Intestinal clearance of H2-antagonists.
Jejunal perfusion of cimetidine resulted in the appearance of lumenal cimetidine sulfoxide in both rats and humans. In the rat, ileal perfusion yielded negligible sulfoxide metabolite as compared with that of the jejunum. Jejunal co-perfusion of an anionic-exchange inhibitor, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, blocked the appearance of drug sulfoxide, and methionine co-perfusion yielded concentration-dependent inhibition of lumenal cimetidine sulfoxide. Intravenous injection of high concentrations of cimetidine sulfoxide did not produce detectable lumenal metabolite levels during jejunal perfusion of drug-free buffer, providing in situ evidence that lumenal metabolite is generated by the small intestine. The extent of the appearance of lumenal sulfoxide was significantly greater for cimetidine than for the other three marketed H2-antagonists in rat jejunum. Variable intestinal clearance of this extensively prescribed class of therapeutic agents may contribute to their absorption variability.
Hui
Y F
YF
College of Pharmacy, University of Michigan, Ann Arbor 48109.
Kolars
J
J
Hu
Z
Z
Fleisher
D
D
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000008:administration & dosage; D000818:Animals; D002927:Cimetidine / Q000031:analogs & derivatives / Q000032:analysis / Q000493:pharmacokinetics; D015738:Famotidine / Q000493:pharmacokinetics; D006635:Histamine H2 Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism*; D008715:Methionine / Q000008:administration & dosage; D010477:Perfusion; D051381:Rats
D006635:Histamine H2 Antagonists; D015738:Famotidine; D002927:Cimetidine; D008715:Methionine; C034042:cimetidine sulfoxide; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid