title: Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine and methotrexate.
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.
authors.affiliation: Institute of Medical Pharmacology, University of Pisa, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Innocenti
authors.forename: R
authors.initials: R
authors.lastname: Danesi
authors.forename: A
authors.initials: A
authors.lastname: Di Paolo
authors.forename: B
authors.initials: B
authors.lastname: Loru
authors.forename: C
authors.initials: C
authors.lastname: Favre
authors.forename: M
authors.initials: M
authors.lastname: Nardi
authors.forename: G
authors.initials: G
authors.lastname: Bocci
authors.forename: D
authors.initials: D
authors.lastname: Nardini
authors.forename: P
authors.initials: P
authors.lastname: Macchia
authors.forename: M
authors.initials: M
authors.lastname: Del Tacca
mesh_terms: D000293:Adolescent; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use; D001682:Biological Availability; D001711:Biotransformation; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D005260:Female; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008727:Methotrexate / Q000493:pharmacokinetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D008727:Methotrexate