Carrier-mediated active transport of histamine H2 receptor antagonists, cimetidine and nizatidine, into isolated rat hepatocytes: contribution of type I system.

The uptake rates of [3H]cimetidine and [14C]nizatidine into isolated rat hepatocytes were studied in order to identify the transport mechanism of histamine H2 receptor antagonists into the liver. In addition, the contributions of the uptake clearance to hepatic clearance for both drugs also were estimated. The uptakes of cimetidine and nizatidine achieved equilibrium in 5 min with cell-to-medium concentration ratios of 12.0 and 3.5, respectively. The uptake systems of both histamine H2 antagonists consisted of a saturable component and a nonsaturable component. The contributions of the carrier-mediated transport system for cimetidine and nizatidine at therapeutic concentrations (3 microM) were 86 and 70%, respectively. The uptakes of both drugs showed temperature dependency and were decreased significantly by various metabolic inhibitors and a sulfhydryl group modifying reagent. Only a slight effect was seen in the replacement of sodium with lithium on both uptakes. The uptake of cimetidine was reduced markedly in parallel with the reduction in the cellular ATP level and was inhibited by other histamine H2 antagonists and various organic cations. Furthermore, both nizatidine and quinidine competitively inhibited cimetidine's uptake. These results demonstrate that cimetidine and nizatidine are taken up into hepatocytes by a common Na(+)-independent transport system, namely the type I organic cation uptake system. By comparing the in vitro hepatic uptake clearance obtained from this study and the in vivo hepatic clearance from pharmacokinetic data, it is suggested that the rate-limiting step in hepatic clearance for cimetidine is drug metabolism, whereas for nizatidine, it is the uptake process.