The hepatic uptake mechanisms and pharmacokinetics of BQ-123, an anionic cyclopentapeptidic endothelin ET(A) receptor antagonist, were studied in rats. Elimination of BQ-123 from plasma after intravenous injection of the compound was very rapid as evidenced by high total body clearance (CLtot, 50 ml/min/kg), which is comparable with hepatic blood flow rate. Within 1 hr after injection, 86% of the dose was excreted as its intact form in the bile. BQ-123 was taken up extensively by isolated rat hepatocytes both Na(+)-dependently and Na(+)-independently. The Na(+)-dependent system transported BQ-123 with higher affinity than did the Na(+)-independent system (Km; 6 and 12 microM, respectively), but its capacity was lower (Vmax; 140 and 390 pmol/min/10(6) cells, respectively). Both uptake systems were found to be active transport systems because of explicit inhibition by metabolic inhibitors. BQ-485, an anionic linear tripeptide, strongly inhibited BQ-123 uptake with Ki values of 1.6 and 2.5 microM for Na(+)-dependent and Na(+)-independent systems, respectively, whereas BQ-587, a cationic cyclopentapeptide, inhibited BQ-123 uptake only slightly. Considering this in vitro finding and the low in vivo CLtot of BQ-587 together, the carrier systems for BQ-123 seem to recognize negatively charged substances selectively. Both Na(+)-dependent and Na(+)-independent uptake of BQ-123 were competitively inhibited by a bile acid (taurocholate) and an organic anion (dibromosulfophthalein). The Ki values were comparable with the Km values of taurocholate and dibromosulfophthalein transport, which suggests that the Na(+)-dependent system corresponds to the bile acid transporter and that the Na(+)-independent system corresponds to the organic anion transporter.