Impairment of liver mitochondrial β-oxidation is an important mechanism of drug-induced liver injury. Four inhibitors of fatty acid oxidation were compared in short-term rat in vivo studies in which the rats were administered one or four doses. The hepatocellular vacuolation represented ultrastructural mitochondrial changes. Urine nuclear magnetic resonance (NMR) spectroscopy revealed that both FOX988 and SDZ51-641 induced a persistent dicarboxylic aciduria, suggesting an inhibition of mitochondrial β-oxidation and incomplete fatty acid metabolism. Etomoxir caused minimal mitochondrial ultrastructural changes and induced only transient dicarboxylic aciduria. CPI975 served as a negative control, in that there were no significant perturbations to the mitochondrial ultrastructural morphology or in the urine NMR composition; however, compound exposure was confirmed by the up-regulation of liver gene expression compared to vehicle control. The liver gene expression changes that were altered by the compounds were indicative of mitochondria, general and oxidative stress, and peroxisomal enzymes involved in β-oxidation, suggestive of a compensatory response to the inhibition in the mitochondria. In addition, both FOX988 and SDZ51-641 up-regulated ribosomal genes associated with apoptosis, as well as p53 pathways linked with apoptosis. In summary, metabonomics and liver gene expression provided mechanistic information on mitochondrial dysfunction and impaired fatty acid oxidation to further define the clinical pathology and histopathology findings of hepatotoxicity.

2006-10-01·Toxicology in Vitro3区 · 医学

Consequences of mitochondrial injury induced by pharmaceutical fatty acid oxidation inhibitors is characterized in human and rat liver slices

3区 · 医学

Article

作者: R.L. Fisher ; P. Bentley ; A.E.M. Vickers

Inhibition of liver mitochondrial beta-oxidation by pharmaceuticals may lead to safety concerns including mitochondrial dysfunction, lipid accumulation, inflammation and necrosis. In this study, the consequences of mitochondrial beta-oxidation inhibition by pharmaceuticals is investigated in human and rat liver slices. The fatty acid oxidation inhibitors Etomoxir and CPI975, inhibit the rate limiting mitochondrial beta-oxidation enzyme carnitine palmitoyltransferase I, while FOX988 and SDZ51-641, sequester mitochondrial coenzyme A to inhibit carnitine palmitoyltransferase II. Mitochondrial dysfunction was evident by a significant decrease of liver slice ATP levels and mitochondrial injury was verified by ultrastructural changes in morphology, manifested as enlarged mitochondria, C- or O-shaped mitochondria, and granular or crystalline inclusions. Gene expression changes were evident prior to changes in mitochondrial morphology. Time- and concentration dependent changes in mitochondrial genes linked with respiration and mitochondrial fatty acid beta-oxidation were associated with an up-regulation of peroxisome fatty acid oxidation genes, likely as a compensatory mechanism for the inhibition of the mitochondrial pathways. Gene expression changes preceding the decline of liver slice ATP and GSH levels included an up-regulation of stress response and oxidative stress gene expression, as well as genes linked with transcription, transporters, proliferation, cell matrix and signaling. In association with the decline of liver slice ATP and GSH was increased apoptosis and inflammation. Caspase activity, a functional indicator of apoptosis, was significantly increased as well as an up-regulation of genes linked with apoptosis. The increased gene and protein expression of the pro-inflammatory cytokine IL-8, produced by endothelial cells, is likely in response to the manifestation of oxidative stress and GSH depletion; further amplifying the oxidative stress response induced by the fatty acid oxidation inhibitors and triggering an inflammatory response. In summary, human and rat liver slices exhibited similar effects to the inhibitors of mitochondrial beta-oxidation, and the mitochondrial injury is associated with apoptosis and inflammation in the liver slices.

1995-04-01·Biopharmaceutics & Drug Disposition4区 · 医学

The effect of food on the absorption of ¹⁴C‐SDZ FOX 988, an antidiabetic agent, in healthy human volunteers

4区 · 医学

Article

作者: Lau, David T.-W. ; Tse, Francis L. S. ; Kalafsky, G.

AbstractThe objective of this study is to examine the effect of food on oral absorption of SDZ FOX 988 (FOX 988), an antidiabetic agent, and circulating levels of its active metabolite, SDZ 53–450 (53–450). Sixteen normal volunteers received a single 10 mg dose of 14C‐FOX 988, either as gelatin capsules or in a suspension (0.5% CMC). For subjects receiving each formulation, four subjects received a meal, consisting of 50% fat by calories, immediately following dosing, while the other four received the same meal at 2 h post‐dose. Serial blood, urine, and fecal samples were collected for 120 h and analyzed for total radioactivity. Blood concentrations of 53–450 were analyzed using an HPLC–UV method. Concomitant administration with food increased the extent of FOX 988 absorption from either suspension or capsule, as shown by an increase in AUC and in urinary recovery of radioactivity. Blood concentrations of 53–450 were only detected in subjects receiving food at dosing. No difference in absorption was observed between the capsule and the suspension. Results from this study showed that oral absorption of FOX 988 is enhanced by co‐administration of food in normal volunteers.

100 项与 SDZ-FOX-988 相关的药物交易

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