Recovery from zoxazolamine paralysis and metabolism in vitro of zoxazolamine in ageing mice.
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A survey of the response of different strains of mice to substances metabolised by microsomal oxidation; hexobarbitone, zoxazolamine and warfarin.
Sixteen strains of mice were compared with respect to their hexobarbitone sleeping time and their zoxazolamine paralysis time. The strains were A2G, CBA, CE, C3H, C57BL, C57L, DBA, F/st, ICFW, NMRI, NZB, Schneider, Simpson, SM, TO and 129/rr. All the strains except 129 Rr were also tested for survival on a diet containing 0.05% racemic Warfarin. There was highly significant interstrain correlation between hexobarbitone sleeping time and zoxazolamine paralysis time (r = 0.72) and between hexobarbitone sleeping time Warfarin survival (r = 0.68). There was a significant correlation between zoxazolamine paralysis time and Warfarin survival (r = 0.56). The correlations can be explained if: (1) there is a genetically determined interstrain variable which is some common component of the microsomal mixed-function oxidase systems involved in the hydroxylation of the three substances; (2) the anticoagulant action of Warfarin is caused more by a hydroxylated metabolite of Warfarin than by Warfarin itself. Phenobarbitone pretreatment shortened hexobarbitone sleeping times and zoxazolamine paralysis times, but its effect was greater in those strains with longer initial hexobarbitone sleeping times and zoxazolamine paralysis times. Piperonyl butoxide pretreatment lengthened hexobarbitone sleeping times, but had no effect on zoxazolamine paralysis times. Warfarin survival was unaltered by pretreatment with either phenobarbital or piperonyl butoxide.
Animals↗
Comparison of the hydroxylation of zoxazolamine and benzo[a]pyrene in human placenta: effect of cigarette smoking.
The in vitro hydroxylation of zoxazolamine was compared with the hydroxylation of benzo[a]pyrene (BP) in full-term placentas from 11 nonsmokers and from 13 women who smoked cigarettes during pregnancy. Cigarette smoking increased the average zoxazolamine and benzo[a]pyrene hydroxylase activities 13- and 39-fold, respectively. A 59-fold range in benzo[a]pyrene hydroxylase activity and a 28-fold range in zoxazolamine hydroxylase activity were found in the placentas of cigarette smokers. A plot of these two enzyme activities showed that zoxazolamine hydroxylase activity was highly correlated, with benzo[a]pyrene hydroxylase activity in the 24 placentas studied (r = 0.98; p less than 0.001). A strong correlation between the above enzymatic activities was also found in 8 placentas which had been stored for 2 yr at -20 degrees C (r = 0.95; p less than 0.001). The results suggest that benzo[a]pyrene and zoxazolamine are metabolized in the human placenta by the same enzyme or by different systems that are under the same regulatory control.
Benzopyrene Hydroxylase↗
On central muscle relaxants, strychnine-insensitive glycine receptors and two old drugs: zoxazolamine and HA-966.
Zoxazolamine is in the centrally-acting muscle relaxant class of drugs, which reportedly act by decreasing CNS interneuronal activity. These drugs, but not anxiolytics, decrease dopaminergic turnover and induce a pacemaker-like discharge pattern in dopaminergic neurons. A mechanism for these effects was not found in previous reports. We observed that (+)-HA-966, an inhibitor of the glycine modulatory site on the NMDA receptor, has a similar effect on dopaminergic impulse flow, which suggested that this may be the possible site of action of classical muscle relaxants. However, a competitive antagonist of NMDA receptors, NPC-12626, had little effect on impulse flow. Binding of 20 nM [3H]-glycine to cortical synaptosomal membranes was inhibited by (+)-HA-966, IC50 = 3.16 microM, but only poorly by zoxazolamine, IC50 V 474 microM, and chlorzoxazone, a related drug, caused no displacement. The drugs were then tested for protection from amphetamine neurotoxicity. Neither 50 mg/kg zoxazolamine nor 30 mg/kg (+)-HA-966 prevented (+)-amphetamine (0.1 mmol/kg plus 10 mg/kg iprindole) depletion of striatal dopamine (DA), but 3.0 mg/kg of MK-801, a non-competitive NMDA receptor antagonist, did protect DA content. Since baclofen induces a regular firing rate in DA neurons, zoxazolamine and (+)-HA-966 were tested for displacement of 10 nM [3H]-1-baclofen from cortical synaptosomal GABAb receptors, but were ineffective. Thus, the effects of these muscle relaxants on DA neurons are mediated by a mechanism other than strychnine-insensitive glycine or GABAb receptors.
