Phenytoin CYP2C9 substrate

Aprepitant may be affected by paroxetine, CYP2C9 substrates (eg, phenytoin, tolbutamide, warfarin), CYP3A4 substrates (eg, alprazolam, cisapride, dexamethasone, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, methylprednisolone, midazolam, paclitaxel, pimozide, triazolam, vinblastine, vincristine, vinorelbine), and oral contraceptives. 

A77 1726 inhibits CYP2C9 and might increase the systemic availabihty of CYP2C9 substrates, such as warfarin and phenytoin (97,98). 

The interaction of losartan with phenytoin has been studied in a randomized, crossover study in 16 healthy volunteers (74). Losartan, a CYP2C9 substrate, had no effect on the pharmacokinetics of phenytoin. However, phenytoin inhibited the CYP2C9-mediated conversion of losartan to its active metabolite, thus potentially reducing its efficacy. 

Attention is warranted when certain sulfonamides (for example sulfaphenazole, sulfadiazine, sulfamethizole, and sulfafurazole) are co-administered with CYP2C9 substrates with narrow therapeutic ranges, such as phenytoin. 

The manufacturers advise caution if leflunomide is given with phenytoin or tolbutamide. The reason is that the active metabolite of leflunomide (A771726) has been shown by in vitro studies to be an inhibitor of the cytochrome P450 isoenzyme CYP2C9, which is concerned with the metabolism of these two drugs. If this inhibition were to occur in vivo it could possibly lead to a decrease in their metabolism and an increase in their toxicity. Although so far there appear to be no clinical reports of an interaction, the manufacturers made a similar prediction with warfarin, another CYP2C9 substrate, which has, in isolated cases, been borne out in practice. See Coumarins + Leflunomide , p.423. 

Although not assessed, this marked leduetion in aprepitant levels could result in reduced eflieaey. In the UK, the manufacturer recommends that concurrent use of aprepitant and strong indueers of CYP3A4, such as rifampicin, be avoided. They also name phenytoin (see also Aprepitant + CYP2C9 substrates , above), carbamazepine, and phenobarbital, and... 

Substrates CYP2C9 Most NSAIDs (including COX-2), warfarin, phenytoin... 

In 14 healthy volunteers fluvoxamine (150-300 mg/day for 5 days) significantly reduced the clearance of tolbutamide (30). This suggests that fluvoxamine should be used with caution when it is co-administered with drugs that are substrates for CYP2C9, such as tolbutamide, phenytoin, and warfarin. 

SSRIs PHENYTOIN t plasma concentrations of phenytoin Phenytoin is a substrate of CYP2C9 and CYP2C19. SSRIs are known to inhibit CYP2C9/10 Monitor plasma phenytoin levels... 

Examples of therapeutic compounds metabolized by CYP2C9 include nonsteroidal antiinflammatory (NSAID) medications, irbesartan, naproxen, and fluvastatin (see Table 43-3). Proposed dose adjustments based on phenotype have been published for CYP2C9 drug substrates such as warfarin, glipizide, tolbutamide, and phenytoin. ... 

Valproic acid inhibits the metabolism of drugs that are substrates for CYP2C9, including pheny-toin and phenobarbital. Valproic acid also inhibits UGT and thus inhibits the metabolism oflam-otrigine and lorazepam. Valproic acid is highly bound to albumin and can displace phenytoin and other drugs this displacement can exacerbate valproic acid s inhibition of phenytoin metabolism. 

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