Disposition of [3H]fluvastatin following single oral doses in beagle dogs and rhesus monkeys with bile fistulae.
The disposition of [3H]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 4 d, and were analyzed for total radioactivity and unchanged fluvastatin. In the dog, peak radioactivity concentrations (Cmax) averaged 7260 ng equiv. mL-1 and the mean time to peak (tmax) was approximately 9 h. In the monkey, the mean radioactivity tmax values were approximately 5 and 13 h following the low and high doses, the respective Cmax 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.
Tse
F L
FL
Department of Drug Metabolism and Pharmacokinetics, Drug Safety, Sandoz Research Institute, Sandoz Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
Dain
J G
JG
Kalafsky
G
G
D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics*; D001658:Biliary Fistula / Q000378:metabolism*; D004285:Dogs; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008253:Macaca mulatta; D008297:Male; D013045:Species Specificity
D000924:Anticholesteremic Agents; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin