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Planta Med 2014; 80(07): 568-576
DOI: 10.1055/s-0034-1368444
Pharmacokinetic Investigations
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Evaluation of In Vitro Absorption, Distribution, Metabolism, and Excretion (ADME) Properties of Mitragynine, 7-Hydroxymitragynine, and Mitraphylline

Vamshi K. Manda
1   National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, USA
,
Bharathi Avula
1   National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, USA
,
Zulfiqar Ali
1   National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, USA
,
Ikhlas A. Khan
1   National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, USA
2   Department of Pharmacognosy, School of Pharmacy, The University of Mississippi, University, MS, USA
,
Larry A. Walker
1   National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, USA
3   Department of Pharmacology, School of Pharmacy, The University of Mississippi, University, MS, USA
,
Shabana I. Khan
1   National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, USA
2   Department of Pharmacognosy, School of Pharmacy, The University of Mississippi, University, MS, USA
› Author Affiliations
Further Information

Publication History

received 20 January 2014
revised 31 March 2014

accepted 02 April 2014

Publication Date:
19 May 2014 (online)

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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 active alkaloids which bind to the opiate receptors. Mitraphylline is also present in the bark of Uncaria tomentosa (catʼs 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 absorption, distribution, metabolism, and excretion (ADME) properties of these compounds and their effect on major efflux transporter P-glycoprotein, using in vitro methods. Quantitative analysis was performed by the Q-TOF LC-MS system. Mitragynine was unstable in simulated gastric fluid with 26 % degradation but stable in simulated intestinal fluid. 7-Hydroxymitragynine degraded up to 27 % in simulated gastric fluid, which could account for its conversion to mitragynine (23 %), while only 6 % degradation was seen in simulated intestinal fluid. Mitraphylline was stable in simulated gastric fluid but unstable in simulated intestinal fluid (13.6 % degradation). Mitragynine and 7-hydroxymitragynine showed moderate permeability across Caco-2 and MDR-MDCK monolayers with no significant efflux. However, mitraphylline was subjected to efflux mediated by P-glycoprotein in both Caco-2 and MDR-MDCK monolayers. Mitragynine was found to be metabolically stable in both human liver microsomes and S9 fractions. In contrast, both 7-hydroxymitragynine and mitraphylline were metabolized by human liver microsomes with half-lives of 24 and 50 min, respectively. All three compounds exhibited high plasma protein binding (> 90 %) determined by equilibrium dialysis. Mitragynine and 7-hydroxymitragynine inhibited P-glycoprotein with EC50 values of 18.2 ± 3.6 µM and 32.4 ± 1.9 µM, respectively, determined by the calcein-AM fluorescent assay, while no inhibition was seen with mitraphylline. These data indicate the possibility of a drug interaction if mitragynine and 7-hydroxymitragynine are coadministered with drugs that are P-glycoprotein substrates.

Key words

Mitragyna speciosa - Uncaria tomentosa - Rubiaceae - intestinal transport - blood brain barrier - P-gp

Supporting Information

 

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