Abstract
Mitragynine, an opioidergic alkaloid present in Mitragyna speciosa (kratom), is metabolized by cytochrome P450 3A (CYP3A) to 7-hydroxymitragynine, a more potent opioid receptor agonist. The extent to which conversion to 7-hydroxymitragynine mediates the in vivo effects of mitragynine is unclear. The current study examined how CYP3A inhibition (ketoconazole) modifies the pharmacokinetics of mitragynine in rat liver microsomes in vitro. The study further examined how ketoconazole modifies the discriminative stimulus and antinociceptive effects of mitragynine in rats. Ketoconazole [30 mg/kg, oral gavage (o.g.)] increased systemic exposure to mitragynine (13.3 mg/kg, o.g.) by 120% and 7-hydroxymitragynine exposure by 130%. The unexpected increase in exposure to 7-hydroxymitragynine suggested that ketoconazole inhibits metabolism of both mitragynine and 7-hydroxymitragynine, a finding confirmed in rat liver microsomes. In rats discriminating 3.2 mg/kg morphine from vehicle under a fixed-ratio schedule of food delivery, ketoconazole pretreatment increased the potency of both mitragynine (4.7-fold) and 7-hydroxymitragynine (9.7-fold). Ketoconazole did not affect morphine’s potency. Ketoconazole increased the antinociceptive potency of 7-hydroxymitragynine by 4.1-fold. Mitragynine (up to 56 mg/kg, i.p.) lacked antinociceptive effects both in the presence and absence of ketoconazole. These results suggest that both mitragynine and 7-hydroxymitragynine are cleared via CYP3A and that 7-hydroxymitragynine is formed as a metabolite of mitragynine by other routes. These results have implications for kratom use in combination with numerous medications and citrus juices that inhibit CYP3A.
SIGNIFICANCE STATEMENT Mitragynine is an abundant kratom alkaloid that exhibits low efficacy at the μ-opioid receptor (MOR). Its metabolite, 7-hydroxymitragynine, is also an MOR agonist but with higher affinity and efficacy than mitragynine. Our results in rats demonstrate that cytochrome P450 3A (CYP3A) inhibition can increase the systematic exposure of both mitragynine and 7-hydroxymitragynine and their potency to produce MOR-mediated behavioral effects. These data highlight potential interactions between kratom and CYP3A inhibitors, which include numerous medications and citrus juices.
Footnotes
- Received November 23, 2022.
- Accepted March 29, 2023.
The present study was supported by National Institutes of Health National Institute on Drug Abuse [Grants DA25267 and UG3/UH3-DA048353-01] (to L.R.M.); University of Florida Foundation (to L.R.M.); and University of Florida Department of Pharmacodynamics Funding (to L.R.M.). The views and opinions expressed in this manuscript are those of the authors only and do not necessarily represent the views, official policy. or position of the US Department of Health and Human Services or any of its affiliated institutions or agencies. Dr. Hampson was substantially involved with this work, consistent with his role as Scientific Officer of Grant UG3-DA048353. He had no substantial involvement in the other cited grants.
The authors declare that they have no conflicts of interest with the contents of this article.
↵1Current affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
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This article has supplemental material available at jpet.aspetjournals.org.
- U.S. Government work not protected by U.S. copyright.
