The effects of chronic oral diltiazem and cimetidine dosing on the pharmacokinetics and negative dromotropic action of intravenous and oral diltiazem in the dog.
The kinetics and negative dromotropic action of intravenous (1 mg kg-1) and oral (5 mg kg-1) diltiazem were studied in dogs after acute doses, after treatment for 3 days with oral diltiazem (5 mg kg-1, t.i.d.), and after 3 days' treatment with oral diltiazem (5 mg kg-1 t.i.d.) and cimetidine (200 mg t.i.d.). Plasma concentrations of diltiazem and two of its metabolites, desacetyldiltiazem and desmethyldiltiazem were measured by HPLC. Chronic oral dosing significantly lowered both the systemic and oral clearance of diltiazem, with no changes in either the volume of distribution or blood binding of diltiazem. Cimetidine treatment resulted in a significant reduction in diltiazem oral clearance from chronic control with no effect on its systemic clearance. The AUCs of both metabolites increased by greater than threefold from acute to chronic oral dosing; however, the ratio of each metabolite's AUC to that of diltiazem AUC was not significantly altered. Cimetidine treatment significantly lowered these ratios. The negative dromotropic potency of diltiazem after the acute oral dose was three times greater than that after intravenous or chronic control dosing. Cimetidine treatment resulted in further lowering chronic oral diltiazem potency. These data indicate that the disposition and negative dromotropic action of diltiazem is dependent both on the route of administration and the duration of treatment, and can be altered by co-administration with cimetidine.
Maskasame
C
C
Department of Anatomy, College of Veterinary Medicine, North Carolina State University, Raleigh 27606.
Lankford
S
S
Bai
S A
SA
D000284:Administration, Oral; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002927:Cimetidine / Q000097:blood / Q000494:pharmacology*; D003864:Depression, Chemical; D004110:Diltiazem / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004285:Dogs; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D007262:Infusions, Intravenous; D009431:Neural Conduction / Q000187:drug effects*; D011485:Protein Binding
D001798:Blood Proteins; D002927:Cimetidine; C037769:deacetyldiltiazem; D004110:Diltiazem; C052825:N-monodemethyldiltiazem