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Abstract
1. Comparative studies on the distribution and metabolism of [2-14C]amobarbital following 50 mg/kg intraperitoneal doses in non-tolerant and tolerant rats are described. Levels of free amobarbital in brain and plasma were significantly lower in tolerant than in non-tolerant rats.
2. Tolerant rats showed faster rates of metabolism and tissue disappearance (t0.5 amobarbital in brain of non-tolerant and tolerant rats; 1.7 and 0.7 h, respectively; in plasma 2.4 and 0.9 h, respectively).
3. Consistently lower brain to plasma ratios of amobarbital in tolerant rats indicated an altered distribution of d:ug in this group. No accumulation or persistence of amobarbital was observed in the central nervous system of rats in either group.
4. The mean percentages of free amobarbital, 3'-hydroxyamobarbital, conjugated 3'-hydroxymetabolite, two other unidentified metabolites and urea excreted by rats were approximately 1.5, 75.1, 8.8, 6.2, 3.5 and 5%, respectively. Tolerant rats metabolized amobarbital in a manner qualitatively similar to the non-tolerant rats.
5. A significant increase in total plasma proteins was observed in tolerant rats compared to the non-tolerant group. Data support the postulate that chronic amobarbital administration induced the synthesis of hepatic hydroxylating enzymes, and also of non-specific plasma protein binding sites, resulting in a lower plasma concentration of free diffusible drug in tolerant than in non-tolerant rats.