the hepatic expression of CYP2C19 could for example be regulated by other tumor-associated inflammatory factors than those regulating CYP3A (Burns et al., 2014). Moreover, different levels of inflammation led to different magnitudes of voriconazole through concentration increases for instance in association with CRP levels (van Wanrooy et al., 2014;Bolcato et al., 2021). In most studies, significant changes in CYP activities occurred in the presence of severe inflammation, characterized by elevated levels of inflammatory markers or a severe disease state, such as AIDS, advanced cancer or polytrauma patients (Gatti et al., 1993;Lee et al., 1993;Farrell et al., 1979;Grieco et al., 1998;Bauer et al., 1994;Harbrecht et al., 2005;Charles et al., 2006;Alexandre et al., 2007;Helsby et al., 2008;Abou Farha et al., 2012;ten Bokum et al., 2015;Hefner et al., 2015;Yasu et al., 2017;Gautier-Veyret et al., 2019). A minority of studies have evaluated the impact of inflammation on drugs PK and metabolism as an independent factor of variability, as only a few have included inflammation factors as covariates, such as biomarkers of renal or liver function (Stanke-Labesque et al., 2020).
Additionally, inflammation may have a different impact on CYPs activities depending on their baseline activity and on genotypic and environmental factors, such has concomitant treatments. Indeed, inflammation further increased the perampanel concentration/dose (C/D) ratio in patients not treated with drug inducers (Yamamoto et al., 2018). Voriconazole is also metabolized by highly polymorphic CYPs and inflammatory marker levels have a differential impact on voriconazole trough concentration whether patients are extensive, intermediate or ultra-rapid metabolized for CYP2C19 (Veringa et al., 2017). Moreover, a recent metaanalysis showed that voriconazole trough concentrations were independently influenced by both CYP2C19 and CYP3A4 genotype, considered individually or by a combined genetic score, in addition to CRP levels (Bolcato et al., 2021). In contrast, another cohort study showed that voriconazole overdoses were significantly associated with elevated CRP levels (>96 mg/L) but that CYP2C19 and CYP3A4 genotype, considered alone or combined in a genetic score, were not significantly different between overdose and non-overdose patients (Gautier-Veyret et al., 2019). Therefore, inflammation and pharmacogenomics may mutually minimize their reciprocal influence on CYP phenotype. Indeed, genotype did not predict correctly the phenotype in patients with inflammatory disease and the effect of inflammation was not as important as expected in CYP variants carriers (Helsby et al., 2008;Goktaş et al., 2015;Burns et al., 2014;O'Neil et al., 2000;Williams et al., 2000;). Consequently, inflammation could induce dynamic phenoconversion, characterized by dynamic phenotypegenotype mismatch, and studies examining the impact of inflammation on CYPs should assess CYP genotypes and phenotypes as covariates. It should however be pointed out that most of the included studies did not take into account routine treatment given to treat the diseases themselves.
Predictive models based on known interactions between molecular, environmental and lifestyle data by computational algorithm are increasingly developed to support the decision to individualize treatment (Iriart, 2019). Simulation of the concentration-time profiles of a drug and its metabolite(s) and concomitant estimation of PK parameters using dynamic physiologically based pharmacokinetic (PBPK) models allow prediction of plasma concentration curves (Sager et al., 2015). There are increasing developments in regulatory guidances (Sager et al., 2015). Inflammatory disease is an example of a special population and numerous PBPK models have been developed and validated to predict IL-6 mediated drug-disease (Machavaram et al., 2013;Xu et al., 2015;Jiang et al., 2016;Radke et al., 2017;Xu et al., 2018;Machavaram et al., 2019). While IL-6 appears to be the key element in modulating CYP activities during inflammation, a recent study developed a model that predicted the impact of systemic CRP levels on CYP3A4 and CYP2C19 activities (Simon et al., 2021). Optimal drug use leads to takes into account the contribution of covariates to predict the dose needed to achieve a target concentration and thus reduce the inter-and intra-individual variability in drug response (Darwich et al., 2021). This review focuses on CYP regulation, but other mechanisms, such as enzymes and transporters, involved in drug absorption, distribution, metabolism and elimination may be involved in changes in drugs PK during inflammatory states, although they are less studied. Studies described changes in plasma protein binding and renal excretion during inflammation that could affect CYP substrates metabolism (Gorski et al., 2000;Hefner et al., 2015;Helland et al., 2018). Plasma protein binding may influence total clearance for low-extraction drugs but not unbound clearance and may or may not influence half-life, depending on clearance and volume of distribution (Boffito et al., 2021). The unbound concentration and not the total concentration must be considered when assessing drug exposure to a highly protein-bound drug, otherwise there is a risk of misinterpretation of lopinavir overexposure (Boffito et al., 2021;Stanke-Labesque et al., 2021). For example, by taking into account plasma protein concentration, the authors concluded that CyA biotransformation by CYP3A may be downregulated by diabetes (Akhlaghi et al., 2012). Decreased albumin concentration may increase the unbound concentration in diabetics, which should theoretically increase CyA metabolic clearance (Akhlaghi et al., 2012). But the lower production of almost all metabolites has shown that the correct hypothesis is rather a reduced CYP activity (Akhlaghi et al., 2012). In fact, CyA metabolites that involved amino acid 1 showed significantly lower dose-normalized AUC values in diabetic patients compared with nondiabetics suggesting that CYP3A4 metabolic activity was not decreased (Mendonza et al., 2008). Its dose-adjusted metabolite-parent concentration ratio was decreased in the diabetic groups, but no difference was found concerning doses and trough levels of CyA in a retrospective study (Wadhawan et al., 2000;Akhlaghi et al., 2012).
