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P-Glycoprotein-Mediated Drug Secretion in Mouse Proximal Tubule Perfused In Vitro

SHUICHI TSURUOKA^*, KOH-ICHI SUGIMOTO^*, AKIO FUJIMURA^*, MASASHI IMAI, YASUSHI ASANO and SHIGEAKI MUTO

^* Department of Clinical Pharmacology, Jichi Medical School, Minamikawachi, Tochigi, Japan.
Department of Pharmacology, Jichi Medical School, Minamikawachi, Tochigi, Japan.
Department of Nephrology, Jichi Medical School, Minamikawachi, Tochigi, Japan.

Correspondence to Dr. Shigeaki Muto, Department of Nephrology, Jichi Medical School, Minamikawachi, Tochigi 329-0498, Japan. Phone: 81-285-58-7346; Fax: 81-285-44-4969; E-mail: smuto{at}jichi.ac.jp

Abstract

Abstract. To examine the functional significance of durg-transporting P-glycoprotein (P-gp), studies were conducted in the isolated and perfused proximal tubule S2 segment from mice disrupting both mdr1a and mdr1b genes [mdr1a/1b(—)(—)] and their wild-type mice. Efflux of the intracellular fluorescence of rhodamine 123, a fluorescence substrate of P-gp, into the lumen was measured, and the decay half-time of the intracellular fluorescence (T_1/2) as an index of the drug-transporting P-gp activity was regarded. In the wild-type mice, the T_1/2 was 34 ± 4 s (n = 36) at the basal period and was increased to 434 ± 41 s by the addition of luminal verapamil, a P-gp inhibitor. In the mdr1a/1b(—)(—) mice, the T_1/2 was 407 ± 16 s (n = 10) at the basal period and was no longer affected by the luminal addition of verapamil. The digoxin content in the kidney after a repeated administration of the drug was markedly elevated in the mdr1a/1b(—)(—) mice. In conclusion, P-gp—mediated drug efflux capacity indeed exists in the apical membrane of proximal tubule cells from the wild-type mice, whereas it is absent in that of the mdr1a/1b(—)(—) mice.

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