WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The pharmacogenetic polymorphisms of both TPMT and ITPA are associated with individual variability in 6-mercaptopurine (6-MP) intracellular metabolism.• The balance between red blood cell (RBC) 6-thioguanine nucleotide (6TGN) and 6-methylated metabolite (6-MMPN) concentrations has an important impact on efficacy in children treated for acute lymphoblastic leukemia.• Hepatotoxicity is a frequent complication of the association 6-MP and methotrexate during maintenance therapy. WHAT THIS STUDY ADDS• RBC 6-TGN concentrations are dependant on TPMT genotype and age, while RBC 6-MMPN concentrations depend on TPMT and ITPA polymorphisms. • Children aged 6 years or less had lower RBC 6-TGN concentrations during maintenance therapy, demonstrating an age effect on 6-MP intracellular metabolism.• Hepatotoxicity is a frequent complication of the association of 6-MP and methotrexate. A 6-MMPN threshold of 5000 pmol/8 ¥ 10 8 RBC was associated with an increased risk of hepatotoxicity. AIMS6-mercaptopurine (6-MP) is used in the treatment of childhood acute lymphoblastic leukaemia (ALL). Its red blood cell (RBC) metabolite concentrations (6-thioguanine [6-TGN] and 6-methylmercaptopurine nucleotides ) are related to drug response. We investigated the impact of non-genetic covariates and pharmacogenetic polymorphisms affecting thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) on 6-MP metabolism and response. METHODSSixty-six children with ALL treated according to EORTC 58951 protocol were included in this study. Six patients had a heterozygous genotype for the most common TPMT polymorphisms, nine for ITPA 94 C > A and 17 for ITPA IVS2 + 21 A > C. 6-MP metabolites concentrations were analyzed by mixed model analysis. RESULTSDuring maintenance, steady-state RBC 6-TGN concentrations were lower in patients aged 6 years or younger ( CONCLUSIONIn this study, age and both TPMT and ITPA genotypes influenced 6-MP metabolism. High 6-MMPN was associated with hepatotoxicity. These pharmacological tools should be used to monitor ALL treatment in children.

The objective was to develop a population pharmacokinetic-pharmacogenetic model of mycophenolic acid following administration of mycophenolate mofetil (MMF) in de novo pediatric renal-transplant patients and identify factors that explain variability. The pharmacokinetic samples were collected from 89 de novo pediatric renal-transplant patients treated with MMF and studied during the first 60 postoperative days. All patients were genotyped for UGT1A8-A9, UGT2B7, and ABCC2. Population pharmacokinetic analysis was performed with the NONMEM and was validated using bootstrap visual predictive check. The pharmacokinetic data were best described by a 2-compartment model with Erlang distribution to describe the absorption phase. The covariate analysis identified body weight as an individual factor influencing central volume of distribution and concomitant immunosuppressive medication and identified body weight and UGT2B7 802C>T genotype as individual factors influencing apparent oral clearance (CL/F) of MMF. CL/F in cyclosporine-MMF-treated patients was 33% higher than in tacrolimus-MMF-treated patients. The CL/F was significantly lower in patients with UGT2B7 802 C/C genotype compared with patients with UGT2B7 802 C/T and 802T/T genotypes, and this effect was independent of concomitant immunosuppressive medication or body weight. The population pharmacokinetic-pharmacogenetic model of mycophenolic acid was validated. Body weight, concomitant medication, and UGT2B7 genotype contribute significantly to the interindividual variability of MMF disposition in pediatric renal-transplant patients.

Metabolising enzymes and transport proteins are largely expressed in human tissues. They have major impact on drug disposition and effects. We studied mRNA expression of phase I and II metabolising enzymes and transporters in fetal tissues at different development stages. Hepatic, duodenal, renal and neurological fetal tissues were studied at 15, 27 and 42 weeks gestation and mRNA expression of 84 enzymes and transporters was analysed by with the RT(2) Profiler PCR array system. There was wide variability in gene expression between different samples. Independently from age, the highest expression levels were observed in the liver and the lowest in the brain for the majority of genes tested. There was significant increase in gene expression with age in duodenal and hepatic tissues.

No abstract

Genotyping at diagnosis identifies patients with a homozygous mutant TPMT and may prevent severe and life-threatening toxicity. ALL treatment monitoring should preferentially be based on repeated determinations of intracellular active metabolites (6-TGN) and methylated metabolites.