Enzyme:CYP2C8

CYP2C8 (cytochrome P450 2C8) is a hepatic drug-metabolizing enzyme of the cytochrome P450 superfamily, encoded by the CYP2C8 gene within the CYP2C gene cluster on chromosome 10q23.33, the same cluster that carries CYP2C9 and CYP2C19. It accounts for roughly 7% of total hepatic cytochrome P450 protein. Its clinical substrate set includes the taxane chemotherapy agent paclitaxel, the meglitinide oral hypoglycaemic repaglinide, the thiazolidinediones, the leukotriene-receptor antagonist montelukast, and the antimalarial amodiaquine. The property that makes CYP2C8 distinctive, and the reason it occupies more clinical attention than its modest substrate list would suggest, is a single drug-interaction story that intersected a genuine pharmaceutical-safety catastrophe.

That catastrophe was the withdrawal of cerivastatin. Cerivastatin (marketed as Baycol and Lipobay) was a statin withdrawn from the world market in August 2001 after it was linked to a substantial number of fatal cases of rhabdomyolysis, a disproportionate share of them in patients who were also taking the fibrate gemfibrozil. The mechanism was worked out afterward, and CYP2C8 was at the centre of it. Janne Backman and colleagues at the University of Helsinki showed in 2002 that gemfibrozil greatly increases plasma concentrations of cerivastatin, and Ogilvie and colleagues established in 2006 that the responsible species is not gemfibrozil itself but its glucuronide metabolite, which is a potent mechanism-based (irreversible) inhibitor of CYP2C8. The cerivastatin episode is one of the clearest cases in which the mechanism of a cytochrome P450 interaction, traced after the fact, explained a real and lethal drug-safety failure.

Tissue distribution

CYP2C8 is predominantly a hepatic enzyme, with the liver carrying the clinically dominant share of CYP2C8-mediated metabolism. Lower-level expression has been described in the kidney, the adrenal gland, and other extrahepatic tissues, but these do not change the clinical picture, which is essentially a hepatic-clearance story.

Function and substrate spectrum

CYP2C8 catalyzes hydroxylation, epoxidation, and dealkylation reactions. The standard probe substrate is paclitaxel, whose 6-alpha-hydroxylation is a CYP2C8-specific reaction used to phenotype the enzyme in vitro; montelukast has also been used as a CYP2C8 probe.

The table below collects the clinically important CYP2C8 substrates with each entry tagged by the contribution CYP2C8 makes to overall clearance: major (CYP2C8 is the predominant route), moderate (CYP2C8 contributes meaningfully but other routes carry comparable load), minor (CYP2C8 contributes but other pathways dominate), and partial (one of several substantial routes). The list is curated for clinical relevance and is not exhaustive; see Comprehensive substrate and interaction tables below for the authoritative maintained resources.

near-complete CYP2C8 substrate table (click to expand)

