Contribution of UGT Enzymes to Human Drug Metabolism Stereoselectivity: A Case Study of Medetomidine, RO5263397, Propranolol, and Testosterone

Abstract

The enantiomeric forms of chiral compounds have identical physical properties but may vary greatly in their metabolism by individual enzymes. Enantioselectivity in UDP-glucuronosyl transferase (UGT) metabolism has been reported for a number of compounds and with different UGT isoforms involved. However, the impact of such individual enzyme results on overall clearance stereoselectivity is often not clear. The enantiomers of medetomidine, RO5263397, and propranolol and the epimers testosterone and epitestosterone exhibit more than 10-fold difference in glucuronidation rates by individual UGT enzymes. In this study we examined the translation of human UGT stereoselectivity to hepatic drug clearance considering the combination of multiple UGTs to overall glucuronidation, the contribution of other metabolic enzymes such as cytochromes P450, and the potential for differences in protein binding and blood/plasma partitioning. For medetomidine and RO5263397, the high individual enzyme (UGT2B10) enantioselectivity translated into ~3-to >10-fold differences in predicted human hepatic in vivo clearance. For propranolol the UGT enantioselectivity was irrelevant in the context of high cytochrome P450 (CYP) metabolism. For testosterone a complex picture emerged, due to differential epimeric selectivity of various contributing enzymes and potential for extrahepatic metabolism. Quite different patterns of CYP and UGT-mediated metabolism were observed across species, as well as differences in stereoselectivity, indicating that extrapolation from human enzyme and tissue data is essential when predicting human clearance enantioselectivity.

Disposition of Hexahydrocannabinol Epimers and Their Metabolites in Biological Matrices following a Single Administration of Smoked Hexahydrocannabinol: A Preliminary Study

“…Differences in the disposition of the investigated epimers were also observed in urine, where the excreted amount of 9(S)-HHC in 6 h was almost double than that of 9(R)-HHC, although the administered dose was the same. A stereoselective mechanism of elimination may be hypothesized due to the stereoselectivity of glucuronidation, as already described for a number of other drugs [ 15 , 16 ].…”

Chemo- and enantioselective intramolecular silver-catalyzed aziridinations of carbamimidates

“…The 5-member dihydrooxazol-2-amine and 6-member 1,3-oxazin-2-amine products using carbamimidates in asymmetric aziridination and ring-opening are found in several compounds with useful bioactivities. 16–19…”

“…The Tces group was not removed directly from 2f due to lability of the aziridine, but is cleaved with mild reductive conditions. 23…”

“…The 5-member dihydrooxazol-2-amine and 6-member 1,3oxazin-2-amine products using carbamimidates in asymmetric aziridination and ring-opening are found in several compounds with useful bioactivities. [16][17][18][19] There is only one example of a NT using a carbamimidate, where Dauban reported Rh-catalyzed intramolecular C-H aminations to give racemic amines. 20 Prompted by promising bioactivities of cyclic carbamimidates, we aimed to develop an asymmetric silver-catalyzed aziridination of homoallylic carbamimidates, where matching the steric bulk from the imine N-protecting group with the chiral ligand would furnish high chemo-and enantioselectivity.…”

“…The Tces group was not removed directly from 2f due to lability of the aziridine, but is cleaved with mild reductive conditions. 23 The carbamimidate is key to the high ee of this system compared to conventional sulfamates and carbamates. Density functional theory (DFT) calculations were conducted to investigate the origin of ee and the effects of ligand (Fig.…”