Intestinal transport and metabolism of cimetidine.

Abstract

The purpose of this research was to investigate the role of the gastrointestinal tract as an organ of cimetidine clearance. In situ single-pass perfusions were conducted to study cimetidine transport and metabolism in rat intestine. Approximately 73% of luminal cimetidine loss was detected as cimetidine sulfoxide in the exiting perfusate of rat jejunum when 0.4 mM was perfused at a flow rate of 0.123 ml/min while a negligible amount of sulfoxide metabolite was observed in rat ileum. Intestinal cimetidine permeability and metabolism demonstrated concentration and pH dependence in rat jejunum. Coperfusion of 0.4 mM cimetidine with 5 mM L-methionine, chlorpromazine, imipramine, and methimazole at a flow rate of 0.123 ml/min significantly inhibited luminal appearance of cimetidine sulfoxide and also significantly decreased cimetidine permeability at steady state. Cimetidine uptake in rat intestinal brush-border membrane vesicles was studied to elucidate the concentration dependence of cimetidine permeability observed in rat perfusion. Cimetidine transport across the rat intestinal brush-border membrane is mediated by a carrier system with $\rm K\sb{m}$ and $\rm V\sb\max$ values of 8.383 $\pm$ 1.200 mM and 6.138 $\pm$ 1.468 nmol/mg protein/30 sec, respectively. The initial uptake rate of cimetidine was enhanced by an outwardly directed H$\sp+$ gradient. The voltage-clamped condition exhibited a decrease in the H$\sp+$ sensitive uptake of cimetidine. An inside negative membrane potential imposed by valinomycin enhanced the uptake of cimetidine in the absence of a proton gradient. These results indicate the involvement of membrane potential difference in cimetidine transport in rat intestinal brush-border membrane vesicles. In the presence of 10 mM ranitidine, procainamide, imipramine, erythromycin, cysteamine, 1-amino-2-methyl-2-propanethiol, and, 2-(ethylthio)ethylamine, the initial uptake of cimetidine was significantly inhibited. The dependence of the appearance of sulfoxide on the amount of cimetidine absorbed indicate that membrane transport controls sulfoxide appearance at low drug perfusion concentrations while cellular sulfoxidation is limiting at high concentrations and longer jejunal residence time (4 mM inlet cimetidine at a flow rate of 0.123 ml/min). Different inhibition profiles between the perfusion and vesicle systems suggest that some inhibitors depress cimetidine flux across the mucosal membrane by reducing the transmembrane concentration gradient. Other inhibitors directly decrease carrier-mediated cimetidine transport across the brush-border membrane.