The suppressive effects of lipopolysaccharide-induced acute phase response on 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 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.
Saitoh
T
T
Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Fuchu, Japan.
Kokue
E
E
Shimoda
M
M
D000210:Acute-Phase Reaction / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics; D000983:Antipyrine / Q000097:blood / Q000493:pharmacokinetics; D015153:Blotting, Western; D001831:Body Temperature / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003864:Depression, Chemical; D004731:Endotoxins / Q000494:pharmacology*; D004926:Escherichia coli / Q000378:metabolism; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011817:Rabbits; D012709:Serum Albumin / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004731:Endotoxins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D004364:Pharmaceutical Preparations; D012709:Serum Albumin; C044101:endotoxin, Escherichia coli; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D000983:Antipyrine