In vitro modulatory effects of ginsenoside compound K, 20(S)-protopanaxadiol, and 20(S)-protopanaxatriol on uridine 5'-diphospho-glucuronosyltransferase activity and expression.

We explored the inhibitory effect of ginsenoside compound K (CK), 20(S)-protopanaxadiol (PPD), and 20(S)-protopanaxatriol (PPT) on six UGT enzyme (UGT1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) activities in human liver microsomes (HLMs) and ten UGT enzyme (UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B10, 2B15, and 2B17) activities in recombinant UGT isoforms.PPD was a potent inhibitor of UGT1A3 activity with IC50 values of 5.62 and 3.38 μM in HLMs and recombinant UGT1A3, respectively. UGT1A3 inhibition by CK and PPD was competitive with Ki values of 17.4 and 1.21 μM, respectively, and inhibition by PPT was non-competitive with a Ki value of 8.07 μM in HLMs. PPD exhibited more than 3.4-fold selectivity for UGT1A3 inhibition compared to other UGT isoforms inhibition, while CK and PPT showed more than 2.16- and 2.21-fold selectivity, respectively.PPD did not significantly increase the mRNA expression of UGT1A1, 1A3, 1A4, 1A9, and 2B7 in hepatocytes.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 metabolized by UGT1A3.