Amphetamine↗
Effect of thymectomy on zoxazolamine paralysis and metabolism in untreated and (PCN) pregnenolone-16alpha-carbonitril- or ACTH-pretreated rats.
The effect of thymectomy on zoxazolamine paralysis and metabolism was investigated in young female untreated and PCN- or ACTH-pretreated rats. Thymectomy performed at least 24 hr before injection of zoxazolamine significantly prolonges paralysis time. Pretreatment with PCN (an inducer of hepatic microsomal enzymes) or ACTH (known to alter protein binding and excretion of zoxazolamine) shortened paralysis in thymectomized animals; but only in comparison to thymus ablated controls. The surgical intervention seemed to decrease the metabolism of zoxazolamine in the 9,000g supernatant fraction of the liver.
Adrenocorticotropic Hormone↗
Zoxazolamine-induced paralysis in two rat substrains: differences in hepatic drug metabolism.
Aldehyde dehydrogenase (ALDH) is involved in the metabolism of endogenous and exogenous aldehydes originating from biogenic amines, lipids, food and drugs. Rat liver contains at least two cytosolic ALDHs that can be stimulated by inducers of drug metabolism. Phenobarbital- type inducers increase ALDH1 activity while polycyclic aromatic hydrocarbons (such as benzo[alpha]pyrene) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increase ALDH3c isoenzyme activity. Two rat substrains were isolated according to a different induction of hepatic ALDH after treatment with phenobarbital (PB). Animals that responded to treatment (RR) and those that did not respond (rr) were inbred and divided into two homogenous groups. These animals constituted an ideal experimental model due to their common origin. Apart from the dramatic induction of cytosolic ALDH1 and ALDH3c, the effects of PB on pentoxy-, ethoxy- and methoxy-resorufin-O-dealkylase (P-, E-, and MROD) between the two substrains were also studied. 3-Methylcholanthrene (3MC) greatly increased ALDH3c levels in both substrains, although it was slightly more pronounced in the rr rats, in which it was assessed either as ALDH3c or as total cytosolic ALDH. A similar trend was also noted in EROD, PROD and MROD activities. Dealkylation of the methoxy group was found to be statistically different between the two substrains (rr > RR). The relevance of the biochemical findings with the in vivo hepatic capacity for drug metabolism was investigated by measuring the duration of zoxazolamine paralysis. Both animal substrains were tested with zoxazolamine either without pretreatment or after administration of PB or 3MC: the paralysis produced by zoxazolamine lasted for a longer period in rr than in RR rats. After pretreatment with PB, the duration of paralysis was greatly reduced, but the differences between the two substrains remained. Pretreatment with various doses of 3MC produced differences in the duration of paralysis in RR and rr rats, although the time period was much shorter than that observed in control animals.
Aldehyde Dehydrogenase↗
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)
Animals↗
[Effect of platinum derivatives on the inducible and repressible liver microsomal enzyme systems in the rat: inhibition of zoxazolamine-hydroxylase and induction of dimethyl-nitrosamine demethylase isoenzymes by cis-dichlorodiamine platinum (cis-PtCl2(NH3)2) and ammonium hexachloroplatinum (PtC16(NH4)2)].
