The major effective components in Shengmai Formula interact with sodium taurocholate co-transporting polypeptide

Zhan, Tao; Yao, Na; Wu, Lingna; Lu, Yanli; Liu, Mingyi; Liu, Fanglan; Xiong, Yan; Xia, Chunhua

doi:10.1016/j.phymed.2019.152916

Cited by 15 publications

(5 citation statements)

References 27 publications

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“…Recently, several scholars got the fact that B2 could induce the upregulation of P-gp and BCRP, and might be a potential substrate of P-gp [45]. For ginsenosides, ginsenoside Rg1 (C6) was potential inhibitor of NTCP (IC 50 = 50.49 μM), whereas ginsenoside Re (C9) was potential substrates of NTCP [46]. Further, DDI between ginsenosides Rb1 (D5), Rc (D3), Rd (D2) and methotrexate (a probe substrate for Mrp2) might occur owing to the decrease in the mRNA and protein levels of Mrp2 [47].…”

Section: Discussionmentioning

confidence: 99%

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.

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Section: Discussionmentioning

confidence: 99%

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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show abstract

“…Recently, several scholars got the fact that B2 could induce the upregulation of P-gp and BCRP, and might be a potential substrate of P-gp [43]. For ginsenosides, ginsenoside Rg1 (C6) was potential inhibitor of NTCP (IC 50 = 50.49 µM), whereas ginsenoside Re (C9) was potential substrates of NTCP [44]. Further, DDI between ginsenosides Rb1 (D5), Rc (D3), Rd (D2) and methotrexate (a probe substrate for Mrp2) might occur owing to the decrease in the mRNA and protein levels of Mrp2 [45].…”

Section: Discussionmentioning

confidence: 99%

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.

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“…The ginsenoside Rg 1 , ophiopogon D', and schisandrin A are potential inhibitors of sodium taurocholate co-transporting polypeptide (NTCP) and probably interact with NTCP-modulating clinical drugs. The ginsenoside Re and schisandrin B are potential NTCP substrates, and their NTCP-mediated uptake could be inhibited by other ingredients in SMF [100]. The ginsenosides Rb 2 , Rc, Rg 2 , Rg 3 , Rd, and Rb 1 are P-gp substrates, and Schisandra Lignans extract (SLE) was found to significantly enhance the uptake and inhibit the efflux ratio of the ginsenosides Rb 2 , Rc, Rg 2 , Rg 3 , Rd, and Rb 1 in Caco-2 and L-MDR1 cells.…”

Section: Shengmai Formulamentioning

confidence: 99%

Research Progress in Chinese Herbal Medicines for Treatment of Sepsis: Pharmacological Action, Phytochemistry, and Pharmacokinetics

Cheng

2021

IJMS

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Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection; the pathophysiology of sepsis is complex. The incidence of sepsis is steadily increasing, with worldwide mortality ranging between 30% and 50%. Current treatment approaches mainly rely on the timely and appropriate administration of antimicrobials and supportive therapies, but the search for pharmacotherapies modulating the host response has been unsuccessful. Chinese herbal medicines, i.e., Chinese patent medicines, Chinese herbal prescriptions, and single Chinese herbs, play an important role in the treatment of sepsis through multicomponent, multipathway, and multitargeting abilities and have been officially recommended for the management of COVID-19. Chinese herbal medicines have therapeutic actions promising for the treatment of sepsis; basic scientific research on these medicines is increasing. However, the material bases of most Chinese herbal medicines and their underlying mechanisms of action have not yet been fully elucidated. This review summarizes the current studies of Chinese herbal medicines used for the treatment of sepsis in terms of clinical efficacy and safety, pharmacological activity, phytochemistry, bioactive constituents, mechanisms of action, and pharmacokinetics, to provide an important foundation for clarifying the pathogenesis of sepsis and developing novel antisepsis drugs based on Chinese herbal medicines.

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The major effective components in Shengmai Formula interact with sodium taurocholate co-transporting polypeptide

Cited by 15 publications

References 27 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

Research Progress in Chinese Herbal Medicines for Treatment of Sepsis: Pharmacological Action, Phytochemistry, and Pharmacokinetics

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