title: Differential effects of targeted disruption of thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics.
abstract: The recessive deficiency in thiopurine methyltransferase (TPMT), caused by germ-line polymorphisms in TPMT, can cause severe toxicity after mercaptopurine. However, the significance of heterozygosity and the effect of the polymorphism on thioguanine or in the absence of thiopurines is not known. To address these issues, we created a murine knockout of Tpmt. Pharmacokinetic and pharmacodynamic studies of mercaptopurine and thioguanine were done in Tpmt(-/-), Tpmt(+/-), and Tpmt(+/+) mice and variables were compared among genotypes. Methylated thiopurine and thioguanine nucleotide metabolites differed among genotypes after treatment with mercaptopurine (P < 0.0001 and P = 0.044, respectively) and thioguanine (P = 0.011 and P = 0.002, respectively). Differences in toxicity among genotypes were more pronounced following treatment with 10 daily doses of mercaptopurine at 100 mg/kg/d (0%, 68%, and 100% 50-day survival; P = 0.0003) than with thioguanine at 5 mg/kg/d (0%, 33%, and 50% 15-day survival; P = 0.07) in the Tpmt(-/-), Tpmt(+/-), and Tpmt(+/+) genotypes, respectively. Myelosuppression and weight loss exhibited a haploinsufficient phenotype after mercaptopurine, whereas haploinsufficiency was less prominent with thioguanine. In the absence of drug challenge, there was no apparent phenotype. The murine model recapitulates many clinical features of the human polymorphism; indicates that mercaptopurine is more affected by the TPMT polymorphism than thioguanine; and provides a preclinical system for establishing safer regimens of genetically influenced antileukemic drug therapy.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, University of Tennessee, Memphis, Tennessee, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Hartford
authors.forename: Erick
authors.initials: E
authors.lastname: Vasquez
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Edick
authors.forename: Jerold E
authors.initials: JE
authors.lastname: Rehg
authors.forename: Gerard
authors.initials: G
authors.lastname: Grosveld
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000818:Animals; D002648:Child; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D006801:Humans; D008297:Male; D015122:Mercaptopurine / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D008780:Methyltransferases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011110:Polymorphism, Genetic; D011687:Purines / Q000378:metabolism; D013866:Thioguanine / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D011687:Purines; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine