Departments of Pharmaceutics (S.H.K., T.I.K., E.C.B., S.R.R.K., C.R.M., A.S.), Translational Drug Development Core (S.H.K., S.R.R.K., C.R.M., A.S.), Medicinal Chemistry (S.O., F.L., C.R.M.), and Pharmacodynamics (S.O., L.F.R., L.R.G.-J., V.L.C.P., A.P., N.P.H., L.R.M., J.L.W., T.H.), College of Pharmacy, University of Florida, Gainesville, Florida; Department of Pharmaceutical, Social and Administrative Sciences, McWhorter School of Pharmacy, Samford University, Birmingham, Alabama (S.O.); Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina (F.L.); Division of Therapeutics and Medical Consequences, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland (A.H.); and Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center at Amarillo, Amarillo, Texas (L.R.M., J.L.W., T.H.).
Departments of Pharmaceutics (S.H.K., T.I.K., E.C.B., S.R.R.K., C.R.M., A.S.), Translational Drug Development Core (S.H.K., S.R.R.K., C.R.M., A.S.), Medicinal Chemistry (S.O., F.L., C.R.M.), and Pharmacodynamics (S.O., L.F.R., L.R.G.-J., V.L.C.P., A.P., N.P.H., L.R.M., J.L.W., T.H.), College of Pharmacy, University of Florida, Gainesville, Florida; Department of Pharmaceutical, Social and Administrative Sciences, McWhorter School of Pharmacy, Samford University, Birmingham, Alabama (S.O.); Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina (F.L.); Division of Therapeutics and Medical Consequences, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland (A.H.); and Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center at Amarillo, Amarillo, Texas (L.R.M., J.L.W., T.H.)
J Pharmacol Exp Ther. 2023 Jun;385(3):180-192. doi: 10.1124/jpet.122.001525. Epub 2023 Apr 5.
Mitragynine, an opioidergic alkaloid present in (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 -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.
在 （Kratom） 中发现的麦角胺是一种阿片样生物碱，它被细胞色素 P450 3A（CYP3A）代谢为 7-羟基麦角胺，这是一种更有效的阿片受体激动剂。麦角胺转化为 7-羟基麦角胺在体内介导其作用的程度尚不清楚。本研究旨在探讨 CYP3A 抑制（酮康唑）如何在体外改变大鼠肝微粒体中麦角胺的药代动力学。该研究进一步探讨了酮康唑如何改变麦角胺在大鼠中的辨别刺激和镇痛作用。酮康唑 [30 mg/kg，口服灌胃（o.g.）] 使麦角胺（13.3 mg/kg，o.g.）的全身暴露增加了 120%，使 7-羟基麦角胺的暴露增加了 130%。7-羟基麦角胺暴露的意外增加表明酮康唑抑制了麦角胺和 7-羟基麦角胺的代谢，这一发现在大鼠肝微粒体中得到了证实。在通过固定比率的食物传递方案辨别 3.2 mg/kg 吗啡和载体的大鼠中，酮康唑预处理增加了麦角胺（4.7 倍）和 7-羟基麦角胺（9.7 倍）的效力。酮康唑对吗啡的效力没有影响。酮康唑使 7-羟基麦角胺的镇痛效力增加了 4.1 倍。麦角胺（高达 56 mg/kg，ip）在酮康唑存在和不存在的情况下均缺乏镇痛作用。这些结果表明，麦角胺和 7-羟基麦角胺均通过 CYP3A 清除，并且 7-羟基麦角胺是麦角胺的代谢物，通过其他途径形成。这些结果对 Kratom 与许多抑制 CYP3A 的药物和柑橘汁联合使用有影响。
麦角胺是一种丰富的 Kratom 生物碱，在 -阿片受体（MOR）上表现出低疗效。其代谢物 7-羟基麦角胺也是一种 MOR 激动剂，但与麦角胺相比，它具有更高的亲和力和效力。我们在大鼠中的结果表明，细胞色素 P450 3A（CYP3A）抑制可增加麦角胺和 7-羟基麦角胺的系统暴露及其产生 MOR 介导的行为效应的效力。这些数据突出了 Kratom 与包括许多药物和柑橘汁在内的 CYP3A 抑制剂之间的潜在相互作用。
