Disposition of [3H]fluvastatin following single oral doses in beagle dogs and rhesus monkeys with bile fistulae
✍ Scribed by Francis L. S. Tse; Jeremy G. Dain; Gaetana Kalafsky
- Publisher
- John Wiley and Sons
- Year
- 1995
- Tongue
- English
- Weight
- 470 KB
- Volume
- 16
- Category
- Article
- ISSN
- 0142-2782
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✦ Synopsis
The disposition of [3H]fluvastatin was examined following single oral doses in dogs (12.4mgkg-I) and monkeys (0.48 and 45.5mg kg-I) 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 (Cm,) averaged 7260ng equiv. mL-' and the mean time to peak (I,,,,) was -9 h. In the monkey, the mean radioactivity tm, values were -5 and 13 h following the low and high doses, the respective C , , values being 1 16 and 10 400 ng equiv. mL-'. 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.