Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine and methotrexate

Cancer Chemotherapy and Pharmacology
F InnocentiM Del Tacca

Abstract

Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine (6-MP) and methotrexate (MTX) was investigated in patients as well as in rats and in HL-60 human leukemic cells. Ten children affected by acute lymphoblastic leukemia (ALL) in remission received daily doses of 6-MP given at 25 mg/m2 and i.v. infusion of high-dose MTX at 2 or 5 g/m2 once every other week. When 6-MP was given alone, the mean peak plasma concentration (Cmax) and area under the curve (AUC) of 6-MP were 72.5 ng/ml and 225.3 h ng ml(-1). Concurrent treatment with MTX at 2 or 5 g/m2 resulted in a mean increase of 108% and 121% in the Cmax and of 69% and 93% in the AUC, respectively. In rats treated with an oral dose of 6-MP at 75 mg/m2, MTX given i.p. at 5 g/m2 produced mean increases of 110% and 230% in the Cmax and AUC of 6-MP, respectively. In HL-60 human leukemic cells incubated with 6-MP at 250 ng/ml, the cumulative intracellular concentration of 6-thioguanine and 6-MP nucleotides was not significantly modified by treatment with 20 micrograms/ml of MTX. The present findings indicate that high-dose MTX enhances the bioavailability of 6-MP as evidenced by the observed increases in the plasma Cmax and AUC of 6-MP in humans and animals.

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Citations

Oct 16, 1999·General Pharmacology·T GiverhaugJ Aarbakke
Jul 15, 1998·British Journal of Clinical Pharmacology·H L McLeod
Oct 12, 2010·Drug Metabolism and Pharmacokinetics·Mutsumi KudoMasahiro Hiratsuka
Sep 4, 2010·Drug Metabolism and Pharmacokinetics·Mutsumi KudoMasahiro Hiratsuka
Mar 22, 2014·Journal of Pharmacokinetics and Pharmacodynamics·Kayode OgungbenroUNKNOWN CRESim & Epi-CRESim Project Groups
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Apr 4, 2017·Indian Journal of Dermatology, Venereology and Leprology·Puneet AgarwalPriyanka Sharma
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Feb 19, 2008·American Journal of Health-system Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists·Hamidreza Montazeri AliabadiAfsaneh Lavasanifar
Oct 26, 2018·Mathematical Medicine and Biology : a Journal of the IMA·Thuy T T LeSebastian Sager
Jan 4, 2021·International Journal of Hematology·Takaaki NakanoKunihiko Kobayashi

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