Back to Search
Start Over
Atypical Kinetics and Albumin Effect of Glucuronidation of 5-n-Butyl-4-{4-[2-(1H-tetrazole-5- yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6- dichlorophenyl)-3H-1,2,4-triazol-3-one, a Novel Nonpeptide Angiotensin Type 1 Receptor Antagonist, in Liver Microsomes and UDP-Glucuronosyl-transferase.
- Source :
-
Molecules (Basel, Switzerland) [Molecules] 2018 Mar 19; Vol. 23 (3). Date of Electronic Publication: 2018 Mar 19. - Publication Year :
- 2018
-
Abstract
- Ib is a new nonpeptide AT1 receptor antagonist, which plays an active role in cardiovascular protection. Ib monoglucuronide has been identified as its main metabolite. A detailed study of Ib glucuronidation is important for predicting potential DDI. Besides, the elucidation of the "BSA effect" in Ib glucuronidation would make obtained kinetic parameters more predictive in IVIVE. "BSA effect" means that there is a significant change in in vitro kinetic parameters when generated from incubations performed in the presence of bovine serum albumin (BSA). Five UGTs (UGT1A3, UGT2B4, UGT2B7, UGT1A9 and UGT1A8) were identified that produced abundant Ib monoglucuronide, especially UGT1A3. We investigated Ib glucuronidation in liver microsomes from different species (rat, dog, human) and in five identified major human UGTs. Ib glucuronidation in liver microsomes and recombinant human UGTs all showed substrate inhibition kinetics. DLM showed the strongest affinity and activity, HLM showed the lowest affinity, and RLM showed the weakest activity. The addition of BSA did not alter the enzyme kinetics, but significantly altered enzyme kinetic parameters resulting in a reduction in K <subscript>m</subscript> value and an increase in CL <subscript>int</subscript> value. However, high concentrations of BSA could significantly attenuate this positive effect on enzyme affinity and activity, and the effect of BSA on the V <subscript>max</subscript> of Ib glucuronidation was opposite in different enzyme sources. In conclusion, this study demonstrated the substrate inhibition kinetics of Ib glucuronidation in the liver metabolism and the effect of BSA on its kinetic parameters, in order to provide more accurate in vitro data for in vivo prediction.<br />Competing Interests: The authors declare that they have no conflict of interest.
- Subjects :
- Adult
Aged
Aged, 80 and over
Angiotensin II Type 1 Receptor Blockers chemistry
Animals
Humans
Isoenzymes metabolism
Kinetics
Metabolome drug effects
Microsomes, Liver drug effects
Middle Aged
Pyrroles chemistry
Recombinant Proteins metabolism
Triazoles chemistry
Angiotensin II Type 1 Receptor Blockers pharmacology
Glucuronides metabolism
Glucuronosyltransferase metabolism
Microsomes, Liver metabolism
Pyrroles pharmacology
Receptor, Angiotensin, Type 1 metabolism
Serum Albumin, Bovine metabolism
Triazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1420-3049
- Volume :
- 23
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecules (Basel, Switzerland)
- Publication Type :
- Academic Journal
- Accession number :
- 29562678
- Full Text :
- https://doi.org/10.3390/molecules23030688