title: Role of UDP-Glucuronosyltransferase 1A1 in the Metabolism and Pharmacokinetics of Silymarin Flavonolignans in Patients with HCV and NAFLD.
abstract: Silymarin is the most commonly used herbal medicine by patients with chronic liver disease. Silymarin flavonolignans undergo rapid first-pass metabolism primarily by glucuronidation. The aims of this investigation were: (1) to determine the association ofUGT1A1*28polymorphism with the area under the plasma concentration-time curves (AUCs) for silybin A (SA) and silybin B (SB); (2) to evaluate the effect ofUGT1A1*28polymorphism on the profile of flavonolignan glucuronide conjugates found in the plasma; and (3) to investigate the role of UGT1A1 enzyme kinetics on the pharmacokinetics of SA and SB. AUCs and metabolic ratios for thirty-three patients with chronic liver disease administered oral doses of silymarin were compared between differentUGT1A1*28genotypes. The AUCs, metabolic ratios, and the profiles of major SA and SB glucuronides did not differ significantly among the threeUGT1A1genotypes. In contrast, an increase in the proportion of sulfated flavonolignan conjugates in plasma was observed in subjects withUGT1A1*28/*28genotype compared to subjects carrying wild type alleles. Differences in SA and SBin vitrointrinsic clearance estimates for UGTIA1 correlated inversely with SA and SB exposures observedin vivoindicating a major role for UGT1A1 in silymarin metabolism. In addition, a significant difference in the metabolic ratio observed between patients with NAFLD and HCV suggests that any effect ofUGT1A1polymorphism may be obscured by a greater effect of liver disease on the pharmacokinetics of silymarin. Taken together, these results suggest the presence of theUGT1A1*28allele does not contribute significantly to a large inter-subject variability in the pharmacokinetics of silybin A and silybin B which may obscure the ability to detect beneficial effects of silymarin in patients with liver disease.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. yxie@must.edu.mo.|State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China. yxie@must.edu.mo.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. mirandasr@gmail.com.
authors.forename: Sonia R
authors.initials: SR
authors.lastname: Miranda
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. janelle.hoskins1@gmail.com.
authors.forename: Janelle M
authors.initials: JM
authors.lastname: Hoskins
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. rhawke@email.unc.edu.
authors.forename: Roy L
authors.initials: RL
authors.lastname: Hawke
mesh_terms: D000328:Adult; D000483:Alleles; D005260:Female; D044947:Flavonolignans / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006526:Hepatitis C / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D000071185:Pharmacogenomic Testing; D011110:Polymorphism, Genetic; D012838:Silymarin / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D000099148:UGT1A1 Enzyme
chemical_list: D044947:Flavonolignans; D014453:Glucuronosyltransferase; D012838:Silymarin; D000099148:UGT1A1 Enzyme
keywords: HCV; NAFLD; UGT1A1; liver disease; pharmacokinetics; polymorphism; silybin A; silymarin