Kivistö K T, Kantola T, Neuvonen P J
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.
Br J Clin Pharmacol. 1998 Jul;46(1):49-53. doi: 10.1046/j.1365-2125.1998.00034.x.
The effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin, two inhibitors of HMG-CoA reductase with different pharmacokinetic properties, were studied.
Two separate randomized, placebo-controlled, cross-over studies, each involving 10 healthy volunteers, were carried out. The general design was identical in both studies. The subjects took either 100 mg itraconazole or matched placebo orally once daily for 4 days. On day 4, 40 mg fluvastatin or 40 mg lovastatin was administered orally. Plasma concentrations of fluvastatin, lovastatin, lovastatin acid, itraconazole and hydroxyitraconazole were determined up to 24 h.
Itraconazole had no significant effect on the Cmax (190 +/- 124 ng ml(-1) vs 197 +/- 189 ng ml(-1) (mean +/- s.d.)) or total AUC (368 +/- 153 ng ml(-1) h vs 324 +/- 155 ng ml(-1) h) of fluvastatin compared with placebo. However, the t1/2,z of fluvastatin was slightly prolonged by itraconazole (2.8 +/- 0.49 h vs 2.4 +/- 0.51 h; P < 0.05). The Cmax of lovastatin was increased about 15-fold (P < 0.01) and the total AUC more than 15-fold (P < 0.01) by itraconazole. Similarly, the Cmax and total AUC of lovastatin acid were increased about 12-fold (95% CI, 5.3 to 17.7-fold; P < 0.01) and 15-fold (95% CI, 4.6 to 26.2-fold; P < 0.01) by itraconazole, respectively. The t1/2,z of lovastatin averaged 3.7 +/- 3.8 h and that of lovastatin acid 4.7 +/- 4.0 h during the itraconazole phase; these variables could not be determined in all subjects during the placebo phase.
Itraconazole, even at a small dosage of 100 mg daily, greatly elevated plasma concentrations of lovastatin and its active metabolite, lovastatin acid. Lovastatin should therefore not be used concomitantly with itraconazole and other potent CYP3A4 inhibitors, or the dosage of lovastatin should be greatly reduced while using a CYP3A4 inhibitor. In contrast, fluvastatin concentrations were not significantly increased by itraconazole, indicating that fluvastatin has much less potential than lovastatin for clinically significant interactions with itraconazole and other CYP3A4 inhibitors.
研究伊曲康唑对氟伐他汀和洛伐他汀这两种具有不同药代动力学特性的HMG-CoA还原酶抑制剂药代动力学的影响。
开展了两项独立的随机、安慰剂对照、交叉研究，每项研究纳入10名健康志愿者。两项研究的总体设计相同。受试者每天口服100 mg伊曲康唑或匹配的安慰剂，持续4天。在第4天，口服40 mg氟伐他汀或40 mg洛伐他汀。测定24小时内氟伐他汀、洛伐他汀、洛伐他汀酸、伊曲康唑和羟基伊曲康唑的血浆浓度。
与安慰剂相比，伊曲康唑对氟伐他汀的Cmax（190±124 ng/ml vs 197±189 ng/ml（均值±标准差））或总AUC（368±153 ng/ml·h vs 324±155 ng/ml·h）无显著影响。然而，伊曲康唑使氟伐他汀的t1/2,z略有延长（2.8±0.49小时 vs 2.4±0.51小时；P<0.05）。伊曲康唑使洛伐他汀的Cmax增加约15倍（P<0.01），总AUC增加超过15倍（P<0.01）。同样，伊曲康唑使洛伐他汀酸的Cmax和总AUC分别增加约12倍（95%CI，5.3至17.7倍；P<0.01）和15倍（95%CI，4.6至26.2倍；P<0.01）。在伊曲康唑治疗阶段，洛伐他汀的t1/2,z平均为3.7±3.8小时，洛伐他汀酸的t1/2,z为4.7±4.0小时；在安慰剂阶段，并非所有受试者都能测定这些变量。
伊曲康唑即使每日剂量仅100 mg，也能大幅提高洛伐他汀及其活性代谢产物洛伐他汀酸的血浆浓度。因此，洛伐他汀不应与伊曲康唑及其他强效CYP3A4抑制剂同时使用，或在使用CYP3A4抑制剂时大幅降低洛伐他汀的剂量。相比之下，伊曲康唑未显著提高氟伐他汀的浓度，表明氟伐他汀与伊曲康唑及其他CYP3A4抑制剂发生临床显著相互作用的可能性远低于洛伐他汀。
