Diltiazem CYP3A4/5/7 substrate

Diltiazem and verapamil inhibit other CYP3A4 substrates, whereas the dihydropyridines do not. 

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. 

The most common interactions with SSRIs are pharmacokinetic interactions. For example, paroxetine and fluoxetine are potent CYP2D6 inhibitors (Table 30-4). Thus, administration with 2D6 substrates such as TCAs can lead to dramatic and sometimes unpredictable elevations in the tricyclic drug concentration. The result may be toxicity from the TCA. Similarly, fluvoxamine, a CYP3A4 inhibitor, may elevate the levels of concurrently administered substrates for this enzyme such as diltiazem and induce bradycardia or hypotension. Other SSRIs, such as citalopram and escitalopram, are relatively free of pharmacokinetic interactions. The most serious interaction with the SSRIs are pharmacodynamic interactions with MAOIs that produce a serotonin syndrome (see below). 

There are two groups dihydropyridines and diltiazem/verapamil. Both groups are metabolized by the CYP3A family of isoenzymes (especially CYP3A4), which are the sites of many of the pharmacokinetic interactions involving this class. Some drugs are substrates for P-gp. 

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, POSACONAZOLE, VORICONAZOLE CALCIUM CHANNEL BLOCKERS Plasma concentrations of dihydropyridine calcium channel blockers are t by fluconazole, itraconazole and ketoconazole. Risk of t verapamil levels with ketoconazole and itraconazole. Itraconazole and possibly posaconazole may t diltiazem levels The azoles are potent inhibitors of CYP3A4 isoenzymes, which metabolize calcium channel blockers. They also inhibit CYP2C9-mediated metabolism of verapamil. Ketoconazole and itraconazole both inhibit intestinal P-gp, which may t bioavailability of verapamil. Diltiazem is mainly a substrate of CYP3A5 and CYP3A5P1, which are inhibited by itraconazole. 75% of the metabolism of diltiazem occurs in the liver and the rest in the intestine. Diltiazem is a substrate of P-gp (also an inhibitor but unlikely to be significant at therapeutic doses), which is inhibited by itraconazole, resulting in t bioavailability of diltiazem Monitor PR, BP and ECG, and warn patents to watch for symptoms/signs of heart failure... 

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. 

D Rifampin significantly reduces the plasma concentrations of the calcium channel blockers verapamil, diltiazem, and nifedipine. Diltiazem is a substrate of Gi P3A4 and rifampin is an inducer of CYP3A4. Rifampin does not interact with metoprolol, aspirin, pravastatin, or nitroglycerin. However, if the patient had been on another HMG-CoA reductase inhibitor such as atorvastatin, lova-statin, or simvastatin instead of pravastatin, rifampin would have reduced the plasma concentrations of these agents since they are also metabolized via CYP3A4. 

Drug Interactions Since sirolimus is a substrate for CYP3A4 and is transported by P-glycoprotein, close attention to interactions with other drugs that are metaboUzed or transported by these proteins is required. As noted above, cyclosporine and sirolimus interact, and their administration should be separated by time. Dose adjustment may be required when sirolimus is coadministered with diltiazem or rifampin. 

Similarly, the calcium channel blockers verapamil and diltiazem are inhibitors of both CYP3A4 and P-glycoprotein. Substrates of these two pathways, such as statins, may have significant increases in blood concentrations when used with these inhibitors. 

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