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.

01 Jan 2008·YAKUGAKU ZASSHIQ4 · MEDICINE

Relationship between Lipophilicities of 1,4-Dihydropyridine Derivatives and Pharmacokinetic Interaction Strengths with Grapefruit Juice

Q4 · MEDICINE

Article

Author: UESAWA, Yoshihiro ; MOHRI, Kiminori

It is well known fact that the strengths of drug interactions with grapefruit juice (GFJ) differ greatly depending on the 1,4-dihydropyridine calcium channel antagonist (DHP) used. However, there are no available data on the relationship between interactions with GFJ and its physicochemical attributes. Therefore we endeavored to study the correlation between calculated logP values, indicating lipophilicity, from chemical structures of DHPs as well as water diffusion, molecular volume, molecular polarization, molecular density, refractive index, topologic polar surface area, and calculated molar refractivity. Thirteen forms of DHP, amlodipine, azelnidipine, benidipine, cilnidipine, efonidipine, felodipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and pranidipine were analyzed due to clinical trials performed with GFJ and these agents. The pharmacokinetic interaction strengths were defined in common logarithmic values of increasing ratios of area under the plasma concentration-time curve (AUC) with GFJ intake compared with controls. Physicochemical properties including three categories of predicted logP values were calculated from the structures of DHPs and their estimated relationship with the interactions. As a result, the logP values indicated significant positive correlations with the interaction strengths. This finding suggests that lipophilicity is an important factor in the strengths of pharmacokinetic interactions of DHPs with GFJ intake.

01 Jan 2007·Journal of International Medical ResearchQ4 · MEDICINE

The Effects of Calcium Channel Blockers are not Related to their Chemical Structure in the Collar Model of the Rabbit

Q4 · MEDICINE

ArticleOA

Author: Anacak, G Yetik ; Reel, B ; Ertuna, E ; Yasa, M ; Ozer, A ; Kerry, Z

Placing a silicone collar around the rabbit carotid artery induces intimal thickening, an early stage in atherosclerosis and restenosis. We investigated whether treatment with oral pranidipine, a new potent, long-lasting dihydropyridine calcium channel blocker (CCB), inhibited collar-induced intimal thickening in addition to the changes in vascular reactivity usually observed in this model. Pranidipine treatment did not inhibit collar-induced intimal thickening. Placing the collar around the carotid artery resulted in the characteristic changes in vascular reactivity, such as increased sensitivity to 5-hydroxytryptamine. Treatment with Nω-nitro-l-arginine (100 μM) and pranidipine, however, did not affect collar-induced changes in vascular reactivity. From results of this and previous studies, we conclude that pranidipine does not prevent collar-induced intimal thickening or collar-induced changes in vascular reactivity. Not all CCBs prevent collar-induced intimal thickening, suggesting that the effects of these agents are not related to their chemical structure and/or their calcium channel-blocking actions.

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Indication	Highest Phase	Country/Location	Organization	Date
Angina Pectoris	IND Application	CN	Zhejiang Otsuka Pharmaceutical Co. Ltd.	26 Jul 2007
Hypertension	IND Application	CN	Zhejiang Otsuka Pharmaceutical Co. Ltd.	26 Jul 2007

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