AJP - Regulatory, Integrative and Comparative Physiology, Vol 268, Issue 1 85-R91, Copyright © 1995 by American Physiological Society
Allometry of pharmacokinetics and pharmacodynamics of the muscle relaxant metocurine in mammals
G. A. Gronert, D. L. Fung, J. H. Jones, S. L. Shafer, S. V. Hildebrand and E. A. Disbrow
Department of Anesthesiology, School of Medicine, University of California, Davis 95616-8634.
We investigated the effects of body size on the pharmacokinetics and
pharmacodynamics of the renally cleared muscle relaxant metocurine. We
hypothesized that pharmacokinetics of the drug would change allometrically
in proportion to physiological time [infinity Mb0.25, where Mb is body
mass] and that pharmacodynamics would be independent of size because of the
highly conserved structure of the acetylcholine receptor. Metocurine
effects during general anesthesia were examined in 17 rats, 8 cats, 6 dogs,
5 pigs, 7 sheep, and 12 horses. Allometric analysis demonstrated size
dependence for pharmacokinetics, which were affected by physiological time
(Mb0.25). Pharmacodynamics were size independent, except for the value for
effect compartment concentration associated with 50% twitch paralysis
(IC50). Data from individual species had a bimodal distribution that was
significant: pigs and sheep were more sensitive than other large species,
and their IC50 appeared 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, and pharmacodynamics were in part size independent.
