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Drug Metabolism and Bioanalysis Letters

Editor-in-Chief

ISSN (Print): 2949-6810
ISSN (Online): 2949-6829

Research Article

Effect of Saccharolactone on CYP-mediated Metabolism of Xenobiotics

Author(s): Dayanidhi Behera*, Pankaj Jain, Vishwanath Kurawattimath and Nagaraj Gowda

Volume 16, Issue 2, 2023

Published on: 07 September, 2023

Page: [121 - 132] Pages: 12

DOI: 10.2174/2949681016666230823094423

Price: $65

Abstract

Background: Saccharolactone is used as a β-glucuronidase inhibitor in in vitro microsomal and recombinant uridine diphosphoglucuronosyl transferases (rUGTs) incubations to enhance glucuronide pathway and, thereby, formation of glucuronide metabolites. We investigated its effect on CYP mediated metabolism of drugs (compound-174, phenacetin and quinidine) using human liver microsomes (HLM) supplemented with Phase-1 and Phase-2 co-factors.

Methods: Compounds were incubated in HLM supplemented with co-factors to assess Phase-1 (NADPH) and Phase-2 (NADPH, alamethicin, saccharolactone and UDPGA) metabolism. CYP phenotype assay for compound-174 was conducted in HLM (± 1-ABT) and human recombinant CYP isoforms. CYP inhibition profile of saccharolactone was also generated in HLM.

Results: The metabolism of compound-174, phenacetin and quinidine in HLM significantly decreased in reactions containing additional components like alamethicin, saccharolactone and UDPGA and indicated that the addition of saccharolactone inhibited the metabolism. Phenacetin and quinidine are known substrates of CYP1A2 and CYP3A4 isoforms. The metabolism of compound- 174 was significantly inhibited in the presence of 1-ABT in HLM, and CYP3A4 and CYP2C8 isoforms were found to be the predominant isoforms responsible for its metabolism. Further evaluation of CYP inhibition in HLM indicated saccharolactone to be a strong inhibitor of CYP1A2, 2D6, 3A4 and 2C8 isoforms with IC50 values of less than 4 mM.

Conclusion: The findings indicated that saccharolactone being a strong inhibitor of CYP1A2, 2D6, 3A4 and 2C8 isoforms (IC50 < 4 mM), resulted in significant inhibition of the metabolism of compound-174, phenacetin and quinidine in HLM and caution should be exercised in using it with proper titration of the concentrations.

Keywords: Cytochrome P450 (CYP), UDP-glucuronosyltransferases (UGT), metabolism, human liver microsomes, saccharolactone, β-glucuronidase, CYP inhibition.

Graphical Abstract
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