(M1430-10-67) Effect of Food on the Pharmacokinetics of Mitragynine in Rats

Purpose: Kratom, (Mitragyna speciosa), is a tropical evergreen tree belonging to the coffee family indigenous to Southeast Asia whose leaves have historically been used as a natural remedy and for its purported stimulating and analgesic properties. The opioidergic activity of kratom is often attributed to its most abundant bioactive alkaloid mitragynine and its metabolite, 7-hydroxymitragynine (7HMG). ^1,2.3 Some of the recent studies found that other metabolites including 9-hydroxycorynantheidine (9-OH COR), mitragynine acid, and mitragynine pseudoindoxyl (MGPI) are the major circulating metabolites of mitragynine. ^4,6 The aim of the current study is to study the effect of type of the food on the oral exposure of mitragynine and its circulating metabolites. The systemic pharmacokinetic studies were performed in rats after fasting and controlled fed conditions by providing a standard and high lipid diet.

Methods: Male Sprague Dawley rats were randomly allocated into three oral dosing groups (N = 5, each group) to receive a single oral dose of mitragynine (25 mg/kg) under fasted, controlled standard diet-fed, and controlled high lipid diet-fed conditions, respectively. Another group of rats received an intravenous dose of mitragynine (10 mg/kg) through a jugular vein cannula to calculate the bioavailability. Blood samples were collected at pre-dose, and 0.08, 0.17, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 18, 24, and 48 hours, post-dose. Plasma was separated from whole blood after centrifugation and plasma concentrations of mitragynine and its metabolites 7-HMG, 9-OH COR, mitragynine acid, and MGPI were monitored using ultra-performance liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters were calculated by non-compartmental analysis using Phoenix (version 8.3).

Results: Oral absorption of mitragynine was delayed in fed condition rats, but total exposure of mitragynine was higher in fed rats than in the fasted animals. Peak plasma concentrations for mitragynine were observed post 2.3 h post-dose in fed rats, while T_max was observed at 0.35 h when mitragynine was dosed to fasted rats. Systemic exposure (AUC) of mitragynine was increased 2.2- and 2.6-fold for standard and high-lipid diet-fed rats than that of fasted state rats. Although the systemic exposures of 7-HMG and 9-OH CORY increased in a similar manner to their parent, the systemic exposure of mitragynine acid was similar in fasted and fed states. MGPI was below the quantification limit in all the plasma samples.

Conclusion: A standard or high-fat meal increased the plasma exposure to a single oral dose of mitragynine. The oral bioavailability will be more than 95% with high lipid diet. The effect of food should be considered while consuming mitragynine or kratom.

References: 1. Avery, Bonnie A., et al. "Comparative pharmacokinetics of mitragynine after oral administration of Mitragyna speciosa (Kratom) leaf extracts in rats." Planta medica 85.04 (2019): 340-346.
2. Maxwell, Elizabeth A., et al. "Pharmacokinetics and safety of mitragynine in beagle dogs." Planta medica 86.17 (2020): 1278-1285.
3. Obeng, Samuel, et al. "Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloids." Journal of medicinal chemistry 63.1 (2019): 433-439.
4. Shyam, Kamble., et al., “Metabolite profiling and identification of enzymes responsible for the metabolism of mitragynine, the major alkaloid of Mitragyna speciosa (kratom)”, Xenobiotica, 49:11 (2019):1279-1288.
5. David, Le., et al., “Analysis of mitragynine and metabolites in human urine for detecting the use of the psychoactive plant kratom.” J Anal Toxicol. 36.9 (2012):616-625.

Acknowledgements: This study was supported by R01 DA047855 and UG3/UH3 DA048353 grants from the National Institute on Drug Abuse.