UGT1A1*28 associates with the increase of propranolol metabolism in beta-thalassemia/ Hb E

Jeeranut Tankanitlert1, Praveena Yamanont2, T Inthong4, Prapin Wirairat4, Sathat Fucharoen3, Noppawan Pumala Morales2. 1Phramongkutklao College of Medicine, Department of Pharmacology 10400, Thailand, 2Mahidol University,Faculty of Science, Department of Pharmacology 10400, Thailand, 3Mahidol University, Thalassemia Research Center, Institute of Molecular Bioscience and Technology, Thailand, 4Mahidol University, National Doping Control Centre 10400, Thailand

Beta-thalassemia/HbE is the most inherited blood disorder in Thailand. The patients usually die of cardiovascular disease resulting from iron accumulation. Chronic anemia in thalassemia usually increases the cardiac output especially when hemoglobin level <7 g/dl . Therefore hyperdynamic state presented in these patients increases tissue perfusion and may increase extraction ratio of the flow-limited drugs such as propranolol which is widely used for the treatment of cardiovascular diseases. The previous studies showed that hyperbilirubinemia in thalassemic patients associated with the polymorphism of UGT1A1 ( UGT1A1*28) which may lead to protein replacement of a drug with high protein binding like propranolol. To examine the effects of UGT1A1*28 on the pharmacokinetics of propranolol, nine thalassemic patients with different UGT1A1 genotypes gave their written informed consent before participating the study. The subjects received a single oral dose of 40 mg propranolol after overnight fasting. Blood samples were collected at different time points after dosing. Propranolol concentration was determined using HPLC method. Our results demonstrated that there was the increase of area under concentration time curve (AUC) in subjects with homozygous genetic variance ; 7/7 genotype (422.3±75.0 min.ng/mL) compared to those in wild-type subjects; 6/6 genotype (210.0± 58.4 min.ng/mL). There are significantly higher elimination rate constant in subjects with homozygous genetic variance than wild-type subjects (0.30±0.5 and 0.19± 0.006 h-1, respectively). Shorter half-life of propranolol was also observed in subjects with homozygous genetic variance (222.0±6.0 min) than those in wild–type subjects ( 138.0±24.0 min). The results of this study suggested that hyperbilirubinemia causing from UGT1A1*28 could increase the metabolism of propranolol. In addition pathological change in the patients may produce synergistic effect of UGT1A1*28. Therefore dosage regimen of propranolol may need to be adjusted in patient with thalassemia.