Nifedipine CYP3A4/5/7 substrate

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

Concomitant treatment with the CYP3A4 substrate nifedipine altered the mean AUC and mean Cmax of repaglinide by 11 and 3% respectively (64). 

Nifedipine was one of the first CYP3A4 substrates to be identified (167,168) and has been the subject of a large number of drug-drug interaction studies both in vitro and in vivo. Pharmacokinetic studies with nifedipine clearly identify inhibitors, such as itraconazole (169) and grapefruit juice (170), and inducers, such as the barbiturates (171) and rifampin (172). 

An ethnic difference - that could be drug-specific -in CYP3A4 activity has been observed for few CYP3A4 substrates (alprazolam, nifedipine), with a lower clearance in Asians than in Caucasians (Xie et al. 2001). 

Not all predicted drug interactions are expected to be clinically significant. For example, nifedipine and cyclosporine are both CYP3A4 substrates, but there is no clinically important drug interaction noticed.To predict the drug interaction, several parameters are expected to be important. These include notably ... 

Nifedipine is a substrate for the cytochrome P450 isoenzyme CYP3A4, and in vitro studies had shown that ximelagatran metabolites might be weak inhibitors of this isoenzyme. However, the lack of a pharmacokinetic interaction with nifedipine suggests that no clinically relevant interaction occurs, and is also unlikely with other CYP3A4 substrates (for a list see Table 1.4 , (p.6)). 

Galetin A, Clarke SE, Houston JB. Multisite kinetic analysis of interactions between prototypical CYP3A4 subgroup substrates midazolam, testosterone and nifedipine. Drug Metab Dispos 2003 31 1108-1116. 

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. 

The UK manufacttners advise caution when cilostazol is given with drugs that are substrates of CYP3A4, especially those with a narrow therapeutic index. They specifically mention cisapride, midazolam, nifedipine and verapamil. Further study is needed to establish these predicted... 

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