EFFECTS OF LOW-DENSITY-LIPOPROTEIN AND ETHINYL ESTRADIOL ON CYCLOSPORINE METABOLISM IN ISOLATED RAT-LIVER PERFUSIONS

The effects of low-density lipoprotein (LDL) on cyclosporine (CyA) metabolism were studied in the isolated perfused rat liver, in a recirculating mode, using Krebs-Ringer buffer in the absence (control perfusion) or presence of LDL (1-mu-M) (LDL perfusion). In the LDL perfusions, CyA concentrations at all sampling times were about 2-fold higher, whereas the biliary excretion of CyA and measured metabolites (AM1, AM9, AM1c, and AM4N) were all lower than those obtained with the control perfusions. At the end of the perfusion (3 hr), the percentage of total CyA remaining (liver, bile, and perfusate) was significantly higher (76 +/- 1.2% to 85 +/- 2.4%) and the percentage of dose metabolized to AM9 was lower (4.8 +/- 1.2% to 2.4 +/- 0.6%) in the LDL perfusions (N = 4). These results further suggest the inhibitory effects of LDL on CyA uptake, and, thereby, its metabolism as we observed previously in isolated rat hepatocyte studies. Because ethinyl estradiol (EE) is known to increase LDL receptors in rats, we investigated the possible involvement of LDL receptors in transporting CyA into liver cells using rats pretreated with EE (5 mg/kg/day sc for 5 days). The effects of LDL in maintaining CyA perfusate concentrations, and in decreasing biliary excretion of CyA and its metabolites in the EE-treated animals, were in the same direction as those noted in animals without EE, but the differences due to LDL were not statistically significant. The CyA remaining increased from 54 +/- 12% to 59 +/- 9%, and the total AM9 formed was decreased from 10.1 +/- 2.8% to 8.3 +/- 1.1%, when LDL was present in the perfusate. However, a pronounced increase in drug metabolism in the EE-treated animals was evident. Because CyA metabolism in microsomes from EE-treated rats was also similarly enhanced, this EE-induced metabolism of CyA appears to be caused by a direct effect of EE on hepatic enzyme activities rather than a consequence of an increase in LDL receptors, resulting in greater internalization and metabolism of CyA.