Cytochrome P450 2C8 Pharmacogenetics: A Review of Clinical Studies

Abstract

Cytochrome P450 (CYP) 2C8 is responsible for the oxidative metabolism of many clinically available drugs from a diverse number of drug classes (e.g., thiazolidinediones, meglitinides, NSAIDs, antimalarials and chemotherapeutic taxanes). The CYP2C8 enzyme is encoded by the CYP2C8 gene, and several common nonsynonymous polymorphisms (e.g., CYP2C8*2 and CYP2C8*3) exist in this gene. The CYP2C8*2 and *3 alleles have been associated in vitro with decreased metabolism of paclitaxel and arachidonic acid. Recently, the influence of CYP2C8 polymorphisms on substrate disposition in humans has been investigated in a number of clinical pharmacogenetic studies. Contrary to in vitro data, clinical data suggest that the CYP2C8*3 allele is associated with increased metabolism of the CYP2C8 substrates, rosiglitazone, pioglitazone and repaglinide. However, the CYP2C8*3 allele has not been associated with paclitaxel pharmacokinetics in most clinical studies. Furthermore, clinical data regarding the impact of the CYP2C8*3 allele on the disposition of NSAIDs are conflicting and no definitive conclusions can be made at this time. The purpose of this review is to highlight these clinical studies that have investigated the association between CYP2C8 polymorphisms and CYP2C8 substrate pharmacokinetics and/or pharmacodynamics in humans. In this review, CYP2C8 clinical pharmacogenetic data are provided by drug class, followed by a discussion of the future of CYP2C8 clinical pharmacogenetic research. Keywordsamodiaquine; CYP2C8; cytochrome P450 2C8; human; ibuprofen; NSAID; paclitaxel; repaglinide; thiazolidinedione The field of pharmacogenetics is aimed at understanding how genetic variation contributes to interindividual variability in drug disposition (i.e., pharmacokinetics) and drug response (i.e., pharmacodynamics). In terms of drug disposition, the cytochrome P450 (CYP) metabolizing enzymes are a major area of study, as they catalyze the oxidative metabolism of numerous drugs and endogenous compounds. Enzymes in the CYP2C family (e.g., CYP2C8, CYP2C9, CYP2C18 and CYP2C19) are significant contributors to drug disposition and metabolize 20% of clinically available drugs [1,2]. Recently, the role of the CYP2C8 isoenzyme has garnered considerable interest in the fields of drug metabolism and pharmacogenetics. This is largely a †Author for correspondence: University of Colorado Denver, School of Pharmacy, Department of Pharmaceutical Sciences, 12700 East 19th Avenue, Box C238-P15, Aurora, CO 80045, USA, Tel.: +1 303 724 6126; Fax: +1 303 724 7266; christina.aquilante@ucdenver.edu. For reprint orders, please contact: reprints@futuremedicine.com Financial & competing interests disclosureDr Aquilante currently holds investigator-initiated research grants from the NIH (K23 DK073197), American College of Clinical Pharmacy and Tibotec Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materia...

In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity

“…CYP450 2C8 (CYP2C8), in particular, has emerged relatively recently as an important enzyme that is responsible for the metabolism of a diverse group of drugs in humans, including repaglinide, pioglitazone, rosiglitazone, paclitaxel, dasabuvir, and the androgen-signaling inhibitor enzalutamide (Daily and Aquilante, 2009;Gibbons et al, 2015). Available data suggest that genetic variation in CYP2C8 can alter drug disposition in vivo (Niemi et al, 2003(Niemi et al, , 2005Kirchheiner et al, 2006).…”

Discovery of a Novel Allelic Variant of CYP2C8, CYP2C8*11, in Asian Populations and Its Clinical Effect on the Rosiglitazone Disposition In Vivo

“…ki.se/cyp2c8.htm). These CYP2C8 genetic polymorphisms have been implicated in the variability of CYP2C8 activity with different phenotypes (Daily and Aquilante, 2009). These different phenotypes are distributed unequally in major ethnic populations.…”

How polymorphisms of the cytochrome P450 genes affect ibuprofen and diclofenac metabolism and toxicity / Kako polimorfizmi gena citokroma P450 utječu na metabolizam i toksičnost ibuprofena i diklofenaka

“…According to a recent report (35), at the locus of the CYP2C8 gene there are 16 allelic variants. These variants are responsible for interindividual and interethnic variability in drug response (36), since their frequencies vary significantly between races and population groups. Clinically the most important variants are CYP2C8*2 to *5 (37,38).…”

“…Reports of hepatotoxic effects of diclofenac (36,48,49) have raised the question whether the gene variants CYP2C8*3, CYP2C9*2,*3 or UGT2B7*2, which code for low-activity enzymes, could worsen these effects. Aithal et al (50) found no such association with CYP2C9*2 or *3 variants, but Daily et al (36) did.…”