[Various mechanisms of the depriming effect of bacterial endotoxin on drug metabolism].

The effect of an endotoxin from Sh. Boydii on the biotransformation of amidopyrine and acetanilide, the activity of microsomal monooxygenases, hemoxygenase, and xanthine oxidase, the lipid peroxidation (LPO) intensity, the phospholipid spectrum, and the solubilization of microsomal membrane components was studied by intraperitoneal injections (2.5 mg/kg) in rats. It was found that the endotoxin inhibits the reactions of C- and N-acetanilide hydroxylation, N-amidopyrine demethylation, acetanilide hydrolysis at the amide bond, conjugation of aminophenol metabolites with glucuronic acid and sulfate, and 4-aminoantipyrine binding to acetate. The endotoxin effect reached maximum 24 h after injection and was observed for 96 h. The inhibition of metabolism of the test preparations is related to a decrease in the content of cytochrome P-450 and in the activity of 1A2, its 2B, 2C, 3A, and 2E1 isoforms. This is obviously caused by activated LPO and enhanced nitric oxide synthesis, as evidenced by a tenfold increase in the content of NO metabolites (nitrites and nitrates) in the blood of test animals. In clinical practice, it is necessary to take into account the possibility of a significant biotransformation of drugs in the acute period of bacterial infection, which may lead to changes in the pharmacological effect and toxicity of some drugs.