Molecular pharmacokinetic studies of drug transport in endotoxemia

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First, the effect of pioglitazone, a potent PPAR-γ ligand, on the endotoxin-induced reduction of cytochrome P450 (CYP) was investigated. Second, the role of TNF-α in the down-regulation of hepatic P-glycoprotein and CYP3A2 and CYP2C11 by endotoxin was investigated using TNF-α-knockout mice. Third, the differential effects of endotoxin derived from various gram-negative bacteria on the expression of hepatic CYP3A2, CYP2C11, P-glycoprotein and Mrp2 were investigated.1. Pretreatment with a potent PPAR-γ ligand, pioglitazone, significantly protected the endotoxin-induced decreases the protein levels of CYP3A2, but not CYP2C11, with no biochemical and histopathological changes in the liver. Also, it significantly protected endotoxin-induced overexpression of iNOS in the liver, but not the overproduction of NO in plasma. It is unlikely that the protective effect of pioglitazone against endotoxin-induced decreases in the protein levels of CYP3A2 in the liver is due to the inhibition of the ov … More erproduction of NO.2. Endotoxin had no effect the expression of P-glycoprotein in TNF-α-knockout mice, suggesting that TNF-α plays a pivotal role in the down-regulation of P-glycoprotein by endotoxin. Endotoxin-induced decreases in the expression of CYP3A2 and CYP2C11 in TNF-α-knockout mice were significantly greater than wild-type mice. These results suggest that TNF-α plays a key role in endotoxin-induced down-regulation of hepatic P-glycoprotein, as well as plays a protective role in the regulation of hepatic CYP3A2 and CYP2C11 against endotoxin-induced acute inflammatory.3. The down-regulation of CYP3A2 by K pneumonia and E. coli endotoxin was greater than that by P. aeruginosa endotoxin. But that of CYP2C11 by all three different endotoxin was almost the same. Both K pneumonia and P. aeruginosa endotoxin significantly down-regulated P-glycoprotein, but did not down-regulate Mrp2. E. coli endotoxin had no effect on the expression of either P-glycoprotein or Mrp2. These results suggest that endotoxin has a differential effect on the protein levels of hepatic CYP3A2 and P-glycoprotein, probably due to bacterial source-differences in the production of some proinflammatory mediators Less