RT Journal Article SR Electronic T1 Nonlinear Pharmacokinetics of 5-Methoxy-N,N-dimethyltryptamine in Mice JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP dmd.111.039107 DO 10.1124/dmd.111.039107 A1 Hong-Wu Shen A1 Xi-Ling Jiang A1 Ai-Ming Yu YR 2011 UL http://dmd.aspetjournals.org/content/early/2011/04/04/dmd.111.039107.abstract AB 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.