Allometry of pharmacokinetics and pharmacodynamics of the muscle relaxant metocurine in mammals.
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.
Gronert
G A
GA
Department of Anesthesiology, School of Medicine, University of California, Davis 95616-8634.
Fung
D L
DL
Jones
J H
JH
Shafer
S L
SL
Hildebrand
S V
SV
Disbrow
E A
EA
D000768:Anesthesia, General; D000818:Animals; D001835:Body Weight; D002415:Cats; D004285:Dogs; D006207:Half-Life; D006736:Horses; D006801:Humans; D008322:Mammals / Q000378:metabolism*; D009467:Neuromuscular Depolarizing Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D011950:Receptors, Cholinergic / Q000502:physiology; D012044:Regression Analysis; D012756:Sheep; D013045:Species Specificity; D013552:Swine; D014403:Tubocurarine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D009467:Neuromuscular Depolarizing Agents; D011950:Receptors, Cholinergic; C032943:metocurine; D014403:Tubocurarine