title: Effects of combined UDP-glucuronosyltransferase (UGT) 1A1*28 and 1A6*2 on paracetamol pharmacokinetics in beta-thalassemia/HbE.
abstract: 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.
authors.affiliation: Department of Pharmacology, Pramongkutklao College of Medicine, Mahidol University, Bangkok, Thailand. scnpm@mahidol.ac.th
authors.forename: Jeeranut
authors.initials: J
authors.lastname: Tankanitlert
authors.forename: Noppawan Phumala
authors.initials: NP
authors.lastname: Morales
authors.forename: Thad A
authors.initials: TA
authors.lastname: Howard
authors.forename: Pranee
authors.initials: P
authors.lastname: Fucharoen
authors.forename: Russell E
authors.initials: RE
authors.lastname: Ware
authors.forename: Suthat
authors.initials: S
authors.lastname: Fucharoen
authors.forename: Udom
authors.initials: U
authors.lastname: Chantharaksri
mesh_terms: D000082:Acetaminophen / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D000328:Adult; D000700:Analgesics / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D044466:Asian People; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006207:Half-Life; D006446:Hemoglobin E / Q000235:genetics; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017086:beta-Thalassemia / Q000201:enzymology / Q000378:metabolism*
chemical_list: D000700:Analgesics; D000082:Acetaminophen; C037386:acetaminophen glucuronide; D006446:Hemoglobin E; C110655:UDP-glucuronosyltransferase, UGT1A6; D014453:Glucuronosyltransferase; C045667:acetaminophen sulfate ester