The Disposition of Oxymatrine in the Vascularly Perfused Rat Intestine-Liver Preparation and Its Metabolism in Rat Liver Microsomes

Huang, Li; Zhong, Yun Ming; Xiong, Xianqing; Cen, Mei Feng; Cheng, Xuan; Wang, Gui Xiang; Chen, Ji Sheng; Wang, Su Jun

doi:10.1016/j.xphs.2015.11.012

Cited by 11 publications

(5 citation statements)

References 21 publications

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“…2a), indicating that these circulating compounds are worth special consideration in the pharmacological research. Besides, the abundant exposure of A1 may be attributed the metabolism of A3 by CYP3As [29]. In addition, the considerable systemic exposure for A3, A1, D3, D2 and D5, seemed to be correlated with the significantly longer t 1/2 values of 2.73-7.22 h than those of B2, C6 and C9 (1.07-1.64 h) (Table 1).…”

Section: Discussionmentioning

confidence: 93%

Multiple circulating alkaloids and saponins from intravenous Kang-Ai injection inhibit human cytochrome P450 and UDP-glucuronosyltransferase isozymes: potential drug–drug interactions

et al. 2020

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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 Cmax and t1/2 values of 0.17–422.70 μmol/L and 1.78–4.33 h, respectively. Additionally, 28 saponins exhibited considerable systemic exposure with t1/2 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 (PPT) type ginsenosides also involved in hepatobiliary and/or renal excretion. Protopanaxadiol (PPD) type ginsenosides were mainly excreted to urine. Furthermore, PPD-type ginsenosides were extensively bound (fu-plasma approximately 1%), whereas astragalosides and PPT-type ginsenosides displayed fu-plasma 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 IC50 values between 8.81 and 92.21 μM. Through kinetic modeling, their inhibition mechanisms towards those CYP and UGT isozymes were explored with obtained Ki values. In vitro-in vivo extrapolation showed the inhibition of systemic clearance for CYP or UGT substrates seemed impossible due to [I]/Ki 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.

show abstract

Section: Discussionmentioning

confidence: 93%

Multiple circulating alkaloids and saponins from intravenous Kang-Ai injection inhibit human cytochrome P450 and UDP-glucuronosyltransferase isozymes: potential drug–drug interactions

et al. 2020

View full text Add to dashboard Cite

show abstract

“…2A), indicating that these circulating compounds are worth special consideration in the pharmacological research. Besides, the abundant exposure of A1 may be attributed the metabolism of A3 by CYP3As [29]. In addition, the considerable systemic exposure for A3, A1, D3, D2 and D5, seemed to be correlated with the significantly longer t 1/2 values of 2.73-7.22 hour than those of B2, C6 and C9 (1.07-1.64 hour) (Table 1).…”

Section: Discussionmentioning

confidence: 94%

Multiple circulating alkaloids and saponins from intravenous Kang-Ai injection inhibit human cytochromes P450 and UDP-glucuronosyltransferase isozymes: potential drug-drug interactions

Qin¹,

Jia

Yang

et al. 2020

Preprint

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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 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 Pharmacokinetics 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 Cmax and t1/2 values of 0.17–422.70 µmol/L and 1.78–4.33 h, respectively. Additionally, 28 saponins exhibited considerable systemic exposure with t1/2 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 PPT-type ginsenosides also involved in hepatobiliary and/or renal excretion. PPD-type ginsenosides were mainly excreted to urine. Furthermore, PPD-type ginsenosides were extensively bound (fu−plasma approximately 1%), whereas astragalosides and PPT-type ginsenosides displayed fu−plasma values of 12.35% and 60.23–87.36%, respectively. Moreover, matrine and oxymatrine both exhibited weak inhibition against CYP3A4 with IC50 values of 387.40 and 604.60 µM. Similar results were observed for astragaloside IV towards CYP2C9, ginsenoside Rg1 against UGT1A1, ginsenoside Re against CYP2C8, ginsenoside Rd against CYP2B6and CYP3A4, and ginsenoside Rc against UGT1A9 with IC50 values between 20.19 and 92.21 µM. Ginsenoside Rb1 showed moderate inhibitory effect against CYP2C9 (IC50 = 8.81 µM). Through kinetic modeling, their inhibition mechanisms towards those CYP and UGT isozymes were explored with obtained Ki values. In vitro-in vivo extrapolation ([I]/Ki = 1.15 for oxymatrine) showed the inhibition of systemic clearance for CYP3A4 substrates seemed more possible, while other major circulating compounds displayed negligible DDI risk due to [I]/Ki no more than 0.1. Conclusions These facts lead to better understanding of chemical basis responsible for therapeutic action of Kang-Ai injection, and facilitate to pay more attention on the DDI for informing its rational clinical use.

show abstract

“…2A), indicating that these circulating compounds are worth special consideration in the pharmacological research. Besides, the abundant exposure of A1 may be attributed the metabolism of A3 by CYP3As [29]. In addition, the considerable systemic exposure for A3, A1, D3, D2 and D5, seemed to be correlated with the signi cantly longer t 1/2 values of 2.73-7.22 hour than those of B2, C6 and C9 (1.07-1.64 hour) ( Table 1).…”

Section: Discussionmentioning

confidence: 94%

Multiple circulating alkaloids and saponins from intravenous Kang-Ai injection inhibit human cytochrome P450 and UDP-glucuronosyltransferase isozymes: potential drug-drug interactions

Qin¹,

Jia

Yang

et al. 2020

Preprint

View full text Add to dashboard Cite

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 Cmax and t1/2 values of 0.17-422.70 μmol/L and 1.78-4.33 h, respectively. Additionally, 28 saponins exhibited considerable systemic exposure with t1/2 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 (PPT) type ginsenosides also involved in hepatobiliary and/or renal excretion. Protopanaxadiol (PPD) type ginsenosides were mainly excreted to urine. Furthermore, PPD-type ginsenosides were extensively bound (fu-plasma approximately 1%), whereas astragalosides and PPT-type ginsenosides displayed fu-plasma 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 IC50 values between 8.81 and 92.21 μM. Through kinetic modeling, their inhibition mechanisms towards those CYP and UGT isozymes were explored with obtained Ki values. In vitro-in vivo extrapolation showed the inhibition of systemic clearance for CYP or UGT substrates seemed impossible due to [I]/Ki 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.

show abstract

The Disposition of Oxymatrine in the Vascularly Perfused Rat Intestine-Liver Preparation and Its Metabolism in Rat Liver Microsomes

Cited by 11 publications

References 21 publications

Multiple circulating alkaloids and saponins from intravenous Kang-Ai injection inhibit human cytochrome P450 and UDP-glucuronosyltransferase isozymes: potential drug–drug interactions

Multiple circulating alkaloids and saponins from intravenous Kang-Ai injection inhibit human cytochrome P450 and UDP-glucuronosyltransferase isozymes: potential drug–drug interactions

Multiple circulating alkaloids and saponins from intravenous Kang-Ai injection inhibit human cytochromes P450 and UDP-glucuronosyltransferase isozymes: potential drug-drug interactions

Multiple circulating alkaloids and saponins from intravenous Kang-Ai injection inhibit human cytochrome P450 and UDP-glucuronosyltransferase isozymes: potential drug-drug interactions

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