Saitoh T, Kokue E, Shimoda M
Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Fuchu, Japan.
J Vet Pharmacol Ther. 1999 Apr;22(2):87-95. doi: 10.1046/j.1365-2885.1999.00195.x.
The acute phase response (APR) was induced by five separate intravenous (i.v.) injections of Escherichia coli lipopolysaccharide (LPS, 17 microg/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 included in each of four groups, a control group and three LPS-treated groups (group I, II and III). The rabbits of the control, group I, II and III were killed at 1, 1, 3 and 7 days after saline (control only) or the LPS injection, respectively. The APR was confirmed by increases in rectal body temperature, plasma concentrations of interleukin-6 and C-reactive protein (CRP). Pharmacokinetics of antipyrine before death were examined in every group. Antipyrine 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 livers 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 maximum velocity (Vmax) values of those enzymes, and the amount of CYP1A1/1A2 and CYP2E1 apoproteins appeared to decrease. Michaelis constant (Km) values 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 clearance of antipyrine returned to the control levels at 7 days after the first LPS injection. These results suggest that the metabolism of drugs, including CYP-dependent drug metabolizing activity, is suppressed markedly in incipient APR induction in rabbits, and the drug metabolizing capacity is returned to normal at 7 days after APR induction.
通过对家兔进行五次单独的静脉注射大肠杆菌脂多糖(LPS,每次17微克/千克)诱导急性期反应(APR),间隔为1小时。该模型用于研究APR对肝微粒体细胞色素P450(CYP)依赖性酶活性(包括药物代谢)的影响。四个组每组纳入五只雌性家兔,一个对照组和三个LPS处理组(I组、II组和III组)。对照组、I组、II组和III组的家兔分别在注射生理盐水(仅对照组)或LPS后的1天、1天、3天和7天处死。通过直肠体温升高、白细胞介素-6和C反应蛋白(CRP)的血浆浓度升高来确认APR。在每组中检查死亡前安替比林的药代动力学。在首次注射LPS后的24小时(对照组和I组)、3天(II组)和7天(III组)给予安替比林(5毫克/千克)。I组中安替比林的总体清除率(Cl(tot))有下降趋势。切除所有肝脏以测量CYP依赖性活性。I组中总CYP含量和几种CYP依赖性活性(氨基比林N-脱甲基化、苯胺4-羟基化和咖啡因3-脱甲基化)降低。这些酶的最大速度(Vmax)值以及CYP1A1/1A2和CYP2E1载脂蛋白的量似乎减少。这些酶的米氏常数(Km)值不受APR影响。II组和III组在首次注射LPS后3天直肠体温恢复正常。首次注射LPS后7天,CRP浓度、白蛋白、总CYP含量和安替比林的血浆清除率恢复到对照水平。这些结果表明,在兔急性期反应初期诱导过程中,包括CYP依赖性药物代谢活性在内的药物代谢受到明显抑制,并且在急性期反应诱导后7天药物代谢能力恢复正常。