In dogs, the metabolism of primidone and the pharmacokinetics of the drug itself as well as its metabolites phenobarbital and phenylethylmalonic acid diamide (PEMA) was followed after single oral doses of 30 mg/kg (0.14 mmole/kg). Primidone was rapidly absorbed, so that maximal serum concentrations were reached after 2 hr, the concentration fell then with a half-life averaging 5 hr in Beagles and 10 hr in Mongrels. PEMA appeared in plasma with a ka of 0.003--0.005 min-1, reached maximal concentrations after about 6.5 hr in Beagles and 12 hr in Mongrels. The elimination half-life averaged 7.5 hr in Beagles and 14 hr in Mongrels. After single oral doses, phenobarbital could only be detected in low concentrations in some Beagles. Phenobarbital had an elimination half-life of 32 +/- 4.8 hr in Beagles and of 70 +/- 16 hr in Mongrels. During continued treatment with daily doses of 30--50 mg/kg primidone, steady-state concentrations of about 15 micrograms/ml (65 nmole/ml) were reached after 6--8 days, the PEMA concentrations showed rather pronounced fluctuations around average values of 8--10 micrograms/ml (39--49 nmole/ml), whereas the concentrations of primidone mainly remained below 5 micrograms/ml (23 nmole/ml). In mice, the anticonvulsant potency of the 3 drugs was determined: Elevations of the electroconvulsant threshold by 40 V were produced by 0.01 mmole/kg of phenobarbital, 0.017 mmole/kg of primidone or 0.37 mmole/kg of PEMA. Taking the anticonvulsant potency of the 3 drugs into consideration, phenobarbital is responsible for more than 85% of the total anticonvulsant activity during continued medication of primidone. The penetration of primidone and its metabolites into the cerebro-spinal fluid was followed: phenobarbital reached steady state levels already after 1--1.5 hr, primidone and PEMA not before 2.5 hr. The concentrations in CSF roughly corresponded to the free drug in plasma. On account of the similarities in metabolism and pharmacokinetics of primidone in dog and man, the former species seems to be a suitable model in epilepsy research. Differences between both species are most pronounced in the Beagle.