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Pharmacology. 2007;79(2):97-103. Epub 2006 Dec 12.

Effects of combined UDP-glucuronosyltransferase (UGT) 1A1*28 and 1A6*2 on paracetamol pharmacokinetics in beta-thalassemia/HbE.

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Department of Pharmacology, Pramongkutklao College of Medicine, Mahidol University, Bangkok, Thailand.


In addition to pathophysiological changes, genetic variations can alter drug pharmacokinetics in patients with thalassemia. Numerous drugs are metabolized by UDP-glucuronosyltransferases (UGT) including paracetamol (PCM), a widely used analgesic. Co-occurrence of the UGT1A1 polymorphism (UGT1A1*28) and the UGT1A6 polymorphism (UGT1A6*2) may affect PCM glucuronidation. To elucidate the effect of these combined polymorphisms on the PCM metabolism in thalassemic patients, 15 beta-thalassemia/hemoglobin E subjects with three different UGT1A genotypes received a single oral dose of 1,000 mg PCM. Drug disposition was determined by HPLC. Patients who have UGT1A6*2 without UGT1A1*28 showed a significant, lower area under concentration-time curve (AUC(0)-->infinity) of PCM, PCM-glucuronide and PCM-sulfate than those of the patients with wild-type UGT1A1 and UGT1A6 (p < 0.05). In addition, a high elimination rate constant and clearance of PCM and its metabolites were also found in these patients (p < 0.05). Ourstudy suggests that a subtherapeutic level of PCM may occur in patients who have UGT1A6*2 without UGT1A1*28.

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