Two platinum derivatives, cis-PtCl2(NH3)2 and PtCl6(NH4)2 have been studied for their effects on the Rat on cytochrome P450 in hepatic parenchyma on zoxazolamine-hydroxylase, a typical inducible system and on the two isoenzymes of dimethyl-nitrosamine demethylase, typical repressible systems. The inhibitory effect of PtCl6(NH4)2 on zoxazolamine-hydroxylase activity, previously shown by the authors, has been confirmed. The cis-PtCl2(NH3)2 also significantly inhibits zoxazolamine-hydroxylase activity. On the other hand, both of the platinum derivatives decrease cytochrome P450 level and enhance the dimethyl-nitrosamine metabolism. These various effects and their relationship are discussed.
Animals↗
In vivo activation of zoxazolamine metabolism by flavone.
The metabolism of zoxazolamine to 6-hydroxyzoxazolamine by liver microsomes from neonatal rats is stimulated severalfold by the in vitro addition of flavone, a naturally occurring compound found in several plant species. The intraperitoneal injection of flavone into neonatal rats causes an immediate several-fold stimulation in the rate of total body metabolism of simultaneously administered zoxazolamine. This is the first demonstration of stimulation of oxidative drug metabolism in vivo by a zenobiotic that is an activator of hepatic microsomal.
Animals↗
Massive liver enlargement accompanied by decreased drug metabolism. Effect of anterior pituitary extract on hepatic ultrastructure, zoxazolamine paralysis, and metabolism in the rat.
The relationship between liver enlargement and drug metabolism was investigated in female rats. Hepatomegaly (e.g., 31% increase in liver weight in a 17-day experiment) was induced by injection of lyophylized anterior pituitary (LAP) extract. The liver enlargement seemed to be due to an increase in the number and the size (enhanced water content and PAS-positive material) of hepatocytes. Electron microscopic examination of the liver revealed slight proliferation of the smooth endoplasmic reticulum and pronounced fragmentation and dilation of the rough endoplasmic reticulum. Zoxazolamine paralysis time was significantly prolonged (+55% and +102%) after 4 and 17 days, respectively, of treatment with LAP. Metabolism of zoxazolamine by the 9000 g supernatant fraction of the liver of rats given LAP for 17 days was reduced by 73%. Thus, the marked hepatomegaly induced by LAP was associated with a prolonged action of the drug which may result from a decrease in hepatic drug metabolism.
Animals↗
Effects of cimetidine on theophylline, acetaminophen, and zoxazolamine toxicity in the intact mouse.
3-Methylcholanthrene treatment of C57BL/6N mice induces significant amounts of cytochromes P1-450, whereas P1-450 levels in 3-methylcholanthrene-treated DBA/2N mice are no different from those in control C57BL/6N or DBA/2N mice. Comparison of 3-methylcholanthrene-treated C57BL/6N and DBA/2N mice thus provides a convenient means of determining the role of P1-450 metabolism in two strains of mice following identical drug treatment regimens. 3-Methylcholanthrene-induced P1-450 is shown to be more effective than other forms of P-450 in detoxifying theophylline and zoxazolamine and in enhancing the toxicity of acetaminophen. Cimetidine in vivo blocks these metabolic pathways, resulting in increased toxicity of theophylline and zoxazolamine and protection against acetaminophen toxicity. These data illustrate the double-edged sword nature of P1-450 metabolism and the possibility of a paradoxical effect of cimetidine during drug-drug interactions in vivo. Cimetidine is shown to inhibit in vivo and in vitro the metabolism by both 3-methylcholanthrene-induced P1-450 and control forms of P-450; these data suggest that cimetidine may be acting at the level of P-450 reduction by NADPH-P-450 oxidoreductase. This same mechanism of action has been previously suggested for ellipticine.
Acetaminophen↗
Disposition of lypophilized (methylmethacrylate-14C, 2-hydroxyethylmethacrylate, butylacrylate) nanoparticles in rats and their effect on zoxazolamine paralysis time.
