Omeprazole CYP2C19 substrate

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. ... 

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... 

Ieiri I, Kubota T, Urae A, et al. Pharmacokinetics of omeprazole (a substrate of CYP2C19) and comparison with two mutant alleles, CYP2C19mi inexon 5 and CYP2C19m2 in exon 4, in Japanese subjects. Clin Pharmacol Ther 1996 59 647-653. 

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). 

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. 

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... 

Substrates CYP2C19 Diazepam, lansoprazole, omeprazole, phenytoin. 

Substrates other than mephenytoin which have caused clinical disturbances in people with deficient CYP2C19 alleles include omeprazol (41), proguanil (42), and citalopram (43). Additional substrates listed (8) include clomipramine, imipramine, diazepam, and propanolol. 

Metabolism of omeprazole and other proton pump inhibitors occurs primarily in the liver (Fig. 37.19). The sulfone, hydroxylated, and O-demethylated metabolites have been reported as products. Omeprazole is a substrate primarily for CYP2C19 and may elevate concentrations of other substrates for this enzyme (e g., diazepam) when given concurrently. The CYP3A4 contributes to a lesser extent. Further oxidation of the sulfone affords additional metabolites. 

Fluconazole and voriconazole almost certainly cause a rise in omeprazole and esomeprazole levels by inhibiting their metabolism by the cytochrome P450 isoenzymes CYP2C19 and CYP3A4. As esomeprazole is an inhibitor of and also a substrate for CYP2C19, it is likely to have the same effect as omeprazole. Ketoconazole only inhibits CYP3A4 and therefore causes a less marked rise in omeprazole levels. Itraconazole would be expected to interact similarly to ketoconazole. 

There was no important pharmacokinetic interaction between azimilide and digoxin, and digoxin did not appreciably alter azimi-lide-induced QTc prolongation. Ketoconazole did not alter the pharmacokinetics of azimilide to a clinically relevant extent, and therefore other CYP3A4 inhibitors are also unlikety to affect azimilide pharmacokinetics. Azimilide did not alter the pharmacokinetics of omeprazole to a clinically relevant extent, and is therefore unlikely to interact with other substrates of CYP2C19. 

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