title: Stereoselective metabolism of propranolol glucuronidation by human UDP-glucuronosyltransferases 2B7 and 1A9.
abstract: Stereoselective metabolism of propranolol side-chain glucuronidation was studied for two recombinant human uridine diphosphate glucuronosyltransferases (UGTs), UGT1A9 and UGT2B7. The S- and R-propranolol side-chain glucuronides produced in the incubation mixtures were assayed simultaneously by RP-HPLC with fluorescent detector. The excitation and emission wavelengths were set at 310 nm and 339 nm, respectively. UGT1A9 prefers catalyzing S-enantiomer to R-enantiomer and the intrinsic clearance (CL(int)) ratios of S-enantiomer to R-enantiomer are 3.8 times and 6.5 times for racemic propranolol and individual enantiomers, respectively. UGT2B7, however, catalyzes slightly less S-enantiomer than R-enantiomer and the CL(int) ratio of S-enantiomer to R-enantiomer is 0.8 times. The high concentration of racemic propranolol (>0.57 mmol/l) and individual enantiomers (>0.69 mmol/l) exhibited substrate inhibition of glucuronidation for UGT2B7, but only the S-enantiomer (>0.44 mmol/l) in racemic propranolol exhibited substrate inhibition for UGT1A9. The substrate inhibition constants (K(si)) were all similar (P > 0.05). Drug-drug interactions were also found between S- and R-enantiomer glucuronidation metabolisms by UGT1A9 and UGT2B7.
authors: Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors: Lushan
authors: L
authors: Yu
authors: Minrong
authors: M
authors: Qian
authors: Yao
authors: Y
authors: Liu
authors: Tongwei
authors: T
authors: Yao
authors: Su
authors: S
authors: Zeng
mesh_terms: D000818:Animals; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes / Q000737:chemistry; D014453:Glucuronosyltransferase / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D011433:Propranolol / Q000737:chemistry; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D013237:Stereoisomerism; D013379:Substrate Specificity; D013997:Time Factors; D000090264:UDP-Glucuronosyltransferase 1A9
chemical_list: D005456:Fluorescent Dyes; D011994:Recombinant Proteins; C000715591:UGT1A9 protein, human; D011433:Propranolol; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9