| Autor: |
Sun EL; Investigative Toxicology, Pharmacia and Upjohn, Inc., Kalamazoo, MI 49007, USA., Feenstra KL, Bell FP, Sanders PE, Slatter JG, Ulrich RG |
| Jazyk: |
angličtina |
| Zdroj: |
Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 1996 Feb; Vol. 24 (2), pp. 221-31. |
| Abstrakt: |
Lifibrol (U-83860), K12.148) is a lipid-lowering drug that has the potential to accumulate in the liver and induce hepatic peroxisome proliferation. To investigate the identity and potential human relevance of persistent lifibrol-related residues in rat liver, rat and human hepatocyte primary cultures were treated with 30 microM of [14C]lifibrol. After a steady uptake for 24 hr, cellular levels of radioactivity became stable for the next 24-48 hr. A nonradioactive lifibrol chase caused an efflux of intracellular radioactivity. Cellular autoradiography revealed the association of radioactivity with small lipid drops at 6 hr exposure and with large lipid drops at 24 hr exposure. HPLC analysis of media revealed that lifibrol acyl glucuronide and a t-butylcarboxylic acid metabolite (U-94613) were the major metabolites of rat and human hepatocytes, respectively. Using an HPLC method suitable for nonpolar metabolites, the analysis of rat and human cell extracts revealed a broad band of multiple, radioactive peaks that had a similar retention and UV spectrum to a synthetic standard of lifibrol cholesterol ester. Folch extracts of liver from rats treated with [14C]lifibrol or unlabeled lifibrol and [14C]acetate had a unique radioactive TLC band that had similar HPLC retention to hepatocyte residues. The group of nonpolar peaks from the hepatocytes was purified by HPLC. Conversion of the lifibrol sec-hydroxy group to a nicotinate ester afforded particle beam-electron impact mass spectra of the cholesterol ester standard and hepatocyte residues. The derivatized rat hepatocyte residue did not contain detectable lifibrol cholesterol ester (M+.816), but did contain molecular ion clusters corresponding to a mixed triglyceride of lifibrol and two fatty acids. Lifibrol-specific product ions of molecular ion clusters centered at M+.1021, 1047, and 1073 were observed at m/z 448, 430, and 310. The major lifibrol-containing triglycerides had a fatty acid composition of C16-C20 with 0-6 unsaturations. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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