Tse F L, Dain J G, Kalafsky G
Department of Drug Metabolism and Pharmacokinetics, Drug Safety, Sandoz Research Institute, Sandoz Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
Biopharm Drug Dispos. 1995 Apr;16(3):211-9. doi: 10.1002/bdd.2510160306.
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.
在患有胆瘘的犬（12.4 mg·kg⁻¹）和猴（0.48和45.5 mg·kg⁻¹）中，给予单次口服剂量后，研究了[³H]氟伐他汀的处置情况。在3或4天的指定时间间隔收集系列血浆以及完整的尿液、粪便和胆汁，并分析总放射性和未变化的氟伐他汀。在犬中，放射性浓度峰值（Cmax）平均为7260 ng等效物·mL⁻¹，达到峰值的平均时间（tmax）约为9小时。在猴中，低剂量和高剂量后放射性tmax的平均值分别约为5和13小时，各自的Cmax值分别为116和10400 ng等效物·mL⁻¹。总放射性的平均AUC与剂量成比例，而氟伐他汀的AUC与剂量超比例，表明吸收与剂量无关但首过效应饱和。在犬中，未变化的氟伐他汀与总放射性的AUC比值约为63%，在猴中，低剂量和高剂量分别为9%和13%。胆汁是放射性的主要排泄途径（犬为56%；低剂量猴为73%；高剂量猴为69%），而在两个物种中，肾脏途径占剂量的比例均小于5%。犬胆汁中约12%的放射性是由于完整的氟伐他汀，相比之下，猴在低剂量和高剂量后分别为0%和7.5%。这些结果表明，氟伐他汀在犬中的代谢程度低于猴，并且表明在研究的剂量范围内，猴中的代谢是饱和的。
