Abstract
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 (CLbile, 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 CLbile, 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 (CLurine, 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 CLurine, 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.
Footnotes
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Send reprint requests to: Yuichi Sugiyama, Ph.D., Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail:sugiyama{at}seizai.f.u-tokyo.ac.jp
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↵1 This work was supported in part by grants from Tokyo Biochemical Research Foundation.
- Abbreviations:
- MTX
- methotrexate
- MX-68
- N-[[4-[(2,4-diamminopteridine-6-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl]-l-homoglutamic acid
- BBMV
- brush border membrane vesicle
- CLbile, p
- biliary excretion clearance defined with respect to the plasma concentration
- CLbile, h
- biliary excretion clearance defined with respect to the hepatic concentration
- CLurine, p
- urinary excretion clearance defined with respect to the plasma concentration
- CLurine, k
- urinary excretion clearance defined with respect to the renal concentration
- Cpss
- steady-state plasma concentration
- cMOAT
- canalicular multispecific organic anion transporter
- EHBR
- Eisai hyperbilirubinemic rat
- SDR
- Sprague-Dawley rat
- DHFR
- dihydrofolate reductase
- Kp, liver
- liver-to-plasma concentration ratio
- Kp, kidney
- kidney-to-plasma concentration ratio
- fh
- unbound fractions in the liver
- fk
- unbound fractions in the kidney
- Received February 23, 1999.
- Accepted June 24, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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