CYP2C9 substrates

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

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.

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. 

In Lewis et al. s (225) QSAR study, eight CYP2C9 substrates where examined. In this case, it appeared as if the acid dissociation constant pXa, the compounds lipophilicity, and the number of hydrogen bond donor atoms are important features (Eq. 1, Table 8). These suggestions are supported by a good correlation with the binding affinity. 

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... 

MODAFINIL ANTIDEPRESSANTS - clomipramine, desipramine - CYP1A2 substrates, CYP2C9 substrates, above T of plasma concentrations of TCAs in a subset of the population (7-10% of Caucasians) who are deficient in CYP2D6 CYP2C19 provides an ancillary pathway for the metabolism of domipramine and desipramine. Modafinil inhibited CYP2C19 reversibly at pharmacologically relevant concentrations i dose of TCAs is often necessary... 

Table10.3 CYP2C9 substrates. The experimentally determined site of metabolism.

CYP isoform specificity predicts the subtype responsible for the main route of metabolism. This type of study started from the work by Manga et al. (52), in which the isoform specificity for CYP3A4, CYP2D6, and CYP2C9 substrates was investigated. Terfloth et al. (53) reported a similar study on the same dataset using ligand-based methods, and the accuracy of prediction was improved substantially. 

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. 

Drug interactions May decrease antihypertensive effects of ACE inhibitors and angiotensin II antagonists decrease of antihypertensive and diuretic effects of thiazides and loop diuretics Agents are CYP2C9 substrates may decease effects of ACE inhibitors, thiazides, and loop diuretics fluconazole Increases levels of celecoxib may increase INR when added to warfarin... 

---