The effect of the acute-phase response on in vitro drug metabolism and plasma protein binding in the horse.

Abstract

The effect of the acute-phase response (APR) on the activity of the hepatic drug-metabolizing system (DMS) and on the binding of phenylbutazone to plasma proteins was investigated in the horse. An APR was induced by intramuscular injections of Freund's complete adjuvant in five horses and, five days later, these horses together with five clinically normal horses were shot and the right ventral lobe of each liver removed. The hepatic microsomal fractions from the liver samples were isolated and significantly lower (p < 0.01) concentrations of cytochromes P450 and b5 and activities of aniline-p-hydroxylase and aminopyrine N-demethylase (43%, 55%, 45% and 30%, respectively) were measured in the livers from the adjuvant-inflamed horses, compared to the controls. Phenylbutazone (PBZ) was administered intravenously (4.4 mg/kg) to a further four horses and plasma protein binding was measured by ultracentrifugation. Five weeks later, these horses were injected with Freund's complete adjuvant and the intravenous administration of PBZ (4.4 mg/kg) was repeated. Inflammation induced a significant increase (p < 0.01) in the unbound fraction of PBZ (5.2 +/- 0.5 as against 1.4 +/- 0.6%). These results suggest that the APR depresses the hepatic DMS and reduces the binding of PBZ to plasma proteins.