Induction of hepatic P-glycoprotein enhances biliary excretion of vincristine in rats.
To clarify the contribution of P-glycoprotein to the biliary excretion of vincristine in rats, the effects of induction of hepatic P-glycoprotein by a phenothiazine treatment on the biliary excretion of [3H]vincristine were investigated. Immunoblot analysis using C219, a monoclonal antibody to P-glycoprotein, demonstrated that the phenothiazine treatment increased the P-glycoprotein level in isolated bile canalicular membrane vesicles approximately 6.5-fold. Transport of [3H]vincristine to canalicular membrane vesicles from the phenothiazine-treated and control rats revealed ATP-dependency, with an overshoot that results from the consumption of medium ATP. The maximum ATP-dependent uptake was increased in canalicular membrane vesicles from the phenothiazine-treated rats approximately 2-fold compared to the control. The biliary excretion of [3H]vincristine was further studied using an indicator dilution method in a single-pass perfused liver. The ratios of the cumulative amount of [3H]vincristine excreted into the bile ot the amount of [3H]vincristine taken up by the liver at 15, 30 and 90 min were significantly increased in the phenothiazine-treated rats by 60, 45 and 25%, respectively, compared to the control rats. Furthermore, the corrected mean residence time of [3H]vincristine in hepatocytes in the phenothiazine-treated rats was reduced to 21 min from that in the control rats (30 min), supporting the contention that the induction of hepatic P-glycoprotein on the bile canalicular membrane function sas a transporter not only in the isolated membrane but also in the more physiological perfused liver system. One must be cautious in the interpretation of the data, however, since phenothiazine can induce other proteins which might affect the behavior of [3H]vincristine.
Watanabe
T
T
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Suzuki
H
H
Sawada
Y
Y
Naito
M
M
Tsuruo
T
T
Inaba
M
M
Hanano
M
M
Sugiyama
Y
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism*; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism*; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D010640:Phenothiazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014750:Vincristine / Q000493:pharmacokinetics*; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D010640:Phenothiazines; D014750:Vincristine; D005723:gamma-Glutamyltransferase; D000469:Alkaline Phosphatase; D017301:Ca(2+) Mg(2+)-ATPase; C031637:phenothiazine