URINARY EXCRETION OF PRIMIDONE AND ITS METABOLITES IN RABBITS

¹ Department of Pharmacology, School of Medicine, Tulane University, New Orleans, Louisiana

After a dose of 400 mg/kg p.o. of primidone, 4% was excreted as phenobarbital whereas ethylphenylmalondiamide and primidone accounted for 48 and 20%, respectively. With multiple doses of primidone, increasing excretion of phenobarbital indicated that phenobarbital was accumulating in the animal. This effect occurred because of slow excretion of the phenobarbital and could not have resulted from accumulation of primidone or gradual increased absorption of the oral doses of primidone. Since the original estimate of 4% conversion of primidone to phenobarbital was based solely on measurement of free phenobarbital, the further metabolism of phenobarbital itself was studied. With phenobarbital-2-C¹⁴ i.v., results indicated that about 40% of the urinary radioactivity was free phenobarbital with a small amount of free p-hydroxyphenobarbital. The major metabolite in the rabbit was presumably p-hydroxyphenobarbitalglucuronide as indicated by countercurrent analyses and ability to be hydrolyzed by -glucuronidase. In these studies with phenobarbital-2-C¹⁴, a circadian rhythm was manifested in the percentage of the radioactivity excreted as phenobarbital and the metabolite.