ALLOMETRY OF PHARMACOKINETICS AND PHARMACODYNAMICS OF THE MUSCLE-RELAXANT METOCURINE IN MAMMALS

We investigated the effects of body size on the pharmacokinetics and p harmacodynamics of the renally cleared muscle relaxant metocurine. We hypothesized that pharmacokinetics of the drug would change allometric ally in proportion to physiological time [proportional to M(b)(0.25), where M(b) is body mass] and that pharmacodynamics would be independen t of size because of the highly conserved structure of the acetylcholi ne receptor. Metocurine effects during general anesthesia were examine d in 17 rats, 8 cats, 6 dogs, 5 pigs, 7 sheep, and 12 horses. Allometr ic analysis demonstrated size dependence for pharmacokinetics, which w ere affected by physiological time (M(b)(0.25). Pharmacodynamics were size independent, except for the value for effect compartment concentr ation associated with 50% twitch paralysis (IC50). Data from individua l species had a bimodal distribution that was significant: pigs and sh eep were more sensitive than other large species, and their IC50 appea red size independent. IC50 was size dependent in more active species ( horse, dog, cat, rat). Although the mechanism is unknown, we speculate that this trend might relate to receptor density within the end plate . Thus pharmacokinetics changed in proportion to physiological time, a nd pharmacodynamics were in part size independent.