Vol. 291, Issue 1, 204-212, October 1999

Nonlinear Disposition Kinetics of a Novel Antifolate, MX-68, in Rats¹

Yong-Hae Han, Yukio Kato and Yuichi Sugiyama

Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan (Y.-H.H., Y.K., Y.S.); and Core Research for Evolutional Science, and Technology (CREST), Japan Science and Technology Corporation, Japan (Y.K., Y.S.)

The excretion and tissue distribution kinetics of a novel antifolate, MX-68, were evaluated under conditions of a continuous steady-state infusion in Sprague-Dawley rats (SDRs). The biliary excretion clearance defined with respect to the hepatic concentration (CL_{bile, h}) was much lower in Eisai hyperbilirubinemic rats with a hereditary deficiency in canalicular multispecific organic anion transporter than that in SDRs, suggesting the involvement of canalicular multispecific organic anion transporter in its transport across the bile canalicular membrane. The CL_{bile, h} in SDRs increased as the infusion rate increased; this can be largely explained by saturation of the intracellular binding of MX-68. On the other hand, the urinary excretion clearance defined with respect to the renal concentration (CL_{urine, k}) was comparable for the two strains but showed an increase and subsequent decrease as the renal concentration increased. This nonlinear profile was also found even when the CL_{urine, k} was normalized by the unbound fraction in kidney. Therefore, this kinetic profile represents the saturation of both reabsorption and secretion. Reabsorption of MX-68 in kidney was supported by its saturable transport by renal brush border membrane vesicles at an inward H⁺ gradient. The liver-to-plasma unbound concentration ratio decreased as the steady-state plasma concentration increased, suggesting that MX-68 is taken up by a saturable mechanism or mechanisms. Thus, the saturation of transport systems across several plasma membranes and intracellular binding in both the liver and kidney produce the nonlinear disposition of MX-68.