Pharmacokinetics and Tissue Distribution of Mitragynine using Human Equivalent Dose in Rats

AI Hazim1, S Ramanathan1, MI Abdul Majid2, SM Mansor1. 1Centre for Drug Research, Universiti Sains Malaysia, Penang, Malaysia, 2Centre for Advanced Analytical Toxicology Services, Universiti Sains Malaysia, Penang, Malaysia

Mitragyna speciosa (Rubiaceae) is an indigenous tree growing in the Southeast Asian countries particularly in Malaysia and Thailand. Decoction of Mitragyna speciosa leaves (ketum drink) is regularly consumed by drug users to manage opiate withdrawal symptoms. The pharmacological effects of this plant were mainly attributed to its principal alkaloid mitragynine. Since then several studies were published on the pharmacokinetics, analgesic and toxicological effects of mitragynine in animal models (1). However, the selection of mitragynine doses employed in these studies was derived empirically without proper scientific basis. In addition, none of these studies evaluated the tissue distribution profile of mitragynine in laboratory animals. This study aimed to determine the pharmacokinetic properties and tissue distribution profile of mitragynine using human equivalent dose in rats. We have recently reported that informal users of ketum drink in the Northern Peninsular of Malaysia consume an average of three glasses (250 ml, each) per day to wean off opioid withdrawal symptoms (2,3). This translates to a daily dose range of 0.3 to 5.7 mg/kg and 1.9 to 35 mg/kg mitragynine in human and rat respectively (4). This dose range was used as a basis for selecting mitragynine dose employed in the present study for both pharmacokinetic and tissue distribution studies. Six male Sprague-Dawely rats were orally treated with a single dose of 20 mg/kg mitragynine. Blood was collected from the tail vein of each rat before and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36 and 48h after mitragynine administration. Another six rats were treated with the same dose of mitragynine and tissues (brain, heart, lung, kidney and liver) were collected 5h following mitragynine administration. The concentration of mitragynine in plasma and tissue homogenates was determined using a validated High Performance Liquid Chromatography-UV (HPLC-UV) method. The data were subjected to non-compartmental PK analysis and one way analysis of variance (ANOVA).The maximum plasma concentration of 0.64 ± 0.09 µg/ml was achieved approximately 5 h following mitragynine administration. The elimination half-life of mitragynine was 8.3 ± 1.4 h and the apparent clearance and volume of distribution were 1.8 ± 0.3 l /h kg and 22.1 ± 5.2 l/kg respectively. Mitragynine was slowly absorbed and eliminated from plasma. A similar prolong absorption was also reported rats (5). Mitragynine was distributed to all examined tissues with the highest concentrations found in the liver followed by the lung, kidney, heart and brain. The preferential relative high distribution of mitragynine in liver probably explains the drug hepatotoxic effect reported in the literature (6). Interestingly the drug, which is lipophilic in nature, was found in a considerable amount in the brain indicating its ability to cross the blood brain barrier and support its analgesic and anxiolytic effects reported earlier (7,8). Findings from the present study demonstrate that mitragynine is slowly absorbed; however it is widely distributed into rat tissues following oral administration. Data from the present work will provide basis to determine human dose of mitragynine if it passes preclinical testing.

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