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.

Fig. 1.

The pharmacokinetic model developed to describe serum 5-MeO-DMT concentration-time profiles in mice after intravenous and intraperitoneal administration. X_a, amount of drug at the absorption site; k_a, absorption rate constant; F, bioavailability; X_C and X_T, amount of drug in the central and peripheral compartment, respectively; V_C and V_T, volume of distribution of 5-MeO-DMT in the central and peripheral compartment, respectively; K_m and V_max, Michaelis-Menten parameters for the saturable elimination of 5-MeO-DMT from the central compartment; CL_CYP2D6, clearance of 5-MeO-DMT from the central compartment by CYP2D6-dependent metabolism, which only occurs in Tg-CYP2D6 mice; CL_D, distribution clearance of 5-MeO-DMT between the central and peripheral compartments.

Fig. 2.

Serum 5-MeO-DMT concentration versus time curves in wild-type (A) and Tg-CYP2D6 mice (B) after intravenous administration. Existence of nonlinear pharmacokinetics is manifested by the dose-normalized serum drug concentration versus time profiles in both wild-type (C) and Tg-CYP2D6 mice (D). Mice were dosed intravenously with 2 (●), 10 (■), or 20 (▲) mg/kg 5-MeO-DMT. Values are means ± S.D. (n = 3 at each time point).

Fig. 3.

Serum 5-MeO-DMT concentration versus time curves in wild-type (A) and Tg-CYP2D6 mice (B) after intraperitoneal administration. Nonlinear pharmacokinetics is obvious from the dose-normalized serum drug concentration versus time profiles in wild-type (C) and Tg-CYP2D6 mice (D). Mice were treated intraperitoneally with 2 (●), 10 (■), or 20 (▲) mg/kg 5-MeO-DMT. Values represent means ± S.D. (n = 4 at each time point).

Fig. 4.

Simultaneous fitting of intravenous and intraperitoneal pharmacokinetic data in both wild-type (A and C) and Tg-CYP2D6 (B and D) mice using the proposed compartmental model (Fig. 1). Values are means ± S.D. (n = 3–4 at each time point). Lines represent the predicted serum 5-MeO-DMT concentrations.

Fig. 5.

Goodness-of-fit plots of a two-compartment model versus a one-compartment model. Shown are model-predicted versus observed drug concentrations of the one-compartment model (A) and the final two-compartment model (B) and standard residuals versus model predictions of the one-compartment model (C) and the final two-compartment model (D).

Fig. 6.

Dose-normalized brain 5-MeO-DMT concentrations at 20 min (A), 30 min (B), and 60 min (C) after intraperitoneal administration of 2, 10, or 20 mg/kg drug in wild-type and Tg-CYP2D6 mice. Data are means ± S.D. (n = 4 in each group). *, p < 0.05, compared with 2 mg/kg treatment for the same genotype of mice; #, p < 0.05, compared with wild-type mice treated with the same dose of drug.