Proadifen (SKF-525A), an inhibitor of cytochrome P-450, augments LPS-induced fever and exacerbates prostaglandin-E 2 levels in the rat

Abstract

Fever in rats was induced by intraperitoneal injection of lipopolysaccharide (LPS; 50 μg/kg) and body temperature was measured by biotelemetry. Inhibitors of cytochrome P-450, SKF-525A and clotrimazole, injected peripherally (15 mg/kg) or into the brain (SKF-525A; 5 μg/rat) augmented fever. SKF-525A given intraperitoneally doubled the increase of the 3 h post-LPS plasma prostaglandin-E 2 (PGE 2) level from 169±37 pg/ml in control/LPS to 343±45 pg/ml in SKF-525A/LPS rats. SKF-525A administered into the brain (lateral ventricle) exacerbated the LPS-induced elevation of PGE2 in cerebrospinal fluid from 31±5 pg/ml in control/LPS to 92±21 pg/ml in SKF-525A/LPS rats. These data support the hypothesis that inhibitors of P-450 augment fever due to exacerbation of the level of PGE2 induced by LPS.