Evaluation Of Rat In Situ Intestinal Permeability Study Of Mitragynine
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Date
2016-08
Authors
Jagabalan, J.D Yuvenesan
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Abstract
Mitragynine the principal alkaloid of M. speciosa leaf has been reported to be responsible for most of its pharmacological effects. Mitragynine has been found to be metabolically stable in liver microsomes. However the oral bioavailability of mitragynine has been reported to be very low. The poor mitragynine oral absorption was due but not limited to, its poor water solubility. It is also important to note that the role of intestinal permeability, cytochrome P450 3A4 enzyme (CYP3A4) and p-glycoprotein (P-gp) efflux system on its oral bioavailability could not be ruled out as well. In view of this, work was undertaken to determine some of its oral absorption properties using in situ rat intestinal perfusate model in rats. For mitragynine quantification in in situ rat intestinal perfusate samples, a reliable HPLC-UV analytical method for simultaneous detection of mitragynine, propranolol and atenolol was developed and validated. The LOQ of mitragynine, propranolol and atenolol were 2.5, 3.75 and 3.75 μg/mL respectively. The within day and day to day accuracy and precision for mitragynine, propranolol and atenolol were all below 5% respectively. Mitragynine is stable in acetonitrile for period of one month when stored in freezer (-20oC). All the analytes have been found to be stable in perfusion buffer upon storage at -20 °C up to one month. The stability was not affected after the samples were subjected to three freeze and thaw cycles and when kept on the bench for 8 hours. Mitragynine is poorly soluble in perfusate buffer (~40μg/mL). Mitragynine demonstrated high intestinal permeability (Peff) (1.11 x 10-4 cm/s) and was comparable to that of the high permeable marker propranolol (Peff) (1.27 x 10-4
cm/s). There was no significant alteration (p > 0.05) in the mean permeability values (Peff) of mitragynine when P-gp and/or CYP3A4 inhibitors were co-administered, thus suggesting the drug is not subjected to pre-systemic elimination related to a P-gp and CYP3A4 system. This study suggests that mitragynine (low solubility & high permeability) can be classified as class II drug according to biopharmaceutical classification system (BCS). The mitragynine oral absorption properties determined in this study could further assist the development of mitragynine oral formulation which would provide adequate absorption for clinical investigations in the future.
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Mitragynine has been found to be metabolically stable , in liver microsomes.