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 meta-analysis 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 inflammation-induced 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).

CYP downregulation was also demonstrated as a consequence of sufficient inflammation and significant temperature elevation (Elin et al., 1975). Therefore, caution should be exercised in case of infection when administering CYP substrates, as this may result in toxicity and ADRs (Vozeh et al., 1978; Blumenkopf and Lockhart, 1983; Levine and Jones, 1983 1; Raaska et al., 2002; Haack et al., 2003; de Leon and Diaz, 2003; Jecel et al., 2005; Darling and Huthwaite, 2011; Espnes et al., 2012; Kwak et al., 2014; Leung et al., 2014; Takahashi et al., 2015; Clark et al., 2018; Khan and Khan, 2019).

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 Bokum et al., 2015; 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 well-described (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; 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).

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 well-studied 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.

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 end-stage 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 (Frye et al., 2002).

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 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 m² (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.

In diabetes (Table 9), CYP metabolism has been shown to be downregulated (Salmela et al., 1980; Pirttiaho et al., 1984). Indeed, antipyrine metabolism was decreased compared with controls in several studies (Salmela et al., 1980; Pirttiaho et al., 1984; Zysset and Wietholtz, 1988). One study using a cocktail approach showed that CYP2B6, CYP2C19 and CYP3A activity decreased, CYP1A2 and CYP2C9 activity increased, and CYP2D6 and CYP2E1 activity was unaffected in type II diabetes (T2D) (Gravel et al., 2019). However, conflicting results exist with tolbutamide and paracetamol half-lifes which were unchanged and increased respectively (Ueda et al., 1963; Adithan et al., 1988). Regarding CYP3A, one study found no impact on amlodipine or immunosuppressant metabolism while nisoldipine clearance was decreased (Wadhawan et al., 2000; Preston et al., 2001; Marques et al., 2002; Akhlaghi et al., 2012). The underlying mechanisms are associated with systemic inflammation and inflammatory cytokines. Indeed, it is well-established that chronic inflammation is involved in the pathophysiology of diabetes and the more complex condition of metabolic syndrome (Gravel et al., 2019). TNF-α can lead to the development of diabetes by affecting insulin action, and levels of inflammatory cytokines and markers are reported to be increased in diabetes patients (Darakjian et al., 2021). In a multivariate analysis, IFN-γ, IL-1β, IL-6 and TNF-α were associated with CYP activities, depending on the CYP isoenzyme (Gravel et al., 2019). However, type I (T1D) and type II diabetes did not appear to have the same impact on CYP metabolism (Dyer et al., 1994; Korrapati et al., 1995; Lucas et al., 1998; Zysset and Wietholtz, 1988; Matzke et al., 2000; Sotaniemi et al., 2002; Wang et al., 2003). The impact of inflammation may be different partly because of obesity, which is more common in T2D (Wang et al., 2003). Indeed, obese patients had a 40% increase in CYP2E1 activity (Lucas et al., 1998; Wang et al., 2003). CYP2E1 increased activity could also be attributed to hypo-insulinemia, as administration of insulin reverses this induction at the mRNA level (Lucas et al., 1998). Moreover, moderate controlled T1D had comparable CYP2E1 activity to healthy volunteers (Wang et al., 2003). This was confirmed in other studies that showed an unaffected metabolic clearance rate of antipyrine in well-controlled (by insulin) T1D (Zysset and Wietholtz, 1988; Sotaniemi et al., 2002). This could also be explained by insulin supplementation and the subsequent correction of ketones that leads to a return to baseline level for CYP2E1 expression (Wang et al., 2003). Indeed, ketones have been shown to be an important modulator of CYP2E1 by enhancing its protein expression and mRNA level (Wang et al., 2003). This has been confirmed with CYP1A2, where fluctuations in growth hormone levels, hyperketonemia and variation in glucose metabolic steady state and HbA1C levels may contribute to these changes (Bechtel et al., 1988; Korrapati et al., 1995; Matzke et al., 2000). The difference in classification criteria for T1D and type 2 diabetes may explain the inconsistent findings (Matzke et al., 2000). Further studies to discriminate between these two entities are needed (Zysset and Wietholtz, 1988).

Overall, CYP3A, 2C19 and 2B6 activity appear to be downregulated while CYP1A2 activity was increased and CYP2D6 activity was unchanged in diabetic patients (Bechtel et al., 1988; Urry et al., 2016; Gravel et al., 2019). Conflicting results remain regarding CYP2C9 and CYP2E1 (Ueda et al., 1963; Adithan et al., 1988; Lucas et al., 1998; Gravel et al., 2019).

Few studies observed the impact of auto-immune disease on CYP activities, such as psoriasis, systemic lupus erythematosus (SLE), Behçet’s disease, rheumatoid arthritis (RA), Crohn’s disease and celiac disease (Table 10). In contrast to what has been observed for CYP2D6 in other inflammatory states, two studies observed CYP2D6 downregulation in patient with SLE (Idle et al., 1978; Baer et al., 1986). However, these studies have some limitations, such as the presence of concomitant medications inhibiting the metabolism of CYP2D6 and the absence of adequate randomization (Baer et al., 1986). Even though RA is one of the most prevalent chronic inflammatory disease, only two case-control studies were found in the literature studying the impact of RA on the PK and PD of verapamil and losartan, respectively (Mayo et al., 2000; Daneshtalab et al., 2006; Smolen et al., 2016). Verapamil is metabolized by CYP3A and 1A2 into norverapamil (Tracy et al., 1999). Verapamil and norverapamil metabolism has been shown to be reduced in patients with RA compared to healthy volunteers (Mayo et al., 2000). Verapamil was not more dromotropic or hypotensive in RA patients (Mayo et al., 2000). Inhibition of CYP2C9 was proportional to RA disease severity in another study, but this was not accompanied by reduced clinical response after losartan administration (Daneshtalab et al., 2006). Same results were found in patients with Behcet’s disease. Indeed, one study observed downregulation of CYP2C9 in Behcet’s patients (Goktaş et al., 2015). However, losartan’s MR in nine patients with Behçet’s disease taking colchicine were similar to those not taking colchicine (Goktaş et al., 2015). This may be because the drug had been taken for only 2 weeks (Goktaş et al., 2015).

In Crohn’s disease, S-verapamil concentration was higher than R-verapamil while the opposite was found in normal conditions and higher plasma levels of propranolol were found in Crohn’s with reduced metabolic activities of CYP1A2, 2D6 and 2C19 (Schneider et al., 1976; Sanaee et al., 2011). Furthermore, there were no difference between healthy controls and Crohn’s disease patients in remission, implying that CYP downregulation is proportional to disease severity and that recovery resulted in a return to baseline metabolic activity (Sanaee et al., 2011). Norverapamil goes through the same process and it is expected that the enantiomers ratio of norverapamil to verapamil remains unchanged (Sanaee et al., 2011).

Celiac disease is an autoimmune disease that is triggered by an immune response to gluten and may result in increased morbidity or mortality (Lebwohl et al., 2018). The reduction in intestinal CYP3A content during celiac disease and its increase after a gluten-free diet indicate that local inflammation reduced CYP3A activity but that it returns to baseline with disease improvement (Lang et al., 1996).

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).

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 (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).

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 × 10⁶ 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, interferon-α-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, 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 antibody-mediated 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).