Sex differences in the fate of N-methyl-14C-pethidine in rats

N-Methyl-14C-labeled pethidine was administered intravenously to male and female rats at a dose of 1.25 mg per kg body weight. The amount of 14CO2 (originating from the N-methyl group) in the expired air of female rats was approximately a half of that expired by males. The amounts of radioactive metabolites (probably mainly deesterified products) in the excretions was higher in females. Pethidine levels in liver reach their maximum later, but attain substantially higher levels in females. The shapes of the curves relating pethidine levels to time are identical for blood and brain, but the brain levels are approximately ten times higher. Their course approximates a simple exponential curve in females, but a curve composed of two exponentials in males. Using the COMANSL computer programme and the data for blood levels, a three-compartment model has been established consisting of a central compartment 1, into which the drug was administered, a rapidly exchanging ("shallow") compartment 2, which is in equilibrium with 1, and a slowly exchanging ("deep") compartment 3, from which it is eliminated. Rate constants computed for the entry into and the exit from 1 were similar (0.23 and 0.22) in males; they could not be determined in females (possibly since they were too high). The passage from 1 to 3 was faster in males (0.07) than in females (0.04), the elimination from 3 was substantially faster in males (1.97) than in females (0.33). Faster demethylation in males is attributed to higher demethylation activity of male liver, known from in vitro experiments and faster rate of alternative pathways in females to higher substrate concentration in the liver. Attention is drawn to the considerable sex differences in the distribution of the drug.