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United States Department of Agriculture

Agricultural Research Service

Research Project: DISCOVERY AND DEVELOPMENT OF NATURAL PRODUCTS FOR PHARMACEUTICAL AND AGROCHEMICAL APPLICATIONS

Location: Natural Products Utilization Research

Title: Evaluation of in vitro absorption, distribution, metabolism, and excretion (ADME) properties of mitragynine, 7-hydroxymitragynine, and mitraphylline

Authors
item Manda, Vamshi -
item Avula, Bharathi -
item Ali, Zulifiqar -
item Khan, Ikhlas -
item Walker, Larry -
item Khan, Shabana -

Submitted to: Planta Medica
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: March 31, 2014
Publication Date: April 2, 2014
Citation: Manda, V.K., Avula, B., Ali, Z., Khan, I.A., Walker, L., Khan, S.I. 2014. Evaluation of in vitro absorption, distribution, metabolism, and excretion (ADME) properties of mitragynine, 7-hydroxymitragynine, and mitraphylline. Planta Medica. 80:568-576.

Interpretive Summary: Mitragyna speciosa (Kratom) root has been used traditionally to relieve symptoms associated with opiate addiction. Literature suggests that the three main ingredients found in Kratom are mitragynine, 7-hydroxymitragynine, and mitraphylline. The current study focuses on studying the absorption, distribution, metabolism, and excretion (ADME) properties of these three compounds using in vitro based assays. This will enable us to understand their drug-like properties for future clinical studies.This is the first report to compare the ADME properties of three major compounds present in Kratom. The results show that mitragynine had superior ADME properties compared to the other two compounds.

Technical Abstract: Mitragyna speciosa (Kratom) is a popular herb in Southeast Asia which is traditionally used to treat withdrawal symptoms associated with opiate addiction. Mitragynine, 7-hydroxymitragynine and mitraphylline are reported to be the central nervous system (CNS) active alkaloids which bind to the opiate receptors. Mitraphylline is also present in the barks of Uncaria tomentosa (Cat’s Claw). Several therapeutic properties have been reported for these compounds but limited information is available on the absorption and distribution properties. This study focuses on evaluating the ADME properties of these compounds and their effect on major efflux transporter P-gp. Quantitative analysis was determined by Q-TOF LC-MS system. Mitragynine was unstable in simulated gastric fluid (SGF) with 26% degradation but stable in simulated intestinal fluid (SIF). 7-hydroxymitragynine degraded up to 27% in SGF which could be accounted for its conversion to mitragynine (23%) while 6% degradation was seen in SIF. Mitraphylline was stable in SGF but unstable in SIF (13.6% degradation). Mitragynine and 7- hydroxymitragynine showed moderate permeability across Caco-2 and MDR-MDCKII monolayers with no significant efflux. However, mitraphylline was subjected to efflux mediated by P-glycoprotein (P-gp) in both Caco-2 and MDR-MDCKII monolayers. Mitragynine was found be metabolically stable in both human liver microsomes (HLM) and S9 fractions. In contrast, both 7-hydroxymitragynine and mitraphylline were metabolized by HLM with half-life (T1/2) of 24 and 50 min, respectively. All the three compounds exhibited high plasma protein binding (>90%) determined by equilibrium dialysis. Mitragynine and 7-hydroxymitragynine inhibited P-gp with EC50 values of 18 ± 3.6 µM and 32 ± 1.9 µM, respectively determined by calcein-AM fluorescent assay while no effect was seen with mitraphylline. These data indicate possibility of drug interaction if mitragynine and 7-hydroxymitragynine are co-administered with drugs that are P-gp substrates.

Last Modified: 11/27/2014
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