Kinetic analysis of hepatobiliary transport of vincristine in perfused rat liver: Possible roles of P-glycoprotein in biliary excretion of vincristine

doi:10.1016/S0168-8278(05)80098-4

Journal of Hepatology

Volume 16, Issues 1–2, 1992, Pages 77-88

https://doi.org/10.1016/S0168-8278(05)80098-4 Get rights and content

Recent studies using bile canalicular membrane vesicles have suggested that P-glycoprotein may play a role in excreting some anticancer drugs from the liver to the bile. At steady state after a continuous single-pass perfusion of a tracer concentration of [³H]vincristine in the rat liver, the extraction ratio was approximately 0.6, and 70% of the extracted drug was excreted into the bile mostly in unchanged form. The liver/perfusate and bile/liver unbound concentration ratios obtained after correction for intracellular binding and the inside-negative membrane potentials and/or pH difference between the inside and outside of the cells, were approximately 2–3 and 160–280, respectively, suggesting a highly concentrated biliary excretion process. We also examined the effects of verapamil, a P-glycoprotein-related transport inhibitor in cancer cells, on the hepatobiliary transport of [³H]vincristine. Verapamil 50 μM in the perfusate caused a decrease in the biliary excretion rate of [³H]vincristine, whereas [¹⁴C]taurocholate (reference compound) remained constant. In contrast, the hepatic uptake rate of [³H]vincristine exhibited minimum reduction, suggesting that verapamil selectively inhibited the biliary excretion of [³H]vincristine at the canalicular membrane. The fact that verapamil had little effect on the initial velocity of [³H]vincristine uptake by isolated hepatocytes also supports the above findings. Since the effect of 150 μM verapamil in the perfusate was not selective for vincristine, the biliary excretion rates of both compounds ([³H]vincristine, [¹⁴C]taurocholate) were reduced by this concentration of verapamil. In conclusion, the concentrative excretion of vincristine into the bile and its selective inhibition by a moderate concentration of verapamil provide indirect evidence for the contribution of P-glycoprotein to the biliary excretion of vincristine in a perfused rat liver system.

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The multi drug resistance (MDR-1 or ABCB1) gene is also involved in the pharmacokinetics of VCR. Upregulation of the MDR-1 gene encoding for P-glycoprotein (P-gp), an efflux pump, results in a decrease in intracellular concentration of VCR and an increase in biliary clearance [14,15]. So far, at least 29 single nucleotide polymorphisms (SNPs) have been described of the MDR-1 gene.
Impaired motor performance in children who completed treatment for acute lymphoblastic leukemia (ALL) may be related to polymorphisms of the metabolising gene CYP3A5 or vincristine toxicity related genes MDR-1 and MAPT.
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The active multidrug transporter P–glycoprotein (Pgp) influences the pharmacokinetics of drugs at several sites in the body due to its presence in various epithelial and endothelial tissues. As a consequence, the oral bioavailabiliy of drugs may be limited by Pgp, whereas excretion may be increased and distribution changed. The role of Pgp is especially clear at the level of the blood–brain barrier, where it prevents Pgp substrates from entering the brain. Numerous studies have been performed to clarify the role of Pgp in the body, but also to influence its function and thereby alter the distribution kinetics of drugs. This also has implications for the intensity of drug effects of various classes of drugs in the brain, such as centrally acting agents, anticancer drugs, and HIV protease inhibitors. Furthermore, it is highly conceivable that a genetically determined polymorphism(s) of Pgp expression exists and that Pgp expression itself can be induced by drugs or environmental conditions. This may lead to substantial intra– and interindividual differences in the disposition of drugs. The pharmacokinetics of drugs may also be altered by Pgp due to its role in modulating the expression of cytochrome P450 3A4 (CYP 3A4). This complicates prediction of the interaction of drugs that are Pgp substrate and are metabolized by CYP 3A4. The reason why Pgp transports such a substantial number of different drugs is, however, still unclear; it seems that Pgp is a complex regulated system with various binding sites.

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¹: Present address: Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Hongo, Bunkyou-ku, Tokyo 113, Japan.

²: Present address: College of Pharmacy, Nihon University, Narashinodai, Funabashi City 274, Japan.

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Regular PaperKinetic analysis of hepatobiliary transport of vincristine in perfused rat liver: Possible roles of P-glycoprotein in biliary excretion of vincristine

Adv Cancer Res

Biochim Biophys Acta

J Biol Chem

J Biol Chem

J Biol Chem

Anal Biochem

Anal Biochem

Biochem. Pharmacol.

J Pharm Sci

J Pharm Sci

Biochem Biophys Res Commun

Biochem Pharmacol

Mechanisms of multidrug resistance and implications for therapy

Jpn J Cancer Res (Gann)

Isolation and expression of a complementary DNA that confers multidrug resistance

Nature

ATP-dependent transport of vinblastine in vesicles from human multidrug-resistant cells

Saturable process involved in active efflux of vincristine as a mechanism of multidrug resistance in P388 leukemia cells

Pharm Res

Kinetic analysis of active efflux of vincristine from multidrug-resistant P388 leukemia cells

Jpn J Cancer Res (Gann)

Membrane vesicles from multidrug-resistant human cancer cells contain a specific 150- to 170-kDa protein detected by photoaffinity labeling

Expression of a multidrug-resistance gene in human tumors and tissues

Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues

Regular Paper
Kinetic analysis of hepatobiliary transport of vincristine in perfused rat liver: Possible roles of P-glycoprotein in biliary excretion of vincristine