Diazepam CYP2C19 substrate

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). 

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)). 

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). 

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. 

Recombinant human CYP2D6 was shown to be selective for the O-demethyla-tion of dextromethorphan at or near the K n for this cytochrome s interaction with this substrate (at a concentration of 3 pM), whereas at higher substrate concentrations CYPs of the cytochrome 2C family contributed significantly to the metabolism of the drug. Similarly, diazepam at a concentration of 100 pM was N-demethylated principally by CYPs 3A4 and 2C19. However, at the lower concentration of 20 pM, the metabolism mediated by CYP3A4 was reduced to 30% that of CYP2C19. 

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. 

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