Effects of model traumatic injury on hepatic drug metabolism in the rat. II. In vivo metabolism of hexobarbital and zoxazolamine.

A previously validated small mammal trauma model, hind-limb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to further investigate the effects of traumatic injury on hepatic drug metabolism in vivo. The pharmacokinetic sequelae of the previously observed post-traumatic decrease in cytochrome P-450 content were demonstrated, using hexobarbital and zoxazolamine as model cytochrome P-450-oxidized drugs. Sleeping times after ip or iv administration of these drugs was prolonged by model injury. Longer sleeping times appeared to be caused by a slower elimination of the drugs from the bloodstream rather than to an increased sensitivity to their central nervous system effects or to an alteration in plasma protein-binding. Detailed pharmacokinetic analyses by the two-compartmental open system model revealed that the major alteration in post-traumatic drug metabolism was decreased in vivo elimination rather than a shift in distribution. These studies further confirm the pharmacokinetic utility of this convenient small mammal trauma model in the study of post-traumatic derangements in hepatic drug metabolism and emphasize the toxicologic importance of these derangements.