Erythromycin CYP3A4/5/7 substrate

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

Figure 12.5 Three MBIs ((a) paroxetine, CYP2D6 (b) furafylline, CYP1A2 (c) erythromycin, CYP3A4) [30] and three substrates ((d) MBDB, CYP2D6 (e) dantrolene, CYP3A4 (f) adinazolam, CYP3A4) of different CYP isoforms.

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. 

Yang B-B, Siedlik PH, Smilhers JA, Sedman AJ, Stem RH. Atorvastatin pharmacokinetic interactions with other CYP3A4 substrates erythromycin and ethinyl estradiol. Pharm Res ( 996) 13 (9 Suppl), S-437. 

The enzyme is the principal participant in N-demethylation reactions where the substrate is a tertiary amine. The list of substrates includes erythromycin, ethylmor-phine, lidocaine, diltiazem, tamoxifen, toremifene, verapamil, cocaine, amiodarone, alfentanil and terfenadine. Carbon atoms in the allylic and benzylic positions, such as those present in quinidine, steroids and cyclosporin A, are also particularly prone to oxidation by CYP3A4, a range of substrates is illustrated in Figure 7.10. 

Sirolimus is metabolized by CYP2A4 and is a substrate of the P-glycoprotein drug efflux pump drugs like voriconazole, itraconazole, fluconazole and erythromycin increase its blood concentration. Conversely, the inducers of CYP3A4 will decrease blood levels of sirolimus. Cyclosporine increases the bioavailability of sirolimus, possibly due to P-GP inhibition and competition for CYP3A4. The bioavailability is more than 30-40% when the two drugs are administered 4 h apart and is more than... 

Mechanism-based inhibitors or suicide substrates seem to be particularly prevalent with CYP3A4. Such compounds are substrates for the enzyme, but metabolism is believed to form products that deactivate the enzyme. Several macrolide antibiotics, generally involving a tertiary amine function, are able to inhibit CYP3A4 in this manner (147,148). Erythromycin is one of the most widely used examples of this type of interaction, although there are other commonly prescribed agents that inactivate CYP3A4 (149-151), and a consideration of this phenomenon partially explains a number of interactions that are not readily explained by the conventional in vitro data (152). 

C]Phenacetin and [N-Methyl-14C]Erythromycin as marker substrates for CYP2E1, CYP2D6, CYP1A2 and CYP3A4, respectively with a 14C-CH20 or 14C-C2H4O read out after a simple and rapid extraction method. 

CYP3A4 inhibitors that have demonstrated P-gp inhibition include erythromycin, itraconazole, cyclosporine, diltiazem, and several protease inhibitors. As a result of considerable overlap with CYP3A4, the true effect of P-gp modulation on drug interactions involving P-gp substrates is unclear. Further, poor differentiation between P gp modulation in the intestine and liver makes it difficult to determine the relative contribution of P-gp to a specific drug interaction. 

Sildenafil is contraindicated in patients who are taking organic nitrates, for their metabolism is blocked and severe and acute hypotension result. Patients with recent stroke or myocardial infarction or whose blood pressure is known to be < 90/50 mmHg should not use it. Sildenafil is a substrate for the P450 isoenzyme CYP3A4 (and to a lesser extent CYP2C9) which gives scope for interaction with inhibitors or inducers of this system. The metabolic inhibitors erythromycin, saquinavir and ritonavir (protease inhibitors used for AIDS), and cimetidine, for example, produce substantial rises in the plasma concentration of sildenafil. 

E Itraconazole. Imatinib is primarily metabolized by the CYP3A4 hepatic enzyme system. Drugs that may inhibit this enzyme (such as ketoconazole, itraconazole, erythromycin, clarithromycin, etc.) may impair clearance of imatinib and result in increased toxicity. Imatinib itself is also a fairly potent inhibitor of the CYP3A4 enzyme and may result in toxicity due to other drugs that are substrates for this enzyme (such as simvastatin, warfarin, benzodiazepines, etc.). The other medications iisted are uniikeiy to affect the function of 0 P3A4 or interact adversely with imatinib. 

The CYP3A4 isozyme is responsible for the metabolism of a large number of endogenous compounds as well as a wide range of drugs (50). Fentanyl, alfentanil, and sufentanil are substrates for CYP3A4, and therefore drugs that inhibit this enzyme, such as erythromycin, HIV protease inhibitors, or cimetidine. 

Very recently two new ligand bound CYP3A4 structures were reported, one with the inhibitor ketoconazole (22) and the second with the substrate erythromycin [45], Unlike the metyrapone case, both of these structures dis-... 

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