The fate of lyophilized (methylmethacrylate-14C, 2-hydroxyethylmethacrylate, butylacrylate) nanoparticles was studied in male Wistar rats after p.o. administration. It was found that at least 4% of the dose of 14C was absorbed from the gastrointestinal tract after a single dose with these nanoparticles. Some radioactivity (less than 0.15% of dose) was found 7 d after administration in lung, spleen and liver. As expected excretion of the label was predominated via the feces. Ten d of p.o. treatment of rats with lyophilized nanoparticles (1 g/kg of body weight) was shown to prolong significantly zoxazolamine paralysis time. This result suggests that lyophilized nanoparticles decreased elimination of zoxazolamine.
Acrylates↗
Alteration of in vivo zoxazolamine metabolism by carbon monoxide in normal and polycyclic hydrocarbon-treated immature male rats.
The effect of carbon monoxide exposure on the in vivo metabolism of zoxazolamine in normal (corn oil-treated) and 3,4-benzpyrene- and 3-methylcholanthrene-treated, immature, male rats was examined. Pre-exposure of the animals for 90 min followed by determination of the duration of drug action while the animals were maintained in the experimental atmosphere resulted in a qualitative difference in response between normal and polycyclic hydrocarbon-treated animals over the concentration range of 150-450 ppm CO. Corn oil-treated animals demonstrated a decreased duration of drug action when exposed to CO, indicating an increase in the bioavailability of drug for metabolism which may be a result of an increase in liver perfusion rates. In contrast, polycyclic hydrocarbon-treated animals demonstrated an increased duration of drug action on exposure to CO. The qualitative difference in response to CO exposure in the two groups of animals may be due to differences in the sensitivity of cytochrome P-450 and cytochrome P-448 with respect to complexing with CO or to lowered intracellular PO2; or to differences in the dependency on blood flow of the rate of in vivo metabolism of zoxazolamine.
Animals↗
Modulation of zoxazolamine metabolism in carrageenan-induced inflammation in rats.
In male rats bearing carrageenan-induced paw edema twenty-four hours after treatment with carrageenan the duration of hexobarbital hypnosis was prolonged and the rate of hepatic hexobarbital metabolism was inhibited. By contrast, treatment with carrageenan potentiates zoxazolamine paralysis time and inhibits zoxazolamine metabolism in both male and female rats. Thus, sex-related differences in the rats bearing carrageenan-induced paw edema and inhibition of drug metabolism are apparently substrate dependent.
Animals↗
Effects of zoxazolamine and related centrally acting muscle relaxants on nigrostriatal dopaminergic neurons.
The effects of zoxazolamine (ZOX) and related centrally acting muscle relaxants on striatal dopamine (DA) metabolism and turnover, and substantia nigra zona compacta DA neuronal impulse flow were studied in rats. ZOX, chlorzoxazone and mephenesin, but not meprobamate, chloral hydrate, diazepam, pentobarbital, ethanol or dantrolene, decreased striatal DA metabolism without affecting striatal DA concentrations. More specifically, ZOX, as a representative muscle relaxant, was shown to decrease striatal DA turnover without directly affecting DA synthesis, catabolism, reuptake, or release. ZOX decreased nigral DA neuronal firing rates and dramatically decreased firing rate variability (normally many of the cells fire with bursting firing patterns but after ZOX the cells often fired with a very regular pacemaker-like firing pattern). ZOX and related centrally acting muscle relaxants appear to decrease striatal DA turnover by decreasing both neuronal firing rate and firing rate variability. The possible relationships between DA neuronal activity and muscle tone are discussed.
Animals↗
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.
Animals↗
Effects of phenobarbitone, cinnarizine, and zoxazolamine on the development of right ventricular hypertrophy and hypertensive pulmonary vascular disease in rats treated with monocrotaline.
The results of this experiment suggest that the addition of zoxazolamine to the diet may prolong the survival and reduce the incidence of right ventricular hypertrophy and hypertensive pulmonary vascular disease in male rats given a single subcutaneous injection of monocrotaline. Phenobarbitone and cinnarizine were ineffective.
Animals↗
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.
Administration, Oral↗