Evaluation of sustained-release granules of chlorphenesin carbamate in dogs and humans

The bioavailability and pharmacokinetic properties of two sustained-release (SR) formulations of chlorphenesin carbamate (CPC) with different in vitro release rates were compared to those of an immediate-release (IR) formulation in beagle dogs and humans. Plasma levels of CPC were determined by HPLC assay. In humans, both SR formulations (SR-1 and SR-2), which have a difference in the rates of in vitro release, showed satisfactory maintenance of plasma concentrations with sufficient bioavailability as compared with the IR formulation, and their bioavailabilities relative to IR (relative bioavailability) were 1.00 and 0.86 for SR-1 and SR-2, respectively. Satisfactory maintenance of plasma concentration was also obtained in dogs, although the gastrointestinal transit time was shorter than that in humans. The relative bioavailabilities under fasting conditions in dogs were 1.05 and 0.90, respectively, and were almost the same in humans. The absorption from the small intestine and colon was almost complete for CPC in rats. It is suggested that the bioavailability of CPC was little affected by the gastrointestinal transit time. The reason that the bioavailability and pharmacokinetic properties of CPC in dogs were similar to those in humans might be due to the continuous absorption of CPC from these SR formulations after arrival in the colon. In this study, the dog was found to be a useful animal model for primary screening of SR formulations containing a drug which can be absorbed from the entire intestine, such as CPC.