Pharmacokinetics of Fluvastatin After Single and Multiple Doses in Normal Volunteers
Pharmacokinetics of Fluvastatin After Single and Multiple Doses in Normal Volunteers
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正常志愿者单次和多次给药后氟伐他汀的药代动力学
DOI：
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发表时间：
1992
影响因子：
2.9
通讯作者：
A. Troendle
中科院分区：
文献类型：
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作者：
F. Tse;J. Jaffe;A. Troendle
氟伐他汀是羟甲基戊二酰辅酶 A 还原酶和胆固醇合成的有效抑制剂，已在 24 名接受 [3H] 氟伐他汀的正常男性志愿者中进行了三项不同研究的药代动力学研究：使用 2 或 10 mg 口服剂量的单剂量研究，使用 2 mg 静脉注射或 10 mg 口服剂量的绝对生物利用度研究，以及使用每天一次口服 40 mg 剂量的多剂量研究6天。收集连续血液和血浆样品以及完整的尿液和粪便，并分析总放射性以及完整的氟伐他汀。尽管由于广泛的首过代谢，2 mg 和 10 mg 剂量的估计生物利用度仅为 19% 至 29%，但氟伐他汀从胃肠道吸收迅速且几乎完全（>90%）。氟伐他汀的药代动力学在 2 至 10 mg 剂量范围内似乎呈线性，如总放射性和母体药物的剂量比例血液水平所示。吸收的氟伐他汀在排泄前完全代谢，胆汁/粪便途径是主要的排泄途径。单次剂量后放射性几乎在 120 小时内完全恢复。氟伐他汀的终末半衰期和总放射性平均分别为0.5至1小时和55至71小时，而氟伐他汀的全身清除率为0.97 L/小时/kg。重复口服 40 mg 剂量的[3H]氟伐他汀不会导致药代动力学特征发生与时间相关的变化，但该剂量产生的母体药物循环水平大于比例增加，因此表明氟伐他汀具有可饱和的首过效应。在每天重复给药期间，氟伐他汀的血浆水平在第一次给药后达到稳态，而总放射性在6天后达到稳态。与母体药物不同，放射性积累程度与终末半衰期不一致，但意味着有效半衰期较短，为 32 至 36 小时。血液放射性谱的终末相似乎代表了一种次要代谢物，该代谢物可逆地结合到特定组织库并从特定组织库中缓慢释放，并且这种结合涉及有限量的药物，无论施用的剂量如何。本报告中描述的口服和静脉注射[3H]氟伐他汀是安全且耐受性良好的。
The pharmacokinetics of fluvastatin, a potent inhibitor of hydroxymethylglutaryl‐CoA reductase and thus cholesterol synthesis, have been studied in 24 normal male volunteers who received [3H] fluvastatin in three different studies: a single‐dose study using oral doses of 2 or 10 mg, an absolute bioavailability study using doses of 2 mg intravenously or 10 mg orally, and a multiple‐dose study using 40 mg orally once daily for 6 days. Serial blood and plasma samples and complete urine and feces were collected and analyzed for total radioactivity as well as for intact fluvastatin. Fluvastatin was rapidly and almost completely (>90%) absorbed from the gastrointestinal tract, although the estimated bioavailability from the 2‐ and 10‐mg doses was only 19 to 29% because of extensive first‐pass metabolism. Fluvastatin pharmacokinetics appeared to be linear over the 2‐ to 10‐mg dose range, as indicated by dose‐proportional blood levels of total radioactivity and the parent drug. Absorbed fluvastatin was completely metabolized before excretion, the biliary/fecal route being the major excretory pathway. The recovery of radioactivity after a single dose was virtually complete within 120 hours. The terminal half‐lives of fluvastatin and total radioactivity averaged 0.5 to 1 hour and 55 to 71 hours, respectively, whereas the total body clearance of fluvastatin was 0.97 L/hour/kg. Repeated oral administration of 40‐mg doses of [3H]fluvastatin resulted in no time‐related change in pharmacokinetic characteristics, but this dose yielded greater than proportional increases in circulating levels of the parent drug, thus suggesting a saturable first‐pass effect on fluvastatin. During repeated daily administration, plasma levels of fluvastatin reached steady state after the first dose, whereas those of total radioactivity approached steady state after 6 days. The degree of accumulation of radioactivity, unlike that of the parent drug, was inconsistent with the terminal half‐life, but instead implied a shorter effective half‐life of 32 to 36 hours. It appears that the terminal phase of the blood radioactivity profile represents a minor metabolite that is reversibiy bound to and slowly released from a specific tissue depot, and that this binding involves a finite amount of drug regardless of the dose administered. The oral and intravenous administration of [3H]fluvastatin described in the present report was safe and well tolerated.