CYP2C19 substrates

FIGURE 4.12 Structures of the CYP2C19 substrates, (S)-mephenytoin and omeprazole, and their metabolites. 

The metabolic activity of CYP2C19 has most frequently been probed, both in vivo and in vitro, using (5)-mephenytoin hydroxylation or mephenytoin SIR ratios. However, other substrates for this enzyme, including diazepam and imipramine, have been identified that have the potential to be used as probes (90,91). However, the most widely used identified CYP2C19 substrate is omeprazole (92). 

In view of their incomplete oral bioavailability, several CYP2C substrates may undergo significant first-pass intestinal metabolism, including the CYP2C9 substrates verapamil (155), losartan (156), fluvastatin (157), and diclofenac (158), and the CYP2C19 substrates (5)-mephenytoin (159) and omeprazole... 

Inter-ethnicity differences observed with different CYP2C19 substrates for subjects with same genotype have been attributed to differences in substrate specificity or enzyme isoforms (Bertilsson 1992). The clearance of omeprazole is higher in Caucasian EMs than in Oriental EMs, due to an higher proportion of heterozygous EMs in this latter population (Ishizaki 1994). 

TablelO.4 CYP2C19 substrates. The experimentally determined site of metabolism.

CYP2C19. Studies have shown that PXR and CAR regulate hepatic CYP2C19 expression in vitro [21, 22], The metabolism and plasma levels of the CYP2C19 substrates omeprazole [74] and voriconazole [129] are affected by the PXR agonists St. John s wort and rifampin, demonstrating that this enzyme is inducible in vivo. 

Metabolism of diazepam to A -desmethyl-diazepam occurs via the cytochrome P450 isoenzyme CYP2C19, and in vitro studies had shown that melagatran was a weak inhibitor of this isoenzyme. However, the lack of a pharmacokinetic interaction with diazepam suggests that no clinically relevant interaction occurs, and is also unlikely with other CYP2C19 substrates (for a list see Table 1.3 , (p.6)). 

Aripiprazole 10 to 30 mg daily had no significant effects on the metabolism of dextromethorphan (CYP2D6 and CYP3A4 substrate), warfarin (CYP2C9 substrate) and omeprazole (CYP2C19 substrate). Aripiprazole is not expected to affect CYPl A2-mediated metabolism. The manufacturers therefore conclude that aripiprazole is unlikely to have clinically significant interactions with drugs that are substrates for these isoenzymes. ... 

Omeprazole and esomeprazole are also inhibitors of CYP2C19, and therefore they may increase the levels of drugs that are metabolised by CYP2C19, such as diazepam. Other CYP2C19 substrates are listed in Table 1.3 , (p.6).h Particular care may be required when giving drugs that... 

No significant changes in plasma levels of diazepam (a CYP2C19 substrate) were observed in healthy volunteers orally administered 10 mg diazepam before or during treatment with 240 mg ginkgo leaf extract daily for 28 days (Zuo et al. 2010). 

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