Cooper K J, Martin P D, Dane A L, Warwick M J, Raza A, Schneck D W
AstraZeneca, Alderley Park, Mereside, Macclesfield, Cheshire, SK10 4TG, UK.
Eur J Clin Pharmacol. 2003 May;59(1):51-6. doi: 10.1007/s00228-003-0573-7. Epub 2003 Apr 1.
To examine in vivo the effect of erythromycin on the pharmacokinetics of rosuvastatin [an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase]. Erythromycin is a potent inhibitor of CYP3A4 that markedly increases circulating levels of some other HMG-CoA reductase inhibitors.
In this randomised, double-blind, two-way cross-over, placebo-controlled trial 14 healthy volunteers were given 500 mg erythromycin or placebo four times daily for 7 days. A single dose of 80 mg rosuvastatin was co-administered on day 4 of dosing. Plasma concentrations of rosuvastatin and active and total HMG-CoA reductase inhibitors were measured up to 96 h after dosing.
Eleven volunteers had data available from both dosing periods. There was no increase in rosuvastatin plasma exposure following co-administration with erythromycin compared to placebo. In fact, following co-administration with erythromycin, rosuvastatin geometric least square mean AUC((0-t)) and C(max) were 20% and 31%, respectively, lower than with placebo. Individual treatment ratios for AUC((0-t)) ranged from 0.48 to 1.17, and for C(max) ranged from 0.33 to 2.19. Essentially all of the circulating active HMG-CoA reductase inhibitors and most (>94%) of the total inhibitors were accounted for by rosuvastatin. Erythromycin did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin.
Erythromycin did not produce any increase in rosuvastatin plasma exposure. This indicates that CYP3A4 metabolism is not an important clearance mechanism for rosuvastatin, a result consistent with previous findings. The small decreases in rosuvastatin AUC((0-t)) and C(max) that occurred as a consequence of short-term treatment with erythromycin are unlikely to have relevance to long-term treatment with rosuvastatin.
理论依据 目的：在体内研究红霉素对瑞舒伐他汀（一种3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂）药代动力学的影响。红霉素是一种强效的CYP3A4抑制剂，可显著提高其他一些HMG-CoA还原酶抑制剂的循环水平。
在这项随机、双盲、双向交叉、安慰剂对照试验中，14名健康志愿者每天4次服用500mg红霉素或安慰剂，共7天。在给药第4天同时给予单剂量80mg瑞舒伐他汀。给药后长达96小时测量瑞舒伐他汀以及活性和总HMG-CoA还原酶抑制剂的血浆浓度。
11名志愿者在两个给药期均有可用数据。与安慰剂相比，与红霉素合用时瑞舒伐他汀的血浆暴露量没有增加。事实上，与红霉素合用时，瑞舒伐他汀的几何最小二乘均值AUC((0-t))和C(max)分别比安慰剂低20%和31%。AUC((0-t))的个体治疗比值范围为0.48至1.17，C(max)的个体治疗比值范围为0.33至2.19。基本上所有循环中的活性HMG-CoA还原酶抑制剂以及大部分（>94%）的总抑制剂均由瑞舒伐他汀构成。红霉素不影响循环中的瑞舒伐他汀所构成的循环活性或总抑制剂的比例。
红霉素未使瑞舒伐他汀的血浆暴露量增加。这表明CYP3A4代谢不是瑞舒伐他汀的重要清除机制，这一结果与先前的发现一致。短期使用红霉素导致瑞舒伐他汀AUC((0-t))和C(max)的小幅下降与瑞舒伐他汀的长期治疗可能无关。
