UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia
| Autor: | Patricia Rae, J. B. Singer, Francis J. Giles, Margaret Dugan, J. M. Meyer, Yi-Hsiang Hsu, Oliver G. Ottmann, Yaping Shou, Aaron Weitzman, Hagop M. Kantarjian, A. S. Robeva |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Adult
Risk Cancer Research medicine.medical_specialty Glucuronosyltransferase Adolescent Genotype Bilirubin Pharmacology chemistry.chemical_compound Recurrence hemic and lymphatic diseases Internal medicine medicine Humans Genetic Predisposition to Disease Aged Hyperbilirubinemia Hematology Polymorphism Genetic biology Myeloid leukemia Imatinib Middle Aged Endocrinology Pyrimidines Oncology chemistry Nilotinib Drug Resistance Neoplasm biology.protein Pharmacogenetics medicine.drug |
| Zdroj: | Leukemia. 21(11) |
| ISSN: | 0887-6924 |
| Popis: | Nilotinib is a novel BCR-ABL inhibitor with significantly improved potency and selectivity over imatinib. In Phase I and Phase II clinical studies of nilotinib in patients with a variety of leukemias, infrequent instances of reversible, benign elevation of bilirubin were observed. Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) glucuronidates bilirubin in humans, and a polymorphism in the promoter of the gene that encodes it has been associated with hyperbilirubinemia during treatment with a number of drugs. Pharmacogenetic analysis of that TA-repeat polymorphism found an association between the (TA)7/(TA)7 genotype and risk of hyperbilirubinemia in Phase I patients with imatinib-resistant/intolerant chronic myeloid leukemia (CML) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL); this result was replicated in two separate analyses of the chronic phase (CP) and accelerated phase (AP) CML arms of a Phase II study. As nilotinib is not known to be glucuronidated by UGT1A1, the combined impact of inhibition of UGT1A1 activity by nilotinib and genetic polymorphism is the most likely cause of the increased rate of hyperbilirubinemia. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|