The nonlinearity in the pharmacokinetics of the cyclopentapeptide endothelin antagonist BQ-123 was studied. Both the total body clearance and tissue-to-plasma concentration ratio (Kp) were investigated in rats under a wide range of steady-state plasma concentrations (Cpss) obtained by changing the intravenous infusion rate of BQ-123. The total body clearance was constant up to a Cpss level of 50 microM, although it was markedly decreased at higher Cpss values, which suggests the existence of a saturable elimination mechanism. A Cpss-dependent nonlinearity in the apparent Kp values (Kp,app) was clearly observed in many organs including lung, heart, spleen, pancreas, adrenal, stomach, intestine, colon, aorta, testis and muscle, where the endothelin ET(A) receptor is known to be localized. By fitting the saturation curves of the Kp,app values, a similar dissociation constant (Kd) was obtained for most organs at 5 to 10 nM, which is close to the reported Kd values of BQ-123 for the endothelin ET(A) receptor. The saturable portion of the Kp,app values observed in vivo showed a good correlation with reported values of the endothelin ET(A) receptor density. Binding of BQ-123 to isolated membrane fractions from several organs demonstrated clear saturability for the lung, heart, spleen and liver with Kd values of 1 to 3 nM. Such specific binding also showed a good correlation with the saturable portion of the Kp,app values. From these results, we concluded that the endothelin receptor(s) is responsible for the nonlinear tissue distribution of BQ-123 in rats.