The anaerobic metabolism of verapamil in rat cecal contents forms nor-verapamil and thiocyanate.
The anaerobic metabolism of verapamil was studied to determine the role the intestinal flora may have on the disposition of verapamil. Metabolites produced by the flora could be the source of adverse reactions reported only with the p.o. controlled release formulations but not with immediate release formulations. Verapamil was found to be metabolized to thiocyanate, nor-verapamil and several more polar metabolites that were detected by either a specific assay for cyanide and thiocyanate or a high-performance liquid chromatography (HPLC) assay, respectively. The rate of thiocyanate formation with an initial substrate concentration of 2 mM verapamil was found to be 0.008 +/- 0.004 microgram/hr/ml of 1:10 cecal suspension. The N-demethylated metabolite, nor-verapamil, was detected in the cecal suspensions but it also disappeared with time. The rate of verapamil disappearance was dependent on the concentration of bacteria in the incubation mixture; the rate being most rapid with the highest concentration of bacteria. Acetonitrile and butyronitrile were also found to be metabolized by the cecal flora. Cyanide as well as thiocyanate were produced from both organo-nitriles. These results suggest that the cyano group of verapamil, acetonitrile and butyronitrile were all cleaved to form cyanide and/or thiocyanate. With verapamil, cleavage of the cyano group would form new chemical entities that could be pharmacologically active and serve as a source of some of the adverse reactions or side-effects reported.
Koch
R L
RL
Department of Pharmaceutics, College of Pharmacy, University of Illinois, Chicago.
Palicharla
P
P
D000097:Acetonitriles / Q000378:metabolism; D000818:Animals; D002432:Cecum / Q000378:metabolism*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003485:Cyanates / Q000032:analysis / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013379:Substrate Specificity; D013861:Thiocyanates / Q000032:analysis / Q000378:metabolism*; D014700:Verapamil / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism*
D000097:Acetonitriles; D003485:Cyanates; D013861:Thiocyanates; C016904:norverapamil; D014700:Verapamil; C032159:acetonitrile