Azie N E, Brater D C, Becker P A, Jones D R, Hall S D
Department of Medicine, Indiana University School of Medicine, Indianapolis, USA.
Clin Pharmacol Ther. 1998 Oct;64(4):369-77. doi: 10.1016/S0009-9236(98)90067-4.
Lovastatin is oxidized by cytochrome P4503A to active metabolites but pravastatin is active alone and is not metabolized by cytochrome P450. Diltiazem, a substrate and a potent inhibitor of cytochrome P4503A enzymes, is commonly coadministered with cholesterol-lowering agents.
This was a balanced, randomized, open-label, 4-way crossover study in 10 healthy volunteers, with a 2-week washout period between the phases. Study arms were (1) administration of a single dose of 20 mg lovastatin, (2) administration of a single dose of 20 mg pravastatin, (3) administration of a single dose of lovastatin after administration of 120 mg diltiazem twice a day for 2 weeks, and (4) administration of a single dose of pravastatin after administration of 120 mg diltiazem twice a day for 2 weeks.
Diltiazem significantly (P < .05) increased the oral area under the serum concentration-time curve (AUC) of lovastatin from 3607 +/- 1525 ng/ml/min (mean +/- SD) to 12886 +/- 6558 ng/ml/min and maximum serum concentration (Cmax) from 6 +/- 2 to 26 +/- 9 ng/ml but did not influence the elimination half-life. Diltiazem did not affect the oral AUC, Cmax, or half-life of pravastatin. The average steady-state serum concentrations of diltiazem were not significantly different between the lovastatin (130 +/- 58 ng/ml) and pravastatin (110 +/- 30 ng/ml) study arms.
Diltiazem greatly increased the plasma concentration of lovastatin, but the magnitude of this effect was much greater than that predicted by the systemic serum concentration, suggesting that this interaction is a first-pass rather than a systemic event. The magnitude of this effect and the frequency of coadministration suggest that caution is necessary when administering diltiazem and lovastatin together. Further studies should explore whether this interaction abrogates the efficacy of lovastatin or enhances toxicity and whether it occurs with other cytochrome P4503A4-metabolized 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, such as simvastatin, fluvastatin, and atorvastatin.
洛伐他汀经细胞色素P4503A氧化生成活性代谢产物，而普伐他汀单独具有活性，且不被细胞色素P450代谢。地尔硫䓬是细胞色素P4503A酶的底物和强效抑制剂，常与降胆固醇药物联合使用。
这是一项在10名健康志愿者中进行的平衡、随机、开放标签的4交叉研究，各阶段之间有2周的洗脱期。研究分组为：(1) 单次服用20 mg洛伐他汀；(2) 单次服用20 mg普伐他汀；(3) 每天两次服用120 mg地尔硫䓬，持续2周后单次服用20 mg洛伐他汀；(4) 每天两次服用120 mg地尔硫䓬，持续2周后单次服用20 mg普伐他汀。
地尔硫䓬显著（P <.05）增加了洛伐他汀的血清浓度-时间曲线下口服面积（AUC），从3607±1525 ng/ml/min（平均值±标准差）增至12886±6558 ng/ml/min，最大血清浓度（Cmax）从6±2增至26±9 ng/ml，但未影响消除半衰期。地尔硫䓬未影响普伐他汀的口服AUC、Cmax或半衰期。在洛伐他汀组（130±58 ng/ml）和普伐他汀组（110±30 ng/ml）中，地尔硫䓬的平均稳态血清浓度无显著差异。
地尔硫䓬显著提高了洛伐他汀血药浓度，但这种效应的程度远大于系统血清浓度预测值，提示这种相互作用是首过效应而非全身效应。这种效应的程度和联合用药的频率表明，地尔硫䓬与洛伐他汀联用时需谨慎。进一步研究应探讨这种相互作用是否会消除洛伐他汀的疗效或增加毒性，以及是否会发生在其他经细胞色素P4503A4代谢的3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（如辛伐他汀、氟伐他汀和阿托伐他汀）身上。