Phase 2 drug metabolic enzymes appear to be affected in a cytokine-specific manner, as infection resulted in a significant downregulation of several genes encoding hepatic uridine 5′diphospho-glucuronosyltransferases (UGT) (Stanke-Labesque et al., 2020). Pregnane X receptor (PXR) and constitutive androstane receptor (CAR), two nuclear receptors, are also cytokine dependent and mediate the expression of glutathione S-transferases (GST), UGTs and sulfo-transferases (SULT) in humans (Wu and Lin, 2019). However, unlike voriconazole, posaconazole's PK did not appear to be influenced by inflammation. This could be explained by a metabolism by phase 2 enzymes mainly (Märtson et al., 2019). Literature reviews on physiological changes related to drug PK and PD during inflammation may be useful to determine what investigations are needed to complement the data in the literature, such as the impact of inflammation on P-gp and other drug transporters, as one study showed that an increase in bioavailability due to downregulation of P-gp could not be ruled out (Sanaee et al., 2011).
Moreover, hepatic transporters that belong to ATP-binding cassette (ABC) and solute carrier (SLC) transporters have been shown to be significantly reduced during inflammatory states in animal and in-vitro studies (Stanke-Labesque et al., 2020). For instance, animals studies have shown that mRNA levels of MRP, OATP or BSEP were decreased in mice during inflammation (Wu and Lin, 2019). NF-κB, a transcription factors involved in the mechanism of action of cytokines on metabolizing enzyme gene expression, is also known to regulate the expression of numerous ABC and SLC transporters, including ABCB1 in humans and MDR1, MRP, BCRP, OATP, NTCP in rats and mice (Wu and Lin, 2019).
Given all of the above, it should be acknowledged that our literature search has some limitations. First, the completeness of the search cannot be guaranteed as we only searched one database and only published articles. Second, there is inevitably heterogeneity between the studies selected due to the different methodologies employed and low comparability between the studies identified. In addition, the diversity of the sources of inflammation studied and assessment of the clinical impact severity limits the robustness and generalizability of the results. Interpretations should therefore be addressed with particular caution.

CONCLUSION
This systematic literature review shows that inflammation is a major contributing factor to CYP metabolic activity variations. The proportion of the drug cleared by CYP metabolism, the patient's genotype and concomitant medications should also be taken into account.
Compelling evidence suggests that inflammation has a differential impact on the various CYP isoforms with a different magnitude. CYP3A and CYP2C19 are downregulated and inflammation has no impact on CYP2D6 activity. Regarding other main CYPs, the impact remains unclear and requires further investigation. Moreover, the effect of inflammation depends on its severity and the inflammatory markers released, even if this remains debated. Indeed, the origin of the inflammation may differ as well as the inflammatory mediators involved, possibly leading to different impact on CYP activities. The reason why some CYP metabolic activities were modulated in some diseases and not in others may be partly explained by this heterogeneity in inflammatory markers.
Nonetheless, some results are still debated such as the impact of vaccination and infection, and further investigations are required to well characterize the impact of inflammation on CYP activity.
CYP is a major source of interindividual variability, and it appears crucial to be able to predict their activity to individualize drug dosing and take into account the patient's underlying pathophysiological conditions and the PK characteristics of the drug concerned. Measurement of inflammation induced CYP phenoconversion and the development of endogenous markers of CYP metabolism should enable the measurement of CYP activity variation due to disease progression and could have implications for personalized medicine and provide new opportunities.
To conclude, inflammatory conditions in patients are a major factor to be considered to predict variability in drug response and avoid efficacy or safety issue in clinical practice.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.