Neuvonen P J, Jalava K M
Department of Clinical Pharmacology, University of Helsinki, Finland.
Clin Pharmacol Ther. 1996 Jul;60(1):54-61. doi: 10.1016/S0009-9236(96)90167-8.
Lovastatin is a cholesterol-lowering drug that can cause myopathy as a rare side effect. Concomitant use of certain drugs (e.g., cyclosporine) increases the risk of skeletal muscle toxicity. Lovastatin is metabolized by CYP3A4. Because itraconazole is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between these drugs.
In this double-blind, randomized, two-phase crossover study, 12 healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a single 40 mg dose of lovastatin. Plasma concentrations of lovastatin, lovastatin acid, itraconazole, hydroxyitraconazole, and creatine kinase were measured up to 24 hours.
On average, itraconazole increased the peak concentration (Cmax) of lovastatin and the area under the lovastatin concentration-time curve (AUC) more than twentyfold (p < 0.001). The mean Cmax of the active metabolite, lovastatin acid, was increased 13-fold (range, tenfold to 23-fold; p < 0.001) and the AUC(0-24) twentyfold (p < 0.001). In one subject plasma creatine kinase was increased tenfold within 24 hours of lovastatin administration during the itraconazole phase but not during the placebo phase. No increase in creatine kinase was observed in the other subjects.
Itraconazole greatly increases plasma concentrations of lovastatin and lovastatin acid. Inhibition of CYP3A4-mediated metabolism probably explains the increased toxicity of lovastatin caused not only by itraconazole but also by cyclosporine, erythromycin, and other inhibitors of CYP3A4. Their concomitant use with lovastatin and simvastatin should be avoided, or the dose of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors should be reduced accordingly.
洛伐他汀是一种降胆固醇药物，可引起肌病这一罕见副作用。某些药物（如环孢素）的联合使用会增加骨骼肌毒性风险。洛伐他汀由细胞色素P450 3A4（CYP3A4）代谢。由于伊曲康唑是CYP3A4的强效抑制剂，我们想研究这两种药物之间可能存在的相互作用。
在这项双盲、随机、两阶段交叉研究中，12名健康志愿者每天口服一次200mg伊曲康唑或安慰剂，持续4天。在第4天，每位受试者服用一剂40mg的洛伐他汀。在24小时内测量洛伐他汀、洛伐他汀酸、伊曲康唑、羟基伊曲康唑和肌酸激酶的血浆浓度。
平均而言，伊曲康唑使洛伐他汀的峰浓度（Cmax）和洛伐他汀浓度-时间曲线下面积（AUC）增加了二十多倍（p<0.001）。活性代谢物洛伐他汀酸的平均Cmax增加了13倍（范围为10倍至23倍；p<0.001），AUC(0 - 24)增加了20倍（p<0.001）。在伊曲康唑阶段，一名受试者在服用洛伐他汀后24小时内血浆肌酸激酶增加了10倍，但在安慰剂阶段未出现这种情况。其他受试者未观察到肌酸激酶升高。
伊曲康唑可大幅提高洛伐他汀和洛伐他汀酸的血浆浓度。CYP3A4介导的代谢受到抑制可能解释了不仅伊曲康唑，还有环孢素、红霉素和其他CYP3A4抑制剂导致洛伐他汀毒性增加的原因。应避免它们与洛伐他汀和辛伐他汀联合使用，或者相应降低3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂的剂量。
