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PERHEXILENE: EFFECTS ON HEPATIC LYSOSOMAL FUNCTION IN RATS
Author(s) -
Sewell Richard B.,
Horowitz John D.,
Grinpukel Susan A.,
Martin Glenn
Publication year - 1989
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.1989.tb01905.x
Subject(s) - hepatic function , function (biology) , medicine , chemistry , endocrinology , biology , microbiology and biotechnology
SUMMARY 1. Perhexilene, a long‐acting anti‐anginal drug, can induce adverse effects on the liver which may be dose‐dependent. At high concentrations, perhexilene causes marked morphological change in hepatocyte lysosomes. The current study examined the effect of ‘therapeutic’ doses of perhexilene on hepatic lysosomal function, particularly the biliary release of lysosomal enzymes, using an isolated perfused rat liver (IPRL) model. 2. Pharmacokinetic studies demonstrated that clearance of single doses of perhexilene by the perfused rat liver was dose‐dependent and established a ‘therapeutic’ dose of 0.6 mg using the IPRL. A 5 day pretreatment regimen of 20 mg/kg per day was shown to produce ‘therapeutic’ perhexilene concentrations of 150–210 ng/ml. 3. At perhexilene concentrations equating the ‘therapeutic’ range in man, the major effect of perhexilene was at the biliary pole of the hepatocyte. In 5 day pretreatment dose studies, lysosomal enzyme excretion into bile was markedly increased. In single dose studies, the increase in biliary lysosomal enzyme output partially reflected an increase in bile water production which was not seen with the 5 day pretreatment regimen. Hepatic and perfusate lysosomal enzyme activities were not affected. 4. This selective effect of perhexilene on hepatocyte‐to‐bile lysosomal excretion may reflect intracellular lysosomal drug localization.