Integrated Analysis on the Physicochemical Properties of Dihydropyridine Calcium Channel Blockers in Grapefruit Juice Interactions

Abstract

Concomitant consumption of grapefruit juice (GFJ) causes increases in the plasma concentration of a variety of drugs due to inhibition of intestinal CYP3A enzyme. Dihydropyridine calcium channel blockers belong to the category of drugs that are most prone to undergo such interaction. Increases in area under the plasma concentration-time curve (AUC) due to GFJ differ greatly depending on the dihydropyridine administered. Therefore, a meta-analysis of each dihydropyridine was performed based on available literature. The criteria for using a publication were: subjects were healthy adults, dihydropyridines were taken with GFJ concomitantly or within one hour after intake of the juice, and the control group administered water in place of GFJ. In these studies, the investigations on GFJ interactions with 13 dihydropyridines such as amlodipine, azelnidipine, benidipine, cilnidipine, efonidipine, felodipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine and pranidipine were reported. As a result of meta-analyses, statistically significant interactions were not identified in amlodipine. Next, correlation analyses between the physicochemical properties and interaction strengths of the dihydropyridines were performed to clarify the cause of the variation in the strengths that was dependent on the dihydropyridine. LogP, molecular weight, topological polar surface area (tPSA), molar refractivity, water diffusion, molecular volume, molecular density, molecular polarizability, and refractive index were calculated from the chemical structures. The interaction strength was defined as the logarithmic values of the increasing AUC ratio. The correlation analyses indicated a relationship of logP and tPSA with the interaction strengths. These findings suggest that the wide difference in the potency of interaction of each dihydropyridine may be explained by the presence of hydrophobic and electrostatic interactions between dihydropyridines and intestinal CYP3A enzyme.