[
carisoprodol structure: see text]
Carisoprodol is a widely used skeletal muscle relaxant and
analgesic and is available as a
prescription drug. Comparative studies were conducted to determine the toxicity of
carisoprodol administered in
corn oil and in 0.5%
methylcellulose by gavage.
Carisoprodol plasma concentrations of rats and mice were measured at the end of the 13-week studies; single-dose plasma
carisoprodol analyses were also performed. Genetic toxicity studies were conducted in Salmonella typhimurium, L5178Y mouse
lymphoma cells, cultured Chinese hamster ovary cells, and peripheral blood erythrocytes of mice. Groups of 10 male and 10 female F344/N rats received 0, 100, 200, 400, 800, or 1,600 mg
carisoprodol per kilogram
body weight in
corn oil by gavage or 0, 100, 200, 400, or 800 mg/kg
carisoprodol in 0.5%
methylcellulose by gavage for 13 weeks. Groups of 10 male and 10 female B6C3F1 mice received 0, 75, 150, 300, 600, or 1,200 mg/kg
carisoprodol in
corn oil by gavage or 0, 600, 1,200, or 1,600 mg/kg
carisoprodol in 0.5%
methylcellulose by gavage for 13 weeks. Among rats that received
carisoprodol in
corn oil, survival was similar to that of the vehicle controls. Survival of rats administered
carisoprodol in 0.5%
methylcellulose was also similar to that of the vehicle controls after adjustment for deaths (two males and one female in the 800 mg/kg group and two females in the 400 mg/kg group). The final mean
body weight gain of males administered 1,600 mg/kg
carisoprodol in
corn oil was significantly less than that of the vehicle controls; the final mean
body weights and
body weight gains of female rats in the 800 and 1,600 mg/kg groups were significantly greater. In the
carisoprodol in 0.5%
methylcellulose study, males in the 200 mg/kg group and females in the 100 and 800 mg/kg groups had significantly greater mean
body weights and
body weight gains than did the vehicle controls. Clinical findings in rats administered
carisoprodol in
corn oil or in 0.5%
methylcellulose included
lethargy,
ataxia,
diarrhea, and prostration; the incidences were dose-related, and females were more sensitive than males to the effects of
carisoprodol. In the
carisoprodol in
corn oil study, differences in hematology and clinical chemistry parameters occurred with no consistent patterns. The effects of
carisoprodol in 0.5%
methylcellulose on hematology and clinical chemistry parameters were not studied. In the
corn oil study, the kidney and liver weights of male and female rats administered 200 mg/kg
carisoprodol or greater were generally significantly greater than those of the vehicle controls. In the 0.5%
methylcellulose study, liver weights were significantly greater in male rats administered 400 or 800 mg/kg and in female rats administered 800 mg/kg
carisoprodol compared to the vehicle controls; however, a consistent effect on the kidney weights was not observed. Nephropathy was observed in male rats administered 400 mg/kg
carisoprodol or greater in
corn oil; the livers of four males in the 1,600 mg/kg group had centrilobular
hypertrophy of hepatocytes. No lesions were observed histopathologically in female rats administered
carisoprodol in
corn oil. In the
carisoprodol in 0.5%
methylcellulose study, the severity of nephropathy in males administered 200 mg/kg or greater was enhanced, and the incidence of nephropathy in female rats in the 800 mg/kg group was slightly greater than that in the vehicle controls. Plasma
carisoprodol concentrations at the end of 13 weeks generally increased with increasing dose in rats administered
carisoprodol in
corn oil or in 0.5%
methylcellulose. The plasma
carisoprodol concentrations in rats administered a single gavage dose of
carisoprodol in
corn oil also increased with increasing dose. In the
carisoprodol in
corn oil mouse study, two females each in the vehicle control and 75 mg/kg groups and one female each in the 150 and 600 mg/kg groups were accidentally killed; all males survived to the end of the study. One male and one female administered 1,600 mg/kg
carisoprodol in 0.5%
methylcellulose died; seven mice were accidentally killed. The mean
body weights and
body weight gains of mice administered
carisoprodol in
corn oil were generally similar to those of the vehicle controls. The final mean
body weights and
body weight gains of all groups of males and females administered
carisoprodol in 0.5%
methylcellulose were significantly less. Clinical findings in the
carisoprodol in
corn oil study included
lethargy,
ataxia,
tremors, and prostration in male and female mice.
