TY - JOUR T1 - Nonlinear Pharmacokinetics of 5-Methoxy-<em>N,N</em>-dimethyltryptamine in Mice JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.111.039107 SP - dmd.111.039107 AU - Hong-Wu Shen AU - Xi-Ling Jiang AU - Ai-Ming Yu Y1 - 2011/01/01 UR - http://dmd.aspetjournals.org/content/early/2011/04/04/dmd.111.039107.abstract N2 - 5-Methoxy-N,N,-dimethyltryptamine (5-MeO-DMT), an abused serotonergic indolealkylamine drug, has been placed into Schedule I controlled substance in the United States since January 19, 2011. Previously we have shown the impact of monoamine oxidase-A and cytochrome P450 2D6 enzymes in 5-MeO-DMT metabolism and pharmacokinetics. This study aimed to investigate 5-MeO-DMT pharmacokinetic properties following intravenous (i.v.) or intraperitoneal (i.p.) administration of three different doses (2, 10 and 20 mg/kg) to CYP2D6-humanized (Tg-CYP2D6) and wild-type control mice. The systemic exposure (AUC) to 5-MeO-DMT was increased non-proportionally with the increase of dose. The existence of nonlinearity in serum 5-MeO-DMT pharmacokinetics was clearly manifested by dose normalized AUC values, which were approximately 1.5 to 2.0-fold (i.v.) and 1.8 to 2.7-fold (i.p.) higher in wild-type or Tg-CYP2D6 mice dosed with 10 and 20 mg/kg of 5-MeO-DMT, respectively, than those in mice treated with 2 mg/kg of 5-MeO-DMT. Furthermore, a two-compartment model including first-order absorption, nonlinear (Michaelis-Menten) elimination and CYP2D6-dependent linear elimination from central compartment was developed to characterize the i.v. and i.p. pharmacokinetic data of 5-MeO-DMT in wild-type and Tg-CYP2D6 mice. In addition, 5-MeO-DMT was readily detected in mouse brain following drug treatment, and brain 5-MeO-DMT concentrations were also increased non-proportionally with the increase of dose. The results establish a nonlinear pharmacokinetic property for 5-MeO-DMT in mice, suggesting that risk of 5-MeO-DMT intoxication may be increased non-proportionally at higher doses. ER -