Augmenting Clinical Interpretability of Thiopurine Methyltransferase Laboratory Evaluation

作者：Demlova Regina; Mrkvicova Martina; Sterba Jaroslav; Bernatikova Hana; Stary Jan; Sukova Martina; Mikuskova Alena; Chocholova Alica; Mladosievicova Beata; Soltysova Andrea; Behulova Darina; Pilatova Katerina; Zdrazilova Dubska Lenka; Valik Dalibor^*

来源：Oncology, 2014, 86(3): 152-158.

DOI：10.1159/000357407

• Acute lymphoblastic leukemia
• Compound heterozygote
• Genotype-phenotype correlation
• Rate-blanked pharmacophenotyping
• Thiopurine methyltransferase

Objective: Individuals with decreased thiopurine methyltransferase (TPMT) activity are at risk of adverse effects of thiopurine administration whereas its increased activity may inactivate drugs faster. We evaluated genotype-phenotype correlations in patients with suspected hematological malignancies and inflammatory bowel disease from our region based on findings of nonlinear TPMT enzyme kinetics previously unreported. Patients and Methods: The study group comprised 267 individuals. They were screened for the most common variants of low TPMT activity. TPMT activity was measured in erythrocytes using the HPLC rate-blanked method. Results: Thirty-three patients (12.4%) were heterozygous (26 were TPMT*13A, 5 TPMT*12, 2 TPMT*13C) and 1 was a compound heterozygote (*23A). Normal and low normal TPMT activities substantially overlapped in wildtype and heterozygous individuals, whereas high activities were found in 29 wild-type genotyped patients. Extreme and life-threatening toxicity was observed in the compound heterozygote patient. Conclusion: Activity measurement performed at diagnosis provides clinicians with information on immediate pharmacokinetic-related adverse events and/or hypermetabolism, and genotyping may indicate the rate of pharmacodynamic thioguanine nucleotide accumulation due to slower overall thiopurine metabolism.

• 出版日期2014