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Exploration of cytochrome P450 inhibition mediated drug-drug interaction potential of kratom alkaloids.

ABSTRACT: In vitro cytochrome P450 inhibition of major kratom alkaloids: mitragynine (MTG), speciogynine (SPG), speciocilliatine (SPC), corynantheidine (COR), 7-hydroxymitragynine (7HMG) and paynantheine (PAY) was evaluated using human liver microsomes (HLMs) to understand their drug-drug interaction potential. CYP450 isoform-specific substrates of CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4/5 were incubated in HLMs with or without alkaloids. Preliminary CYP450 inhibition (IC₅₀) data were generated for each of these isoforms. In addition, the type of inhibition and estimation of the inhibition constants (K_i) of MTG and COR were determined. Among the tested alkaloids, MTG and COR were potent inhibitors of CYP2D6 (IC₅₀, 2.2 and 4.2 ?M, respectively). Both MTG and COR exhibited competitive inhibition of CYP2D6 activity and the K_i were found to be 1.1 and 2.8 ?M, respectively. SPG and PAY showed moderate inhibition of CYP2D6 activity. Additionally, moderate inhibitory effects by SPC, MTG, and SPG were observed on CYP2C19 activity. Interestingly, inhibition of only midazolam hydroxylase CYP3A4/5 activity by COR, PAY, and MTG was observed while no inhibitory effect was observed when testosterone was used as a probe substrate. In conclusion, MTG and COR may lead to clinically significant adverse drug interactions upon coadministration of drugs that are substantially metabolized by CYP2D6.

SUBMITTER: Kamble SH

PROVIDER: S-EPMC7902086 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Exploration of cytochrome P450 inhibition mediated drug-drug interaction potential of kratom alkaloids.

Kamble Shyam H SH Sharma Abhisheak A King Tamara I TI Berthold Erin C EC León Francisco F Meyer P Katharina L PKL Kanumuri Siva Rama Raju SRR McMahon Lance R LR McCurdy Christopher R CR Avery Bonnie A BA

Toxicology letters 20191107

In vitro cytochrome P450 inhibition of major kratom alkaloids: mitragynine (MTG), speciogynine (SPG), speciocilliatine (SPC), corynantheidine (COR), 7-hydroxymitragynine (7HMG) and paynantheine (PAY) was evaluated using human liver microsomes (HLMs) to understand their drug-drug interaction potential. CYP450 isoform-specific substrates of CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4/5 were incubated in HLMs with or without alkaloids. Preliminary CYP450 inhibition (IC<sub>50</sub>) data were generated fo ...[more]

PMID: 31707106

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Project description:BackgroundKang-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.MethodsPK 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.ResultsAfter dosing, 9 alkaloids were found with C max and t 1/2 values of 0.17-422.70 μmol/L and 1.78-4.33 h, respectively. Additionally, 28 saponins exhibited considerable systemic exposure with t 1/2 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 (f u-plasma approximately 1%), whereas astragalosides and PPT-type ginsenosides displayed f u-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.ConclusionsWe 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.

Dataset Information

Exploration of cytochrome P450 inhibition mediated drug-drug interaction potential of kratom alkaloids.

Publications

Exploration of cytochrome P450 inhibition mediated drug-drug interaction potential of kratom alkaloids.

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