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.