Disposition of primidone, phenylethylmalonamide, and phenobarbital in the rabbit
Hunt, R.J.; Miller, K.W.
Drug Metabolism and Disposition the Biological Fate of Chemicals 6(1): 75-81
1978
ISSN/ISBN: 0090-9556 PMID: 23277 Document Number: 132105
The disposition of primidone (PRM), employed in the treatment of grand mal and psychomotor epilepsy, and its metabolites, phenylethylmalonamide (PEMA) and phenobarbital (PB), following i.v. administration of PRM to rabbits was investigated. Kinetic analysis of the plasma concentration-time data demonstrated that PRM, PEMA and PB each disappear from the plasma in a manner that can be described by a biexponential equation. The mean values for the terminal log-linear portions of the plasma concentration curves were approximately 2.3, 8.8 and 30.7 h for PRM, PEMA and PB, respectively. The formation of PEMA and PB following i.v. administration of PRM was quite rapid, with both compounds detectable in the plasma within 5 min of PRM administration. The plasma levels of all 3 drugs following the administration of PRM could be fitted to a 4-compartment pharmacokinetic model by use of nonlinear regression analysis. From both plasma and urine data, approximately 40% of an i.v. dose of PRM is metabolized to PEMA, 40% is metabolized to PB and approximately 20% is excreted as unchanged PRM. No attempt to isolate minor metabolites was made, but evidence for a N-glucuronide conjugate of PEMA was obtained. When rabbits were pretreated with phenytoin (PHE) for 5 days prior to i.v. administration of PRM, the total body clearances of PRM and its metabolites formed in vivo were increased. The rates of formation of the metabolites also appeared to be more rapid in the PHE-pretreated animals.