DISPOSITION OF [H-3] FLUVASTATIN FOLLOWING SINGLE ORAL DOSES IN BEAGLE DOGS AND RHESUS-MONKEYS WITH BILE FISTULAS

The disposition of [H-3]fluvastatin was examined following single oral doses in dogs (12.4 mg kg(-1)) and monkeys (0.48 and 45.5 mg kg(-1)) with bile fistulae. Serial plasma and complete urine, feces, and bile were collected at designated intervals for 3 or 4d, and were analyzed for total radioactivity and unchanged fluvastatin. In the dog, peak radioactivity concentrations (C-max) averaged 7260 ng equiv. mL(-1) and the mean time to peak (t(max)) was similar to 9 h. In the monkey, the mean radioactivity t(max) values were similar to 5 and 13 h following the low and high doses, the respective C-max values being 116 and 10 400 ng equiv. mL(-1). The mean AUC of total radioactivity was proportional to the dose while that of fluvastatin was overproportional to dose, suggesting dose independent absorption but saturable first-pass effect. The AUC ratio of unchanged fluvastatin versus total radioactivity was approximately 63% in the dog, and 9% and 13% for the low and high doses, respectively in the monkey. The bile was the major excretory route of radioactivity (dog, 56%; low-dose monkey, 73%; high-dose monkey, 69%) whereas the renal pathway accounted for < 5% of the dose in both species. Approximately 12% of the biliary radioactivity in the dog was due to intact fluvastatin, compared with 0% and 7.5% after the low and high doses in the monkey. These results showed a smaller extent of fluvastatin metabolism in the dog than in the monkey, and suggested that metabolism in the monkey was saturable in the dose range studied.