title: Nonlinear pharmacokinetics of 5-methoxy-N,N-dimethyltryptamine in mice.
abstract: 5-Methoxy-N,N,-dimethyltryptamine (5-MeO-DMT), an abused serotonergic indolealkylamine drug, was placed into Schedule I controlled substance status in the United States as of January 19, 2011. In previous studies, we have shown the impact of monoamine oxidase A and cytochrome P450 2D6 enzymes on 5-MeO-DMT metabolism and pharmacokinetics. The aim of this study was to investigate 5-MeO-DMT pharmacokinetic properties after intravenous or intraperitoneal administration of three different doses (2, 10, and 20 mg/kg) to CYP2D6-humanized (Tg-CYP2D6) and wild-type control mice. Systemic exposure [area under the curve (AUC)] to 5-MeO-DMT was increased nonproportionally with the increase in 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 (intravenous) and 1.8- to 2.7-fold (intraperitoneal) higher in wild-type or Tg-CYP2D6 mice dosed with 10 and 20 mg/kg 5-MeO-DMT, respectively, than those in mice treated with 2 mg/kg 5-MeO-DMT. Furthermore, a two-compartment model including first-order absorption, nonlinear (Michaelis-Menten) elimination, and CYP2D6-dependent linear elimination from the central compartment was developed to characterize the intravenous and intraperitoneal pharmacokinetic data for 5-MeO-DMT in wild-type and Tg-CYP2D6 mice. In addition, 5-MeO-DMT was readily detected in mouse brain after drug treatment, and brain 5-MeO-DMT concentrations were also increased nonproportionally with the increase of dose. The results establish a nonlinear pharmacokinetic property for 5-MeO-DMT in mice, suggesting that the risk of 5-MeO-DMT intoxication may be increased nonproportionally at higher doses.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 541 Cooke Hall, Buffalo, NY 14260-1200, USA.
authors.forename: Hong-Wu
authors.initials: HW
authors.lastname: Shen
authors.forename: Xi-Ling
authors.initials: XL
authors.lastname: Jiang
authors.forename: Ai-Ming
authors.initials: AM
authors.lastname: Yu
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D002853:Chromatography, Liquid; D008732:Methoxydimethyltryptamines / Q000097:blood / Q000493:pharmacokinetics*; D051379:Mice; D053719:Tandem Mass Spectrometry
chemical_list: D008732:Methoxydimethyltryptamines