PHYSIOLOGICALLY-BASED PHARMACOKINETICS MODEL OF PRIMIDONE AND ITS METABOLITES PHENOBARBITAL AND PHENYLETHYLMALONAMIDE IN HUMANS, RATS, AND MICE

Physiologically based pharmacokinetic modeling of the parent chemical primidone and its two metabolites phenobarbital and phenylethylmalonam ide (PEMA) was applied to investigate the differences of primidone met abolism among humans, rats, and mice. The model simulated previously p ublished pharmacokinetic data of the parent chemical and its metabolit es in plasma and brain tissues from separate studies of the three spec ies. Metabolism of primidone and its metabolites varied widely among a sample of three human subjects from two separate studies, Estimated p rimidone metabolism, as expressed by the maximal velocity V-max, range d from 0 to 0.24 mg . min(-1) . kg(-1) for the production of phenobarb ital and from 0.003 to 0.02 mg . min(-1) . kg(-1) for the production o f PEMA among three human subjects. Further model simulations indicated that rats were more efficient at producing and clearing phenobarbital and PEMA than mice. However, the overall metabolism profile of primid one and its metabolites in mice indicated that mice were at higher ris k of toxicity owing to higher residence of phenobarbital in their tiss ues and owing to the carcinogenic potential of phenobarbital as illust rated in long-term bioassays, This result was in agreement with a rece ntly finished National Toxicology Program (NTP) carcinogenicity study of primidone in rats and mice.