Tolbutamide CYP2C9 substrate

Figure 7.5 Mucosal-to-submucosal (m-s), Tapp values across human buccal culture of midazolam (CYP3A4 substrate), bufuralol (CYP2D6 substrate), tolbutamide (CYP2C9 substrate), and the nonmetabolized, high-permeability control compound caffeine (average SEM, N = 1 — 3 replicates). (Asterisk) in the presence of CYP inhibitors (CYP3A4-ketoconazole CYP2D6-quinidine CYP2C9-suphaphenazole). In all treatments integrity of the culture was verified by permeation of Lucifer yellow (< 2.0 x 10-6 cm/s). Results from internal study by Absorption Systems Company.

FIGURE 4.11 Structures of the CYP2C9 substrates, warfarin, tolbutamide, (S (-flurbiprofen, and diclofenac, and their metabolites. 

In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites with the known cytochrome CYP2C9 substrates/inhibitors, tolbutamide, and nifedipine. However, clinical consequences were negligible. 

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. 

Not known. Based on in vitro data, both entacapone and tolcapone were thought to potentially interfere with the metabolism of drugs by the cytochrome P450 isoenzyme CYP2C9, such as 5-warfarin. " However, the above study shows that entacapone does not alter 5-warfarin pharmacokinetics, and tolcapone is also thought not expected to interact by this mechanism because it does not interact with tolbutamide , (p.516), another CYP2C9 substrate. 

Not understood. The effect dextropropoxyphene has on the metabolism of the warfarin enantiomers does not appear to have been studied. Dextropropoxyphene does not interact with other cytochrome P450 isoenzyme CYP2C9 substrates such as tolbutamide , (p.486), although it does interact with the CYP3A4 substrate carbamazepine , (p.527). There is also the possibility that the paracetamol component had some part to play (see also Coumarins + Paracetamol (Acetaminophen) , p.438). Alternatively, these eases may just represent idiosyncratic reactions. 

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. 

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. 

In vivo probe substrates are available to assess the activity of particular enzymes, for example midazolam for CYP3A4/5, caffeine for CYP1A2 and tolbutamide for CYP2C9 [14],... 

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. ... 

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