Clofibrate and Nafenopin (SU-13437): Effects on plasma clearance and tissue distribution of chylomicron triglyceride in the dog

Abstract

Adult male dogs, which received orally for 21 days either no drug, 75 mg/kg/day of clofibrate or 25 mg/kg/day of nafenopin, were injected iv with¹⁴C-labeled chylomicron-lipid, essentially chylomicron-triglyceride fatty acid, at 0.2 g of fat per kilogram body weight. At times from 2–160 min after injection, samples of blood, liver, skeletal muscle and adipose tissue were removed, weighed and assayed for¹⁴C-lipid content. Also, in other dogs treated for 14 days, samples of skeletal muscle and adipose tissue were removed before and after treatment by biopsy for measurement of lipoprotein lipase activity. Chylomicron-¹⁴C was cleared more rapidly from the plasma of nafenopin-treated and to a lesser extent of clofibrate-treated dogs than controls. Thet _0.5 for clearance was ca. 31 min for control, 12 min for nafenopin-treated and 20 min for clofibrate-treated dogs. The total skeletal muscle mass of nafenopintreated animals took up 40–50% of the injected chylomicron-triglyceride during the first 20 min after injection, as compared with ca. 25–30% for clofibratetreated and 20–25% for control dogs. Also in treated dogs lesser percentages of the cleared chylomicron-¹⁴C appeared in the liver soon after injection and more in adipose tissue at later times. These observations could be related partially to a measured ability of clofibrate to increase adipose tissue lipoprotein lipase activity (ca. 50%) and of nafenopin to increase a lipase activity of skeletal muscle (ca. 20%). These data suggest that clofibrate and particularly nafenopin lower plasma triglycerides by increasing their clerance by the peripheral tissues.