Department of Drug Metabolism and Pharmacokinetics, Glenmark Pharmaceuticals Limited, Glenmark Research Centre, MIDC Mahape, Navi-Mumbai, Maharashtra, India.
Department of Biological Research, Glenmark Pharmaceuticals Limited, Glenmark Research Centre, MIDC Mahape, Navi-Mumbai, Maharashtra, India.
Drug Metab Bioanal Lett. 2023;16(2):121-132. doi: 10.2174/2949681016666230823094423.
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.
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.
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 IC values of less than 4 mM.
The findings indicated that saccharolactone being a strong inhibitor of CYP1A2, 2D6, 3A4 and 2C8 isoforms (IC < 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.
蔗糖内酯作为一种β-葡萄糖醛酸苷酶抑制剂，用于体外微粒体和重组尿苷二磷酸葡萄糖醛酸转移酶（rUGTs）孵育中，以增强葡萄糖醛酸途径，从而形成葡萄糖醛酸代谢物。我们研究了它对人肝微粒体（HLM）中添加了 1 期和 2 期共因子的药物（化合物-174、非那西汀和奎尼丁）CYP 介导代谢的影响。
在添加共因子的 HLM 中孵育化合物，以评估 1 期（NADPH）和 2 期（NADPH、拉米替丁、蔗糖内酯和 UDPGA）代谢。在 HLM（±1-ABT）和人重组 CYP 同工酶中进行化合物-174 的 CYP 表型测定。还在 HLM 中生成了蔗糖内酯的 CYP 抑制谱。
在含有拉米替丁、蔗糖内酯和 UDPGA 等额外成分的反应中，HLM 中化合物-174、非那西汀和奎尼丁的代谢显著减少，表明添加蔗糖内酯抑制了代谢。非那西汀和奎尼丁是 CYP1A2 和 CYP3A4 同工酶的已知底物。在 HLM 中存在 1-ABT 的情况下，化合物-174 的代谢显著受到抑制，并且发现 CYP3A4 和 CYP2C8 同工酶是其代谢的主要同工酶。进一步在 HLM 中评估 CYP 抑制作用表明，蔗糖内酯是 CYP1A2、2D6、3A4 和 2C8 同工酶的强抑制剂，IC 值小于 4mM。
研究结果表明，蔗糖内酯是 CYP1A2、2D6、3A4 和 2C8 同工酶（IC < 4mM）的强抑制剂，导致化合物-174、非那西汀和奎尼丁在 HLM 中的代谢显著抑制，因此在使用时应谨慎，并适当调整浓度。
