Unusual serum profiles of phenprobamate, a centrally skeletal muscle relaxant, were observed in Sprague Dawley rats receiving multiple doses of phenprobamate suspension. The concentrations of phenprobamate were higher after the morning doses than after the evening doses, synchronizing with the day-night pattern of drug administration. Crossover studies were conducted to investigate the apparent time-dependent kinetics of phenprobamate. Phenprobamate emulsion was orally administered as a single dose to a group of six rats at 0900 hr and again, after a washout period of 3 days, at 2100 hr. Another group of six rats was treated similarly with intraperitoneal drug administration. Blood samples were collected at various times for 12 hr. The AUCs were 146.56 +/- 31.77 micrograms.hr/ml for the morning oral dose and 111.31 +/- 21.32 micrograms.hr/ml for the evening oral dose (P less than 0.001). Administered intraperitoneally, the AUCs were 179.89 +/- 37.50 and 185.58 +/- 28.51 micrograms.hr/ml for the morning and evening doses, respectively, the difference of which was not significant. The paired t test indicated a significant morning-evening difference in AUC following oral but not intraperitoneal drug administration. This suggests the absorption rather than metabolism as a contributing factor to the time-dependent kinetics of phenprobamate in rats.