Pharmacodynamics of zoxazolamine and chlorzoxazone in rats

Zoxazolamine is used for the pharmacologic assessment of possible changes in oxidative enzyme activity (paralysis time test) in rodents, whereas one of its metabolites, chlorzoxazone, is used clinically as a skeletal muscle relaxant. In this investigation, the pharmacodynamics of the two compounds were characterized in normal adult rats to determine their suitability for studies of the kinetics of drug action in disease states. Upon i.v. infusion 5 min beyond the onset of loss of the righting reflex (LRR) and concomitant blood sampling, serum concentrations of either drug were higher at the onset than at the offset of LRR, suggestive of a distribution disequilibrium. When zoxazolamine was infused at three different rates to onset of LRR, the pharmacologic end point was reached in 10 to 53 min. Drug concentrations in serum and brain at onset of LRR increased with increasing infusion rate, whereas drug concentrations in cerebrospinal fluid (CSF) were infusion rate independent and essentially identical to CSF concentrations at offset of LRR. Similar experiments (five infusion rates) with chlorzoxazone revealed drug infusion rate dependence even of CSF concentrations at the onset of LRR; only at very slow infusion rates (onset of effect in greater than or equal to 50 min) were onset concentrations in CSF essentially equal to offset concentrations. Neither drug produced measurable metabolite concentrations in the CSF. It is concluded that zoxazolamine but not chlorzoxazone distributes rapidly between CSF and the biophase, metabolites of either drug do not contribute measurably to the pharmacologic effect, and neither drug is subject to development of functional tolerance under the experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)