The suppressive effects of lipopolysaccharide-induced acute phase responseon hepatic cytochrome P450-dependent drug metabolism in rabbits

The acute phase response (APR) was induced by five separate intravenous (i. v.) injections of Escherichia coli lipopolysaccharide (LPS, 17 mu g/kg each time) in rabbits, with intervals of 1 h. This model was used to study the effects of APR on the activities of hepatic microsomal cytochrome P450 (CYP )-dependent enzyme including drug metabolism. Five female rabbits were incl uded in each of four groups, a control group and three LPS-treated groups ( group I, II and In). The rabbits of the control, group I, II and III were k illed at 1, 1, 3 and 7 days after saline (control only) or the LPS injectio n, respectively, The APR was confirmed by increases in rectal body temperat ure, plasma concentrations of interleukin-6 and C-reactive protein (CRP). P harmacokinetics of antipyrine before death were examined in every group. An tipyrine was administered (5 mg/kg) at 24 h (control and group I), 3 days ( group II) and 7 days (group III) after the first LPS injection, Total body clearance (Cl-tot) of antipyrine tended to decrease in group I. All the liv ers were excised for measuring CYP-dependent activities. Total CYP content and several CYP-dependent activities (aminopyrine N-demethylation, aniline 4-hydroxylation and caffeine 3-demethylation) decreased in group I, The max imum velocity (V-max) values of those enzymes, and the amount of CYP1A1/ 1A 2 and CYP2E1 apoproteins appeared to decrease. Michaelis constant (K-m) val ues of those enzymes were not affected by the APR. Rectal body temperature recovered to normal at 3 days after the first LPS injection in group II and III. The concentration of CRP, albumin, total CYP content and the plasma c learance of antipyrine returned to the control levels at 7 days after the f irst LPS injection. These results suggest that the metabolism of drugs, inc luding CYP-dependent drug metabolizing activity, is suppressed markedly in incipient APR induction in rabbits, and the drug metabolizing capacity is r eturned to normal at 7 days after APR induction.