Interaction of verapamil and cimetidine: stereochemical aspects of drug metabolism, drug disposition and drug action.
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 x nmol x ml-1 vs. 41.2 +/- 33.7 min x nmol x ml-1; P less than .003) and R-verapamil (124.7 +/- 112.2 min x nmol x ml-1 vs. 156.8 +/- 105.0 min x nmol x ml-1; P less than .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 less than .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 x min-1; P less than .05) whereas secretion of the R-enantiomer remained unchanged (276 +/- 91 vs. 222 +/- 43 ml x 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.
Mikus
G
G
Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Federal Republic of Germany.
Eichelbaum
M
M
Fischer
C
C
Gumulka
S
S
Klotz
U
U
Kroemer
H K
HK
D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D002927:Cimetidine / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D013237:Stereoisomerism; D014700:Verapamil / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology
D002927:Cimetidine; D014700:Verapamil