Perhexilene: Effects on Hepatic Lysosomal Function in Rats

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.

Drug‐induced phospholipidosis

“…Cells of the macrophage system, such as the pulmonary macrophages and the Kupffer cells of the liver, scavenge the lamellar bodies and facilitate their removal for further clearance of the lamellar body/xenobiotic complex. Enhanced lysosomal enzyme release and a dose‐dependent clearance of CADs into the bile may be suggestive for an enhanced exocytotic activity [50]. It is probable, that such mechanism is limited to certain drugs and may be saturable.…”

Drug-induced Phospholipidosis -Pathological Aspects and Its Prediction

“…Cells of the macrophage system, such as pulmonary macrophages and hepatic Kupffer cells, scavenge lamellar bodies and facilitate their removal for further clearance of the lamellar body/ xenobiotic complex. Enhanced lysosomal enzyme release and a dose-dependent clearance of drugs into the bile may be indicative of enhanced exocytotic activity 26 . T h e s e c o n d a r y e f f e c t s o f i n c r e a s e d c e l l u l a r phospholipid, e.g., inhibition of protein synthesis, inhibition of lysosomal phospholipase (PL) C as well as impairment of protein kinase C, have been discussed elsewhere 15 .…”