Influence of CYP2C8 polymorphisms on the hydroxylation metabolism of paclitaxel, repaglinide and ibuprofen enantiomers in vitro.

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Yu L, Shi D, Ma L, Zhou Q, Zeng S

Influence of CYP2C8 polymorphisms on the hydroxylation metabolism of paclitaxel, repaglinide and ibuprofen enantiomers in vitro.

Biopharm Drug Dispos. 2013 Jul;34(5):278-87. doi: 10.1002/bdd.1842. Epub 2013 Jun 3.

PubMed ID

23536207 [ View in PubMed

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Abstract

CYP2C8 plays an important role in the metabolism of various drugs, such as paclitaxel, repaglinide and ibuprofen. Polymorphisms in the CYP2C8 gene were shown to influence interindividual differences in the pharmacokinetics of paclitaxel, repaglinide and ibuprofen enantiomers. In this study, three CYP2C8 allelic variants (CYP2C8.2, CYP2C8.3 and CYP2C8.4) and wild-type CYP2C8 (CYP2C8.1) were co-expressed for the first time with human cytochrome P450 oxidoreductase (POR) and cytochrome b5 by using a baculovirus-assisted insect cell expression system. Further, the effects of genotype-phenotype correlations of CYP2C8 alleles on the metabolism of paclitaxel, repaglinide and ibuprofen enantiomers were evaluated. The CLint values of CYP2C8.2, CYP2C8.3 and CYP2C8.4 for paclitaxel were 47.7%, 64.3% and 30.2% of that of CYP2C8.1 (p<0.01). The CLint values of CYP2C8.2 and CYP2C8.4 for repaglinide were 77.9% and 80.2% of that of CYP2C8.1 (p<0.05), respectively, while the CLint value of CYP2C8.3 was 1.31-fold higher than that of CYP2C8.1 (p<0.05). The relative CLint values of CYP2C8.2, CYP2C8.3 and CYP2C8.4 were 110.5%, 72.3% and 49.7% of that of CYP2C8.1 and were 124.6%, 83.4% and 47.4% of that of CYP2C8.1 for R-ibuprofen and S-ibuprofen, respectively. Comparing hydroxylation by CYP2C8.1 and CYP2C8.3 resulted in higher and lower intrinsic clearance of repaglinide and ibuprofen enantiomers, respectively. These in vitro findings were consistent with the pharmacokinetics in volunteers who were heterozygous or homozygous carriers of CYP2C8*3. The results of this study provide useful information for predicting CYP2C8 phenotypes and may contribute to individualized drug therapy in the future.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Ibuprofen	Prostaglandin G/H synthase 1	Protein	Humans	Yes	Inhibitor	Details

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Dexibuprofen	Cytochrome P450 2C8	Protein	Humans	No	Substrate	Details
Ibuprofen	Cytochrome P450 2C8	Protein	Humans	Unknown	Substrate	Details
Paclitaxel	Cytochrome P450 2C8	Protein	Humans	Unknown	Substrate	Details