Midazolam CYP3A4/5/7 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.

The metabolism of several CYP3A4 substrates in microsomes from the upper small intestine has been compared with liver microsomal metabolism. The results are summarized in Table 13.3. Thus, microsomes from the human upper small intestine can metabolize CYP3A4 substrates at rates approaching those found in human liver microsomes. However, the rate of metabolism in intestinal microsomes can be highly variable (8-fold for sirolimus [17] and 18- to 29-fold for midazolam [19]). 

FIGURE 4.20 Structures of the CYP3A4 substrates, erythromycin, nifedipine, testosterone, and midazolam, and their metabolites. 

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. 

Delavirdine should not be used in combination with drugs that are CYP3A4 substrates such as pimozide, midazolam, triazolam, amiodarone, propafenone and ergot derivatives. Inducers of the hepatic P-450 system, rifampin, rifabutin, pheno-barbital, phenytoin or carbamazepine, should not be used in combination with delaviridine. It also increases the plasma levels of HIV protease inhibitors. 

Meanwhile, the currently marketed CYP3A4 inducers can profoundly affect the pharmacokinetics of coadministered CYP3A4 substrates, e.g., rifampin on midazolam (139) or triazolam (140). Clearly, the most frequent outcome is a loss of efficacy, which is perhaps less serious than inhibition interactions, although the consequences of coadministering rifampin with the oral contraceptive pill can lead to contraceptive failure (141-143). 

For substrates exhibiting non-Michaelis-Menten kinetics (e.g., several CYP3A4 substrates), a wider range of substrate concentrations may be required to accurately determine reaction kinetics. CYP3A4 should be measured with at least two substrates, one exhibiting positive cooperativity (e.g., testosterone) and one exhibiting autoinhibition (e.g., midazolam). 

Zdravkovic M, Olsen AK, Christiansen T, et al. A clinical study investigating the pharmacokinetic interaction between NN703 (tabimorelin), a potential inhibitor of CYP3A4 activity, and midazolam, a CYP3A4 substrate. Eur J Clin Pharmacol 2003 58(10) 683-688. 

In a double-blind, crossover kinetic and dynamic study of the interaction of ketoconazole with alprazolam and triazolam, two CYP3A4 substrate drugs with different kinetic profiles, impaired clearance by ketoconazole had more profound clinical consequences for triazolam than for alprazolam (32). By the same mechanism ketoconazole also inhibits the metabolism of midazolam (33). 

Of aU the HIV protease inhibitors, saquinavir is the least potent inhibitor of CYP3A4. Nonetheless, it is recommended that the drug not be coadministered with ergot derivatives, triazolam, midazolam, or other CYP3A4 substrates with a low therapeutic index. Saquinavir clearance is increased with CYP3A4 induction thus coadministration of rifampin, nevirapine, or efavirenz lowers saquinavir concentrations and should be avoided. The effect of nevirapine or efavirenz on saquinavir may be partially or completely reversed with ritonavir. 

Telithromycin has several clinically significant drug interactions similar to those for erythromycin. It is both a substrate and a strong inhibitor of CYP3A4. Coadministration of rifampin, a potent inducer of CYP, decreases the serum concentrations of telithromycin by 80%. CYP3A4 inhibitors (e.g., itraconazole) increase peak serum concentrations of telithromycin. Serum concentrations of CYP3A4 substrates (e.g., pimozide, cisapride, midazolam, statins, cyclosporine, phenytoin) are increased by telithromycin. Telithromycin also increases peak serum concentrations of metoprolol and digoxin. 

Modafinil is an inducer of the cytochrome P450 isoenzyme CYP3A4. The manufacturers therefore predict that it may reduce the levels of drugs that are CYP3A4 substrates. They specifically name the protease inhibitors, buspirone, calcium-channel blockers, ciclosporin, midazolam, and the statins [note that only some statins, namely atorvastatin, lovastatin and... 

The pharmacokinetics of intravenous fulvestrant were not affected by rifampicin, an inducer of the cytochrome P450 isoenzyme CYP3A4, or ketoconazole, an inhibitor of CYP3A4. In addition, intramuscular fulvestrant did not affect the pharmacokinetics of midazolam, a substrate of CYP3A4. It is therefore unlikely that fulvestrant will be affected by drug interactions involving this isoenzyme. ... 

The findings of the first study with oral and intravenous midazolam suggest that the effect of echinacea on CYP3A4 substrates might depend on the whether they have high or low oral bioavailability and whether they have high or low hepatic clearance. Further study is needed. 

Maraviroc had no clinically relevant effect on the pharmacokinetics of lamivudine, zidovudine, or a combined oral contraceptive containing ethinylestradiol and levonoi estreL No clinically important effect was seen with the CYP3A4 substrate midazolam. Food may reduce the absorption of maraviroc, but this is probably not clinically relevant. 

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