Effects of furazolidone on duration of righting reflex loss induced with hexobarbital and zoxazolamine in the rat.

Effects of furazolidone (FZ) on the sleeping time induced with hexobarbital (HEX) and paralysis time induced by zoxazolamine (ZOX) were investigated by measuring the length of time required to recover from righting reflex loss in rats after oral administration of FZ at doses of 50, 100, 200 and 400 mg/kg/day for 4 successive days. Administration of 50 mg/kg to rats of both sexes induced no effect on the HEX sleeping time, but of 100 mg/kg FZ or more induced prolongation of sleeping time dose-dependently. In female rats, HEX sleeping time of the control group was twice that of the male rats, but HEX sleeping time after receiving FZ above 200 mg/kg was approximately the same as in the male rats. ZOX paralysis time exhibited no sex differences in the control rats, and it was significantly prolonged by FZ at a dose of 100 mg/kg or more. No significant differences in blood levels of HEX and ZOX at the time of recovery were found between the control and FZ treated rats, suggesting that FZ produced prolongation of the drug effects was due to the maintenance of the blood levels rather than the change in the sensitivities of rats at the receptor sites. Body weight gains were inhibited in the rats treated with FZ at doses over 100 mg/kg. Cytochrome P-450 content in hepatic microsomes in the rats which received 100 mg/kg FZ were slightly increased. It is suggested that successive oral administration of FZ to rats at high doses impaired drug clearance and this resulted in the prolongation of HEX sleeping and ZOX paralysis times.

Effects of ciprofloxacin and enrofloxacin on zoxazolamine kinetics, plasma concentration and sleeping times in mice.

The treatment of CD1 male mice with either ciprofloxacin (CP) or enrofloxacin (EF) prior to zoxazolamine (ZX) administration increased the mean ZX sleeping times to, respectively, 162 and 156% of the control (ZX alone). At the end of the sleeping time, the mean ZX plasma concentration in controls was 27.2 micrograms/ml and was not different in EF- or CP-treated groups (87% and 95% of controls, respectively). The animals coadministered with CP or EF and ZX eliminated the latter more slowly than the controls. The estimated zero-time drug concentration of the disposition curves of both the CP- and EF-treated groups as well as the apparent half-life of elimination and apparent overall rate of elimination of the CP-treated group were different from the control values.

Inhibitory effects of beryllium chloride on rat liver microsomal enzymes.

A single i.v. dose (0.1 mmol Be2+/kg) of beryllium chloride prolonged the duration of pentobarbital-induced sleep and zoxazolamine-induced paralysis, in rats. The effects are correlated with changes of the pharmacokinetic parameters and with the in vitro inhibition of both aliphatic and aromatic hydroxylation of pentobarbital and zoxazolamine. In vitro N-demethylation of meperidine and aminopyrine was partially inhibited while O-demethylation of quinidine was unaffected by liver microsomes of rats pretreated with beryllium salt. The findings give clues that beryllium chloride inhibits some forms of cytochrome P-450, especially those responsible for hydroxylation of substrates, like pentobarbital and zoxazolamine.

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)

Effect of praseodymium chloride on liver microsomal enzymes of rats.

A single i.v. dose (5 mg/kg) of a light lanthanon, praseodymium, prolonged the duration of hexobarbital-induced sleep and zoxazolamine-induced paralysis, as well as it modified pharmacokinetic parameters of hexobarbital and zoxazolamine, in rats. Half-lives (t1/2) and area under the curve (AUC) were increased, while elimination coefficient (beta) and clearance (Cl) were decreased. However, in daily doses of 1 mg/kg i.p. for 15 days, praseodymium did not alter pharmacological effects and pharmacokinetic parameters. The in vitro hydroxylation of hexobarbital and zoxazolamine by liver microsomes was inhibited when the animals were treated previously with a single i.v. dose (5 mg/kg) of praseodymium chloride. In these animals, the amount of cytochromes P-450 and b5 were reduced significantly, whereas that of NADPH-cytochrome c reductase remained unchanged. The pretreatment of animals with phenobarbital normalized the microsomal enzyme impairment caused by praseodymium.

Dose-dependent pharmacokinetics of zoxazolamine in the rat.

Zoxazolamine (ZX) is a model substrate frequently used in studies on (methylcholanthrene-inducible) hepatic cytochrome P-450 activity. The iv pharmacokinetics of ZX were studied in rats at four dose levels: 5 mg X kg-1 (n = 6), 25 mg X kg-1 (n = 6), 50 mg X kg-1 (n = 5), and 60 mg X kg-1 (n = 4). Concentrations of ZX in blood, as well as the urinary excretion of unchanged ZX and chlorzoxazone, were determined. The apparent systemic clearance (CLs,app) decreased with increasing dose from 52.6 +/- 3.9 at 5 mg X kg-1 to 9.3 +/- 0.4 ml X min-1 X kg-1 at 60 mg X kg-1. The apparent elimination half-life, t1/2,app, increased from 16.1 +/- 0.3 min to 141 +/- 28.5 min. There was only slight concentration dependency of plasma protein binding: 86.0 +/- 0.9% at 4.2 +/- 0.2 micrograms X ml-1 (n = 6) vs. 80.4 +/- 0.4% at 27.1 +/- 1.1 micrograms X ml-1 (n = 6). Since from clearance and protein binding data nonrestrictive clearance of ZX could be inferred, this small change in binding was regarded as irrelevant for the interpretation of pharmacokinetic data of ZX. The blood-plasma concentration ratio was larger than unity: 2.11 +/- 0.09 at 5.4 +/- 0.9 micrograms X ml-1, and 1.85 +/- 0.08 at 47.9 +/- 4.9 micrograms X ml-1 (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)