Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/12819
Title: Perhexilene: effects on hepatic lysosomal function in rats.
Authors: Sewell, Richard B;Horowitz, J D;Grinpukel, S A;Martin, G
Affiliation: Gastroenterology Unit, Austin Hospital, Heidelberg, Victoria, Australia.
Issue Date: 1-Jan-1989
Citation: Clinical and Experimental Pharmacology & Physiology; 16(1): 25-32
Abstract: 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 changes 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.
Internal ID Number: 2706806
URI: http://ahro.austin.org.au/austinjspui/handle/1/12819
URL: http://www.ncbi.nlm.nih.gov/pubmed/2706806
Type: Journal Article
Subjects: Acetylglucosaminidase.metabolism
Animals
Bile.drug effects.enzymology
Dose-Response Relationship, Drug
Female
Glucuronidase.metabolism
In Vitro Techniques
Liver.drug effects.enzymology
Lysosomes.drug effects.enzymology.pathology
Metabolic Clearance Rate
Models, Biological
Perhexiline.pharmacokinetics.pharmacology
Rats
Rats, Inbred Strains
Appears in Collections:Journal articles

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