INTERACTION OF VERAPAMIL AND CIMETIDINE - STEREOCHEMICAL ASPECTS OF DRUG-METABOLISM, DRUG DISPOSITION AND DRUG-ACTION

  • 1 June 1990
    • journal article
    • research article
    • Vol. 253  (3) , 1042-1048
Abstract
The pharmacokinetics, metabolism and pharmacodynamics of verapamil (160 mg p.o. of a pseudoracemic mixture) were evaluated in six healthy volunteers before and after coadministration of cimetidine (400 mg b.i.d.). Enantiomers of verapamil and enantiomers of three major urinary metabolites (norverapamil, D-617 and D-620) were determined in plasma and urine by gas chromatography-mass spectrometry. Coadministration of cimetidine led to a significant increase in the area under the plasma concentration vs. time curve of S-verapamil (29.2 .+-. 31.8 min .times. nmol .times. ml-1 vs. 41.2 .+-. 33.7 min .times. nmol .times. ml-1; P < .003) and R-verapamil (124.7 .+-. 112.2 min .times. nmol .times. ml-1 vs. 156.8 .+-. 105.0 min .times. nmol .times. ml-1; P < .01). The increase was significantly greater for the pharmacologically more potent S-enantiomer compared to R-verapamil (150.3 .+-. 37 vs. 117.8 .+-. 15%; P < .05). As a consequence, coadministration of cimetidine increased the negative dromotropic effect of verapamil on atrioventricular conduction in five of six subjects. In addition, fractional metabolic clearance to D-620 and D-617 decreased for both enantiomers. Tubular secretion of S-D-617 was inhibited by cimetidine (342 .+-. 104 vs. 238 .+-. 52 ml .times. min-1; P < .05) whereas secretion of the R-enantiomer remained unchanged (276 .+-. 91 vs. 222 .+-. 43 ml .times. min-1). Thus, cimetidine interacts with both hepatic and renal verapamil elimination in a stereoselective manner. The increase in total plasma concentration of verapamil combined with an increase in eutomer/distomer ratio produces a more pronounced pharmacological effect of verapamil when cimetidine is coadministered.