Interactions of vinblastine and vincristine with methotrexate transport in isolated rat hepatocytes.
The accumulation of methotrexate (MTX) in the presence of vinblastine (VBL) and vincristine (VCR) was studied in isolated rat hepatocytes. In accordance with our recent study on vindesine (VDS), we found VBL and VCR to reduce net MTX accumulation significantly at 15 min after MTX addition. Drug concentrations of 100 microM VBL and 500 microM VCR led to 67% and 82% reductions in intracellular MTX, respectively. Since there was only a slight inhibition of MTX efflux by 100 microM VBL, the accumulation data demonstrate that the major effect of VBL is on MTX influx. Dixon-plot analyses are suggestive of competitive inhibition of the MTX influx, yielding inhibition constants (Ki values) of 55 microM for VBL and 110 microM for VCR. Since the Ki values correspond grossly to plasma levels obtained in humans shortly after the infusion of therapeutic doses of the vinca alkaloids studied herein, the interaction with MTX uptake could serve to diminish the toxicity of MTX to nonmalignant cells.
Department of Pharmacology, University of Tromsø, Norway.
E
E
Smeland
R M
RM
Bremnes
A
A
Bessesen
R
R
Jaeger
J
J
Aarbakke
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004347:Drug Interactions; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014747:Vinblastine / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology*
D014750:Vincristine; D014747:Vinblastine; D008727:Methotrexate