Sex specificity in methadone analgesia in the rat: a population pharmacokinetic and pharmacodynamic approach.

Abstract

To quantify the extent to which a sex-specific dichotomy in the temporal evolution of the analgesic effect, after intravenous (i.v.) methadone injection in the rat, relates to the pharmacokinetics (PK) and pharmacodynamics (PD) that mediate the dose-to-effect pathway. Tail-flick analgesia was measured after i.v. methadone injection (0.35 mg/kg) in female (n = 16) and male (n = 16) Sprague-Dawley rats. The PK were evaluated in separate female (n = 56) and male (n = 56) rats after they had received the same dose of methadone i.v. (0.35 mg/kg). A bicompartmental model described the kinetics and a sigmoid Emax model-related drug effect vs. simulated concentrations (pharmacodynamics) at the times of effect measurement. All model parameters as well as interanimal and assay variabilities were estimated with a mixed-effects population method using the program NONMEM. The area under the effect-time curve (AUCE0-120) was (mean +/- interanimal SD) 1859+/-346 min in the females, which was significantly lower than the 4871+/-393 min in the males (P < 0.0001). On the contrary, the profiles of concentration vs. time were higher in females and, therefore, corresponded inversely to the effect vs. time-relative magnitudes. The central volume of distribution, V1, was 1.94+/-0.37 l/kg for female rats and 3.01+/-0.33 l/kg for male rats. Also, the central clearance was 0.077+/-0.006 l/min/kg and 0.102+/-0.005 l/min/ kg, respectively, for female and male rats. Both parameters differed significantly between sexes (P < 0.0001). The pharmacodynamic maximum observed effect parameter (Emax) was 37%+/-29% in female rats and 85%+/-16% in male rats, and these values were significantly different (P < 0.0001). The parameter for the concentration eliciting half of Emax (EC50) was 24.1+/-7.5 microg/l in female rats and 20.3+/-2.9 microg/l in male rats, and the Hill-related exponent, gamma, was 6.3+/-3.9 in female rats and 5.5+/-4.1 in male rats. These parameters did not differ significantly (at the P < 0.05 level). A sex-specific dichotomy in the methadone antinociceptive effect, in the rat, was not proportionally related to plasma concentrations. Each sex corresponded to a distinct subpopulation of the PK parameters and one of the pharmacodynamic parameters (Emax). When the course of a drug involves PK or PD subpopulations, PK/PD modeling can afford the safest prediction of the effect-time evolution for a particular dose.