Abstract

1. We explored the inhibitory effect of ginsenoside compound K (CK), 20(S)-protopanaxadiol (PPD), and 20(S)-protopanaxatriol (PPT) on six uridine 5′-diphospho-glucuronosyltransferase (UGT) enzyme (UGT1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) activities in human liver microsomes (HLMs) and 10 UGT enzyme (UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B10, 2B15, and 2B17) activities in recombinant UGT isoforms.

2. PPD was a potent inhibitor of UGT1A3 activity with half-maximal inhibitory concentration values of 5.62 and 3.38 μM in HLMs and recombinant UGT1A3, respectively. UGT1A3 inhibition by CK and PPD was competitive with inhibitory constant (K_i) values of 17.4 and 1.21 μM, respectively, and inhibition by PPT was non-competitive with a K_i value of 8.07 μM in HLMs. PPD exhibited more than 3.4-fold selectivity for UGT1A3 inhibition compared with other UGT isoforms inhibition, while CK and PPT showed more than 2.16- and 2.21-fold selectivity, respectively.

3. PPD did not significantly increase the mRNA expression of UGT1A1, 1A3, 1A4, 1A9, and 2B7 in hepatocytes.

4. Given the low plasma concentrations of PPD in healthy human subjects and the absence of induction potential on UGT isoforms, we conclude that PPD cause no pharmacokinetic interactions with other co-administered drugs metabolised by UGT1A3.

摘要

1. 我们探讨了人参皂苷化合物 K (CK)、20( S )-原人参二醇 (PPD) 和 20( S )-原人参三醇 (PPT) 对六种尿苷 5'-二磷酸-葡萄糖醛酸转移酶 (UGT) 酶 (UGT1A1、1A3) 的抑制作用、1A4、1A6、1A9 和 2B7) 在人肝微粒体 (HLM) 中的活性和 10 UGT 酶（UGT1A1、1A3、1A4、1A6、1A9、2B4、2B7、2B10、2B15 和 2B17 同种型重组 UGT）活性

2. PPD 是一种有效的 UGT1A3 活性抑制剂，在 HLM 和重组 UGT1A3 中的半数最大抑制浓度值分别为 5.62 和 3.38 μM。CK 和 PPD 对 UGT1A3 的抑制与抑制常数 ( K _i ) 值分别为 17.4 和 1.21 μM 具有竞争性，PPT 的抑制是非竞争性的，HLM 中的K _i值为 8.07 μM。与其他 UGT 异构体抑制相比，PPD 对 UGT1A3 抑制的选择性超过 3.4 倍，而 CK 和 PPT 分别显示超过 2.16 和 2.21 倍的选择性。

3. PPD 未显着增加肝细胞中 UGT1A1、1A3、1A4、1A9 和 2B7 的 mRNA 表达。

4. 鉴于健康人类受试者中 PPD 的血浆浓度较低，并且不存在对 UGT 同种型的诱导潜力，我们得出结论，PPD 不会与由 UGT1A3 代谢的其他共同给药药物引起药代动力学相互作用。