Inhibition of human UDP‐glucuronosyltransferase enzymes by midostaurin and ruxolitinib: implications for drug–drug interactions

2020 ◽  
Vol 41 (6) ◽  
pp. 231-238 ◽  
Author(s):  
Zhe Wang ◽  
Xiaoyu Wang ◽  
Yaqin Jia ◽  
Hang Yin ◽  
Yuyi Feng ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Udp Glucuronosyltransferase

Piceatannol exhibits potential food-drug interactions through the inhibition of human UDP-glucuronosyltransferase (UGT) in Vitro

2020 ◽  
Vol 67 ◽  
pp. 104890
Author(s):  
Lili Jiang ◽  
Zhen Wang ◽  
Xiaoyu Wang ◽  
Shujuan Wang ◽  
Zhe Wang ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Udp Glucuronosyltransferase ◽  
Potential Food

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

2020 ◽  
Author(s):  
Zifei Qin ◽  
Mengmeng Jia ◽  
Jing Yang ◽  
Han Xing ◽  
Zhao Yin ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Interactions ◽  
Renal Excretion ◽  
Therapeutic Effects ◽  
Specific Substrate ◽  
Ginsenoside Re ◽  
No Inhibition ◽  
Human Cytochrome ◽  
Udp Glucuronosyltransferase

Abstract 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.

In vitro selective inhibition of human UDP-glucuronosyltransferase (UGT) 1A4 by finasteride, and prediction of in vivo drug–drug interactions

2015 ◽  
Vol 232 (2) ◽  
pp. 458-465 ◽  
Author(s):  
Seung Jun Lee ◽  
Jung Bae Park ◽  
Doyun Kim ◽  
Soo Hyeon Bae ◽  
Young-Won Chin ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Selective Inhibition ◽  
Udp Glucuronosyltransferase

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

2020 ◽  
Author(s):  
Zifei Qin ◽  
Mengmeng Jia ◽  
Jing Yang ◽  
Hang Xing ◽  
Zhao Yin ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Renal Excretion ◽  
Systemic Exposure ◽  
Therapeutic Effects ◽  
Specific Substrate ◽  
Ginsenoside Re ◽  
Ginsenoside Rd ◽  
Udp Glucuronosyltransferase

Abstract 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.

Identification and characterization of in vitro inhibitors against UDP-glucuronosyltransferase 1A1 in uva-ursi extracts and evaluation of in vivo uva-ursi-drug interactions

2018 ◽  
Vol 120 ◽  
pp. 651-661 ◽  
Author(s):  
Jung Bae Park ◽  
Doyun Kim ◽  
Jee Sun Min ◽  
Su Jeong ◽  
Doo-Yeoun Cho ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Udp Glucuronosyltransferase ◽  
Identification And Characterization

Comparison of the drug-drug interactions potential of ibrutinib and acalabrutinib via inhibition of UDP-glucuronosyltransferase

2021 ◽  
pp. 115595
Author(s):  
Xiaoyu Wang ◽  
Zhe Wang ◽  
Xiaoyu Fan ◽  
Mingrui Yan ◽  
Lili Jiang ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Udp Glucuronosyltransferase

In vitro inhibition of human UDP-glucuronosyltransferase (UGT) 1A1 by osimertinib, and prediction of in vivo drug-drug interactions

2021 ◽  
Author(s):  
Zhe Wang ◽  
Xiaoyu Wang ◽  
Zhen Wang ◽  
Yaqin Jia ◽  
Yuyi Feng ◽  
...  
Keyword(s):  
Drug Interactions ◽  
In Vitro Inhibition ◽  
Udp Glucuronosyltransferase
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