Interspecies Scaling of the Pharmacokinetics of N-Nitrosodimethylamine

Abstract

The pharmacokinetics of N-nitrosodimethylamine was studied in patas monkeys following i.v. doses of 0.5, 1.0, and 5.0 mg/kg and a p.o. dose 1.0 mg/kg, and in Swiss mice at i.v. doses of 1.0 and 2.0 mg/kg. In the patas monkey the pharmacokinetics was linear over the i.v. dose range studied. The mean clearance (Cl), steady-state volume of distribution (V_ss), mean residence time, and elimination half-life (t_½) were 103.3 ± 26.7 (SD) ml/min, 3061 ± 821 ml, 30.8 ± 10.8 min, and 21.1 ± 8.5 min, respectively. Assuming that the pharmacokinetics was linear at the p.o. dose used, the p.o. bioavailability of N-nitrosodimethylamine in the monkey was 49%. The pharmacokinetics was also linear in mice, and the average Cl,V_ss, mean residence time, and t_½ were 3.81 ml/min, 21.0 ml, 5.5 min, and 11.9 min, respectively. These data and data for rats, hamsters, rabbits, dogs, and pigs taken from the literature were used to scale Cl and V_ss to body weight using the allometric equation. The resulting equation for Cl was Cl = 49.7B^0.998 and the equation for V_ss was V_ss = 748B^1.05 where B is body weight in kg. The fit of the data to the equation was excellent in both cases. Using these equations and assuming a body weight of 70 kg for humans, the Cl and V_ss for N-nitrosodimethylamine in humans are estimated to be 3450 ml/min and 64,800 ml, respectively.