Multiple Circulating Alkaloids and Saponins from Intravenous Kang-Ai Injection Inhibit Human Cytochrome P450 and UDP-glucuronosyltransferase Isozymes: Potential Drug-drug Interactions

Background: Kang-Ai injection is widely used as an adjuvant therapy drug for many cancers, leukopenia, and chronic hepatitis B. Circulating alkaloids and saponins are believed to be responsible for therapeutic effects. However, their pharmacokinetics (PK) and excretion in vivo and the risk of drug-drug interactions (DDI) through inhibiting human cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes remain unclear.

Methods: PK and excretion of circulating compounds were investigated in rats using a validated ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS) method. Further, the inhibitory effects of nine major compounds against eleven CYP and UGT isozymes were assayed using well-accepted specific substrate for each enzyme.

Results: After dosing, 9 alkaloids were found with and values of 0.17-422.70 μmol/L and 1.78-4.33 h, respectively. Additionally, 28 saponins exhibited considerable systemic exposure with values of 0.63-7.22 h, whereas other trace saponins could be negligible or undetected. Besides, over 90% of alkaloids were excreted through hepatobiliary and renal excretion. Likewise, astragalosides and protopanaxatriol () ginsenosides also involved in hepatobiliary and/or renal excretion. Protopanaxadiol () ginsenosides were mainly excreted to urine. Furthermore, - ginsenosides were extensively bound ( approximately 1%), whereas astragalosides and - ginsenosides displayed values of 12.35% and 60.23-87.36%, respectively. Moreover, matrine, oxymatrine, astragaloside IV, ginsenoside Rg1, ginsenoside Re, ginsenoside Rd, ginsenoside Rc, and ginsenoside Rb1 exhibited no inhibition or weak inhibition against several common CYP and UGT enzymes IC values between 8.81 and 92.21 μM. Through kinetic modeling, their inhibition mechanisms towards those CYP and UGT isozymes were explored with obtained K values. In vitro-in vivo extrapolation showed the inhibition of systemic clearance for CYP or UGT substrates seemed impossible due to [I]/K no more than 0.1.

Conclusions: We summarized the PK behaviors, excretion characteristics and protein binding rates of circulating alkaloids, astragalosides and ginsenosides after intravenous Kang-Ai injection. Furthermore, weak inhibition or no inhibition towards these CYP and UGT activities could not trigger harmful DDI when Kang-Ai injection is co-administered with clinical drugs primarily cleared by these CYP or UGT isozymes.