Grapefruit juice and cimetidine inhibit stereoselective metabolism of nitrendipine in humans

Abstract

The effects of grapefruit juice (150 ml at -15, -10, -1/4, +5, and +10 hours) and cimetidine (200 mg at the same times) on the stereoselective pharmacokinetics and effects of 20 mg oral racemic nitrendipine were investigated in a placebo-controlled crossover study in nine healthy men. In all subjects the AUC of racemic nitrendipine was increased by grapefruit juice (mean increase 106%; 95% confidence interval 64% to 158%) and cimetidine treatment (+154%; 95% confidence interval 77% to 265%). Comparable results were obtained for the peak plasma drug concentration and for both parameters of (S)- and (R)-nitrendipine. There were highly significant differences in the area under the concentration-time curve and peak plasma drug concentration between enantiomers within all treatments. Grapefruit juice had no effect on this stereoselectivity, but cimetidine increased the mean S/R ratio of areas under the curve (2.25) by 20% (95% confidence interval 12% to 29%) compared with placebo treatment (1.89). Half-lives and time to reach peak concentration of the enantiomers were not different within and between treatments. There were no consistent effects on blood pressure with all treatments, but in most subjects there was a small temporary increase in heart rate after intake of nitrendipine. Grapefruit juice and cimetidine did not affect these hemodynamic parameters and did not cause additional adverse effects.

Food–drug interaction: grapefruit juice augments drug bioavailability—mechanism, extent and relevance

“…Other dihydropyridines exhibiting the interaction to a similar extent are nisoldipine (Bailey et al, 1993b;Takanaga et al, 2000) and nicardipine . A milder but significant interaction has been detected with nitrendipine, pranidipine and nimodipine that exhibited bioavailability increments of 100, 73 and 50%, respectively (Soons et al, 1991;Fuhr et al, 1998;Hashimoto et al, 1998). However, little or no effect has been detected for nifedipine and amlodipine (Rashid et al, 1993;Josefsson et al, 1996;Vincent et al, 2000).…”

Interaction between Grapefruit Juice and Praziquantel in Humans

“…The biotransformation of praziquantel seems to be mediated mainly by CYP3A4. As grapefruit juice selectively inhibits the CYP3A4-mediated drug metabolism in the small intestine (8,15,19), the increase in the bioavailability of praziquantel in this study suggests that it could also be metabolized in the small intestine. This is the mechanism proposed for the increased oral bioavailability observed for other drugs metabolized by CYP3A4 when taken with grapefruit juice; however, more studies are needed to determine the mechanisms involved in its biotransformation.…”

Assessment of Intestinal Availability (FG) of Substrate Drugs of Cytochrome P450s by Analyzing Changes in Pharmacokinetic Properties Caused by Drug–Drug Interactions

“…The blood concentrations of the metabolites of cyclosporin A and midazolam were significantly increased after administration of intraduodenal drug doses compared with intravenous doses in patients under anhepatic conditions during liver transplantation surgery (Kolars et al, 1991;Paine et al, 1996). The area under the blood concentration-time curve (AUC) for many substrate drugs of CYP3A is increased several fold by prior intake of grapefruit juice (GFJ), which strongly inhibits the activity of intestinal CYP3A in vivo (Soons et al, 1991;Ducharme et al, 1995). Consequently, even though the expression of CYP3A in the small intestine is approximately 1/100 of its expression in the liver (Paine et al, 1997), the estimation of F G should not be undervalued.…”