An investigation into the influence of cimetidine on the biovailability and pharmacokinetics of nifedipine and the importance of metabolic polymorphism on this interaction

[摘要] English: Nifedipine is a calcium channel blocker used in the treatment of stable, variant and unstable angina, mild to severe hypertension and Raynaud's phenomenon. Its disposition after oral administration is dependent on rate and extent of absorption, first-pass hepatic metabolism and oxidative phenotype of the subject.Cimetidine is a third generation H2-receptor antagonist. It blocks histamine-induced gastric acid secretion and has also been shown to interact with the microsomal cytochrome P-450 linked monooxygenase system, thus inhibiting drug metabolism. It may thus be possible to seperate the inhibitory effect ofcimetidine on specific enzyme systems in the liver from its gastric H2-receptor antagonising effect.The influence of cimetidine on the bioavailability and pharmacokinetics of nifedipine was investigated as well as the importance of metabolic polymorphism on such an interaction if it existed.Twenty healthy, non-smoking male volunteers of which ten were known to be effective oxidisers of sparteine, nine non-metabolisers and one poor oxidiser, participated in the study.Following an overnight fast, each subject was given a single AdalatR capsule containing 10mg nifedipine. Blood was taken at regular intervals and nifedipine plasma levels were determined by gaschromatography. The study was divided into four different profile days of which two were bioavailability and pharmacokinetic studies of nifedipine. During the other two days, these studies were repeated while the subjects wereat steady-state for cimetidine given as TagametR. During the latter two days nifedipine was taken with either 200ml of water or with 200ml of diluted hydrochloric acid (0.1% w/v; 0.028M). These two days were randomised.The following pharmacokinetic parameters of nifedipine were calculated and compared for the different phases: Cmax, AUDC, t 1/2;z, Tmax, Cl-tot/f, MT-vsys and V-sys/f. Point estimates and 90% confidence intervals were calculated for the different phases.Comparison of the two nifedipine-only phases suggests the existence of a large intra-subject variation in regard to Cmax and AUDC. This could be the result of a period effect and/or a carry over effect of cimetidine on nifedipine clearance which could still have been present after a 6 day wash-out period.Cimetidine pre-treatment clearly and significantly increased Cmax and AUDC values of nifedipine. This is most probably because of an attenuated first-pass clearance of nifedipine by cimetidine.Concomitant ingestion of diluted HCI and nifedipine in cimetidine pre-treated subjects, resulted in a significant reduction in the rate of nifedipine absorption when compared to the phase without HCI.These findings can be interpreted to differentiate between cimetidine's effects on nifedipine kinetics given as AdalatR capsules, i.e. inhibition of gastric acid secretion and inhibition of the hepatic monooxygenase system.Cimetidine pre-treatment had the effect of narrowing the coefficients of variation (CV) of nifedipine Cmax and AUDC. This could serve as a guideline in designing protocols for nifedipine bioavailability studies.The ability of subjects to metabolise sparteine oxidatively is not correlated with their ability to eliminate nifedipine.

[发布机构] University of the Free State