Drug metabolism and morphologic changes in the liver of nafenopin-treated rats

Nafenopin (2-methyl-2[p-(1,2,3,4-tetrahydro-1-naphthyl) phenoxy] propionic acid), a phenolic ether with hypolipidemic properties, given to rats of both sexes for 3 or 14 days, caused an increase in liver weight, peroxisome (microbody) proliferation and smooth endoplasmic reticulum accumulation in hepatocytes. In females, 3 days of nafenopin administration elicited a significant reduction of zoxazolamine paralysis time and an enhancement of its metabolism by the 9,000 g supernatant fraction of the liver. In contrast, treatment of males resulted in a prolongation of paralysis and a decrease of zoxazolamine hydroxylation. The serum cholesterol and triglyceride levels were not changed by short-term administration of the hypolipidemic drug to female rats, but there was a lowering of triglycerides in the males. Given for 14 days, nafenopin reduced paralysis time to the same extent in both sexes. The in vitro metabolism of zoxazolamine was similar to that observed after short-term nafenopin administration. A significant fall in serum triglycerides was noted in both females and males. The sex difference in zoxazolamine metabolism was not dependent on endogenous testosterone.