Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism
| Autor: | B. C. Israel, Robert A. Blouin, D. B. Hill, Steven I. Shedlofsky, Craig J. McClain |
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| Rok vydání: | 1994 |
| Předmět: |
Adult
Lipopolysaccharides Male medicine.medical_specialty Lipopolysaccharide Metabolic Clearance Rate Administration Oral Hexobarbital Pharmacology Sepsis chemistry.chemical_compound Cytochrome P-450 Enzyme System Theophylline Pharmacokinetics Internal medicine medicine Humans Interleukin-6 Tumor Necrosis Factor-alpha Chemistry Acute-phase protein Orosomucoid General Medicine medicine.disease Endotoxins C-Reactive Protein Endocrinology Liver Tumor necrosis factor alpha Chemical and Drug Induced Liver Injury Antipyrine Drug metabolism Research Article medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 94:2209-2214 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci117582 |
| Popis: | In experimental animals, injection of gram-negative endotoxin (LPS) decreases hepatic cytochrome P450-mediated drug metabolism. To evaluate this phenomenon in a human model of gram-negative sepsis, LPS was administered on two consecutive days to healthy male volunteers during which time a cocktail of antipyrine (AP-250 mg), hexobarbital (HB-500 mg), and theophylline (TH-150 mg) was ingested and the apparent oral clearance of each drug determined. Each subject had a control drug clearance study with saline injections. In the first experiment, six subjects received the drug cocktail 0.5 h after the first dose of LPS. In the second experiment, another six subjects received the drug cocktail 0.5 h after the second dose of LPS. In both experiments, LPS caused the expected physiologic responses of inflammation including fever with increases in serum concentrations of TNF alpha, IL-1 beta, IL-6, and acute phase reactants. In the first experiment, only minor decreases in clearances of the probe drugs were observed (7-12%). However in the second experiment, marked decreases in the clearances of AP (35, 95% CI 18-48%), HB (27, 95% CI 14-34%), and TH (22, 95% CI 12-32%) were seen. The decreases in AP clearance correlated with initial peak values of TNF alpha (r = 0.82) and IL-6 (r = 0.86). These data show that in humans the inflammatory response to even a very low dose of LPS significantly decreases hepatic cytochrome P450-mediated drug metabolism and this effect evolves over a 24-h period. It is likely that septic patients with much higher exposures to LPS have more profound inhibition of drug metabolism. |
| Databáze: | OpenAIRE |
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