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Related Experiment Videos

Perhexilene: effects on hepatic lysosomal function in rats.

R B Sewell1, J D Horowitz, S A Grinpukel

  • 1Gastroenterology Unit, Austin Hospital, Heidelberg, Victoria, Australia.

Clinical and Experimental Pharmacology & Physiology
|January 1, 1989
PubMed
Summary

Perhexilene, an anti-anginal drug, increases lysosomal enzyme release into bile at therapeutic doses. This effect on liver cells may be linked to how the drug is stored within lysosomes.

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Area of Science:

  • Hepatology
  • Pharmacology
  • Drug Metabolism

Background:

  • Perhexilene is an anti-anginal medication known to cause dose-dependent liver toxicity.
  • High concentrations of perhexilene induce significant morphological changes in hepatocyte lysosomes.

Purpose of the Study:

  • To investigate the impact of therapeutic perhexilene doses on hepatic lysosomal function.
  • To specifically examine the effect on the biliary release of lysosomal enzymes using an isolated perfused rat liver (IPRL) model.

Main Methods:

  • Established a 'therapeutic' perhexilene dose (0.6 mg) in the IPRL model based on pharmacokinetic studies.
  • Administered a 5-day pretreatment regimen (20 mg/kg/day) to achieve therapeutic perhexilene concentrations (150-210 ng/ml).
  • Analyzed lysosomal enzyme excretion into bile and hepatic/perfusate enzyme activities.

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Main Results:

  • Therapeutic perhexilene concentrations significantly increased lysosomal enzyme excretion into bile.
  • This increase was associated with enhanced bile water production in single-dose studies, but not in the 5-day pretreatment regimen.
  • No significant changes were observed in hepatic or perfusate lysosomal enzyme activities.

Conclusions:

  • Perhexilene selectively affects lysosomal enzyme excretion at the hepatocyte biliary pole at therapeutic concentrations.
  • The findings suggest a potential link between intracellular lysosomal drug localization and the observed effect on biliary excretion.
  • This mechanism may contribute to the liver adverse effects associated with perhexilene therapy.