Ataxia,
lethargy, convulsions, and prostration were observed in all dosed groups of males and females administered
carisoprodol in 0.5%
methylcellulose. In the
carisoprodol in
corn oil study, liver weights were significantly greater in males administered 300 mg/kg or greater and in females administered 150 mg/kg or greater than in the vehicle controls. In the
carisoprodol in
corn oil study, no gross or microscopic lesions were considered related to
carisoprodol administration. Minimal to mild centrilobular
hypertrophy was observed in the liver of all dosed groups of males and in females in the 1,200 and 1,600 mg/kg groups in the
carisoprodol in 0.5%
methylcellulose study. The testis weights of males administered 1,200 mg/kg
carisoprodol in
corn oil were significantly less than those of the vehicle controls; the sperm motility of males in this group was also significantly less than that of the vehicle controls. There were no significant differences in vaginal cytology parameters between dosed and vehicle control females. At the end of the
carisoprodol in
corn oil study, the concentration of
carisoprodol was above the limit of detection in the plasma of only one male mouse each in the 300 and 1,200 mg/kg groups and in four females in the 1,200 mg/kg group. In mice administered a single gavage dose of
carisoprodol in
corn oil, plasma concentrations increased with increasing dose; peak plasma concentrations occurred at 20 to 120 minutes in males and 60 to 120 minutes in females. In the
carisoprodol in 0.5%
methylcellulose study, plasma
carisoprodol concentrations of female, but not male, mice increased with increasing dose; peak plasma
carisoprodol concentrations occurred at 30 minutes postdosing in all groups of males and females. Results of proportionality and bioavailability studies indicated that single gavage doses of 200 to 800 mg/kg
carisoprodol in 0.5%
methylcellulose in rats or 300 to 1,200 mg/kg in mice were dose proportional; absolute bioavailability values increased with increasing dose, ranging from 15% to 32% for rats and from 18% to 38% for mice. For rats, the bioavailability of
carisoprodol in 0.5%
methylcellulose was approximately fivefold that of
carisoprodol in
corn oil; the Cmax values of the dose in 0.5%
methylcellulose were approximately threefold those of the dose in
corn oil. For mice, no significant difference was observed in the bioavailability of
carisoprodol between the vehicles; however, the Cmax values of the dose in 0.5%
methylcellulose were 1.5 to 1.75 times those of the dose in
corn oil.
Carisoprodol was not mutagenic in any of four strains of Salmonella typhimurium, with or without S9 metabolic activation. It did induce mutations in L5178Y mouse
lymphoma cells in the absence of S9; with S9, no mutagenic activity was noted in this assay. Results of the sister chromatid exchange test with
carisoprodol in cultured Chinese hamster ovary cells were considered equivocal with and without S9.
Chromosomal aberrations in cultured Chinese hamster ovary cells were clearly increased by
carisoprodol treatment, particularly in the presence of S9. No significant increases in the frequency of micronucleated erythrocytes were observed in peripheral blood samples from male and female mice administered
carisoprodol by gavage for 13 weeks. In conclusion,
carisoprodol induced
ataxia and prostration in rats and mice, increases in liver weights in rats and mice, and nephropathy in male rats. The bioavailability of
carisoprodol in 5%
methylcellulose was greater than in
corn oil. The no-observed-adverse-effect (NOAEL) level of
carisoprodol administered in
corn oil or in 0.5%
methylcellulose was determined to be 100 mg/kg, compared to the clinical dose of 20 mg/kg per day for adults and 5 to 7.5 mg/kg per day for children.