Substrate	Therapeutic class	CYP2C8 contribution	Clinical notes
Amiodarone	Antiarrhythmic	partial	Mixed CYP2C8 + CYP3A4.
Amodiaquine	Antimalarial	major	CYP2C8 is the predominant route, converting amodiaquine to the active N-desethylamodiaquine. Relevant to the large-scale use of amodiaquine-containing antimalarial combinations in malaria-endemic regions.
Cabazitaxel	Taxane antineoplastic	partial	Mixed CYP3A4 (dominant) + CYP2C8.
Cerivastatin	Statin (withdrawn)	major	Withdrawn worldwide in 2001 after fatal rhabdomyolysis; the gemfibrozil-cerivastatin CYP2C8 interaction was a principal contributor (see opening section).
Chloroquine	Antimalarial	partial	Mixed CYP2C8 + CYP3A4 + CYP2D6.
Dasabuvir	Direct-acting antiviral (hepatitis C)	major	CYP2C8 is the predominant route; FDA labeling addresses CYP2C8-inhibitor interactions.
Enzalutamide	Androgen-receptor inhibitor (prostate cancer)	partial	Mixed CYP2C8 + CYP3A4.
Ibuprofen	NSAID	partial	Mixed CYP2C8 + CYP2C9.
Imatinib	Tyrosine kinase inhibitor (oncology)	partial	Mixed CYP3A4 (dominant) + CYP2C8.
Loperamide	Antidiarrheal opioid	partial	Mixed CYP2C8 + CYP3A4 + CYP2C9.
Montelukast	Leukotriene-receptor antagonist (asthma)	major	Also used as a CYP2C8 probe substrate.
Paclitaxel	Taxane antineoplastic	major	The standard CYP2C8 probe substrate (6-alpha-hydroxylation).
Pioglitazone	Thiazolidinedione (oral hypoglycaemic)	major	CYP2C8 is the predominant route; gemfibrozil co-prescription raises pioglitazone exposure substantially.
Repaglinide	Meglitinide (oral hypoglycaemic)	major	The canonical CYP2C8 interaction substrate. Gemfibrozil raises repaglinide exposure roughly eight-fold, with a corresponding risk of serious hypoglycaemia; the combination is contraindicated. Repaglinide also has a CYP3A4 component.
Rosiglitazone	Thiazolidinedione (oral hypoglycaemic)	major	CYP2C8 is the predominant route; the in-vivo human marker reaction for CYP2C8 activity in several studies.
Sorafenib	Tyrosine kinase inhibitor (oncology)	partial	Mixed CYP3A4 + CYP2C8 + glucuronidation.
Torsemide	Loop diuretic	partial	Mixed CYP2C9 (dominant) + CYP2C8.

Phenotype categories

CYP2C8 does not have a clinically actionable poor-metabolizer / intermediate / normal / ultrarapid phenotype classification in routine practice, and there is no CPIC dosing guideline for CYP2C8. Functional genetic variants exist and are described below, but their effects are substrate-dependent and modest, and pre-prescription CYP2C8 genotyping is not standard practice. The clinically actionable CYP2C8 variable is not the patient's genotype but the presence of an interacting co-prescription, above all gemfibrozil.

Major variants

• \*1, the reference allele.
• \*2 (rs11572103, Ile269Phe), a decreased-function allele for several substrates, most common in African-ancestry populations. It has been studied in the context of amodiaquine metabolism, which is clinically relevant given the use of amodiaquine antimalarials in sub-Saharan Africa.
• \*3 (rs11572080 and rs10509681 in cis, Arg139Lys and Lys399Arg), the most extensively studied CYP2C8 variant, common in European-ancestry populations (allele frequency roughly 10 to 15%). Its functional effect is substrate-dependent: decreased activity for some substrates and near-normal or increased activity for others, which is part of why CYP2C8 has resisted a simple metabolizer-phenotype scheme. \*3 is in linkage disequilibrium with the CYP2C9 \*2 allele on the shared chromosome 10 CYP2C cluster.
• \*4 (rs1058930, Ile264Met), a decreased-function allele found mainly in European-ancestry populations.

Inhibitors

The defining CYP2C8 inhibitor stories both involve glucuronide metabolites that are mechanism-based (irreversible) inhibitors, which is pharmacologically unusual and clinically important because mechanism-based inhibition does not resolve on the timescale of the inhibitor's own elimination:

• Gemfibrozil is the dominant CYP2C8 inhibitor. The active inhibitory species is gemfibrozil 1-O-beta-glucuronide, a potent mechanism-based inhibitor. Because the inhibition is irreversible, CYP2C8 activity recovers only as new enzyme is synthesized, over days, and timing a CYP2C8-substrate dose away from the gemfibrozil dose does not avoid the interaction. Gemfibrozil is contraindicated or strongly cautioned against with repaglinide, the glitazones, and dasabuvir.
• Clopidogrel is also a mechanism-based CYP2C8 inhibitor, again via an acyl-glucuronide metabolite. The clopidogrel-repaglinide interaction was recognised more recently than the gemfibrozil interaction and raises repaglinide exposure meaningfully. As with CYP2B6, clopidogrel sits in more than one pharmacogenomic and drug-interaction story at once.
• Trimethoprim is a moderate reversible CYP2C8 inhibitor.

