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Disposition of [ 3 H]fluvastatin following single oral doses in beagle dogs and rhesus monkeys with bile fistulae
Author(s) -
Tse Francis L. S.,
Dain Jeremy G.,
Kalafsky Gaetana
Publication year - 1995
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2510160306
Subject(s) - fluvastatin , cmax , beagle , pharmacokinetics , urine , endocrinology , chemistry , medicine , feces , oral administration , metabolism , pharmacology , biology , paleontology , simvastatin
The disposition of [ 3 H]fluvastatin was examined following single oral doses in dogs (12.4 mg kg −1 ) and monkeys (0.48 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 (C max ) averaged 7260 ng equiv. mL −1 and the mean time to peak ( t max ) was ∼ 9 h. In the monkey, the mean radioactivity t mzx values were ∼ 5 and 13 h following the low and high doses, the respective C max values being 116 and 10400 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 indepedent 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.