Teksin Zeynep S, Lee Insong J, Nemieboka Noble N, Othman Ahmed A, Upreti Vijay V, Hassan Hazem E, Syed Shariq S, Prisinzano Thomas E, Eddington Natalie D
Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201, USA.
Eur J Pharm Biopharm. 2009 Jun;72(2):471-7. doi: 10.1016/j.ejpb.2009.01.002.
Salvinorin A is an unregulated potent hallucinogen isolated from the leaves of Salvia divinorum. It is the only known non-nitrogenous kappa-opioid selective agonist, and rivals synthetic lysergic acid diethylamide (LSD) in potency. The objective of this study was to characterize the in vitro transport, in vitro metabolism, and pharmacokinetic properties of Salvinorin A. The transport characteristics of Salvinorin A were assessed using MDCK-MDR1 cell monolayers. The P-glycoprotein (P-gp) affinity status was assessed by the P-gp ATPase assay. In vitro metabolism studies were performed with various specific human CYP450 isoforms and UGT2B7 to assess the metabolic characteristics of Salvinorin A. Cohorts (n = 3) of male Sprague Dawley rats were used to evaluate the pharmacokinetics and brain distribution of Salvinorin A (10 mg/kg, intraperitoneal (i.p.) over a 240-min period. A validated UV-HPLC and LC/MS/MS method was used to quantify the hallucinogen concentrations obtained from the in vitro and in vivo studies, respectively. Salvinorin A displayed a high secretory transport in the MDCK-MDR1 cells (4.07 +/- 1.34 x 10(-)5 cm/s). Salvinorin A also stimulated the P-gp ATPase activity in a concentration (5 and 10 microM)-dependent manner, suggesting that it may be a substrate of (P-gp). A significant decrease in Salvinorin A concentration ranging from 14.7 +/- 0.80% to 31.1 +/- 1.20% was observed after incubation with CYP2D6, CYP1A1, CYP2C18, and CYP2E1, respectively. A significant decrease was also observed after incubation with UGT2B7. These results suggest that Salvinorin A maybe a substrate of UGT2B7, CYP2D6, CYP1A1, CYP2E1, and CYP2C18. The in vivo pharmacokinetic study showed a relatively fast elimination with a half-life (t1/2) of 75 min and a clearance (Cl/F) of 26 L/h/kg. The distribution was extensive (Vd of 47.1 L/kg); however, the brain to plasma ratio was 0.050. Accordingly, the brain half-life was relatively short, 36 min. Salvinorin A is rapidly eliminated after i.p. dosing, in accordance with its fast onset and short duration of action. Further, it appears to be a substrate for various oxidative enzymes and multi-drug resistant protein, P-gp.
Salvinorin A是一种从神圣鼠尾草叶子中分离出来的不受管制的强效致幻剂。它是唯一已知的非含氮κ-阿片受体选择性激动剂，其效力可与合成的麦角酸二乙酰胺（LSD）相媲美。本研究的目的是表征Salvinorin A的体外转运、体外代谢和药代动力学特性。使用MDCK-MDR1细胞单层评估Salvinorin A的转运特性。通过P-糖蛋白（P-gp）ATP酶测定评估P-gp亲和力状态。用各种特定的人CYP450同工型和UGT2B7进行体外代谢研究，以评估Salvinorin A的代谢特性。使用雄性Sprague Dawley大鼠群体（n = 3）评估Salvinorin A（10 mg/kg，腹腔注射（i.p.））在240分钟内的药代动力学和脑部分布。分别使用经过验证的UV-HPLC和LC/MS/MS方法对体外和体内研究获得的致幻剂浓度进行定量。Salvinorin A在MDCK-MDR1细胞中表现出高分泌转运（4.07 +/- 1.34 x 10(-)5 cm/s）。Salvinorin A还以浓度（5和10 microM）依赖性方式刺激P-gp ATP酶活性，表明它可能是P-gp的底物。分别与CYP2D6、CYP1A1、CYP2C18和CYP2E1孵育后，观察到Salvinorin A浓度显著降低，范围为14.7 +/- 0.80%至31.1 +/- 1.20%。与UGT2B7孵育后也观察到显著降低。这些结果表明Salvinorin A可能是UGT2B7、CYP2D6、CYP1A1、CYP2E1和CYP2C18的底物。体内药代动力学研究表明消除相对较快，半衰期（t1/2）为75分钟，清除率（Cl/F）为26 L/h/kg。分布广泛（Vd为47.1 L/kg）；然而，脑血浆比为0.050。因此，脑半衰期相对较短，为36分钟。腹腔注射给药后，Salvinorin A迅速消除，这与其起效快和作用持续时间短一致。此外，它似乎是各种氧化酶和多药耐药蛋白P-gp的底物。