Inducers

CYP2C8 is inducible through the pregnane X receptor and constitutive androstane receptor pathways. Rifampin is the clinically relevant inducer, reducing exposures of CYP2C8 substrates; carbamazepine and other classical enzyme inducers also induce CYP2C8 to a smaller degree.

Clinical implications, summary

• The gemfibrozil interaction. The single most important CYP2C8 clinical fact is that gemfibrozil, through its mechanism-based-inhibitor glucuronide, dramatically raises the exposure of CYP2C8 substrates. For repaglinide this means an roughly eight-fold rise in exposure and a real risk of serious hypoglycaemia; the combination is contraindicated. For cerivastatin it contributed to fatal rhabdomyolysis and the medicine's withdrawal. When a fibrate is needed in a patient on a CYP2C8 substrate, fenofibrate (which does not carry the CYP2C8-inhibitory liability) is the usual alternative to gemfibrozil.
• No genotype-guided dosing. There is no CPIC guideline for CYP2C8 and no routine pre-prescription genotyping. The variant alleles have real but substrate-dependent and modest effects, and the dominant clinical lever for CYP2C8 is interaction avoidance, not genotype.
• Amodiaquine and antimalarial use. CYP2C8 is the principal enzyme metabolizing amodiaquine, an antimalarial used at large scale in artemisinin-combination therapy in malaria-endemic regions. The interplay of CYP2C8 genotype, amodiaquine pharmacokinetics, and the safety of amodiaquine-containing regimens is an active research area, particularly given the African-ancestry prevalence of the \*2 allele.

Comprehensive substrate and interaction tables

The substrate and interaction tables on this page are curated for clinical relevance, not for completeness. Three authoritative external resources maintain comprehensive lists of CYP2C8 substrates, inhibitors, and inducers, and the wiki recommends them to any reader who needs an exhaustive look-up:

• Flockhart Cytochrome P450 Drug Interaction Table, maintained by the Department of Medicine at Indiana University School of Medicine. The most widely cited clinical-reference cytochrome P450 table; substrate-, inhibitor-, and inducer-tiered, updated regularly. Available at https://drug-interactions.medicine.iu.edu/.
• U.S. Food and Drug Administration Drug Development and Drug Interactions Table, the regulatory-grade list FDA uses for labeling and clinical-trial design decisions. Smaller than Flockhart but every entry is FDA-vetted. Available via the FDA Center for Drug Evaluation and Research clinical drug interaction page.
• PharmGKB, the pharmacogenomics knowledge base hosted at Stanford University; the CYP2C8 gene page indexes substrate-, inhibitor-, and inducer-relationships with their underlying primary literature. Available at https://www.pharmgkb.org/.

For a comprehensive review of CYP2C8 covering metabolism, interactions, and clinical relevance in exhaustive detail, the Backman et al. 2016 review in Pharmacological Reviews is the definitive dedicated reference; the Daily and Aquilante 2009 review in Pharmacogenomics remains a useful focused account of the CYP2C8 pharmacogenetic literature.

See also

• Enzyme:CYP2C9, Enzyme:CYP2C19 (the other members of the chromosome 10 CYP2C gene cluster)
• Enzyme:CYP3A4, Enzyme:CYP2D6, Enzyme:CYP1A2, Enzyme:CYP2B6, Enzyme:UGT1A1 (other drug-metabolizing enzymes covered in the wiki)
• Repaglinide, Paclitaxel, Amodiaquine (canonical clinical CYP2C8 examples)
• Gemfibrozil (the canonical CYP2C8 mechanism-based inhibitor)
• Category:Drug-metabolizing enzymes