Pharmacokinetics of saturably metabolized amobarbital

Abstract

The pharmacokinetics of intravenously administered amobarbital (5–40 mg/kg) and its major metabolite, hydroxyamobarbital, were evaluated by GLC monitoring in the blood and urine of dogs. The induction of alkalosis and acidosis by adjustment of respiration rates and by modification of blood pH showed relatively instantaneous and significant changes in apparent blood levels of the amobarbital that could be assigned to variable ratios of ionized to un- ionized drug, with the latter showing greater partition into peripheral tissues, i.e., an effective change in apparent volumes of distribution. It was demonstrated that metabolism of amobarbital was a saturable process and largely zero order over the entire dose ranges studied. The rate of appearance of hydroxyamobarbital was of the same magnitude for the various doses. Enzymic induction by prior chronic administration of phenobarbital dramatically increased the rate of metabolism, and the operational pharmacokinetic model was consistent with the two-compartment open body model with first-order transferences. This model also held at all times for intravenously administered hydroxyamobarbital. The administration of SKF 525 greatly inhibited the rate of amobarbital metabolism in the dog.