Bramer S L, Brisson J, Corey A E, Mallikaarjun S
Department of Clinical Pharmacokinetics/Pharmacodynamics & Metabolism, Otsuka America Pharmaceutical, Inc., Rockville, MD 20850, USA.
Clin Pharmacokinet. 1999;37 Suppl 2:69-77. doi: 10.2165/00003088-199937002-00008.
To assess the effects of cilostazol on lovastatin pharmacokinetics.
This was a single-centre, open-label, multiple dose, sequential treatment study. Participants received single oral doses of lovastatin 80 mg on days 1, 7 and 9, as well as oral cilostazol 100 mg twice daily on days 2 to 8, followed by a single oral 150 mg cilostazol dose on day 9.
15 healthy, nonsmoking male or female volunteers (aged 18 to 60 years) were enrolled, and 12 completed the study.
Pharmacokinetic parameters were calculated using plasma concentrations of lovastatin and its beta-hydroxy metabolite and of cilostazol and its metabolites. Differences in the pharmacokinetics of each drug when given alone or in combination were assessed by analysis of variance.
The maximum observed plasma concentration (Cmax) of lovastatin or its metabolite did not differ significantly when lovastatin was given alone and when it was given with 100 mg of cilostazol. The mean ratios of the area under the plasma concentration-time curve from zero to the time of the last measurable concentration (AUCt) for lovastatin coadministered with 100 mg of cilostazol to that with lovastatin given alone were 1.6 for lovastatin and 1.7 for its metabolite. With 150 mg of cilostazol, lovastatin Cmax did not change, whereas Cmax of the metabolite increased 2.2-fold. The mean AUCt ratios for lovastatin given with 150 mg cilostazol/lovastatin given alone were 1.6 and 2.0 for lovastatin and its metabolite, respectively. All increases in lovastatin and metabolite AUC were statistically significant, except for the 1.6-fold increase in lovastatin AUC with 150 mg of cilostazol. Maximum steady-state plasma drug concentration (Cssmax) and AUC during a dosage interval (AUC tau) for cilostazol 100 mg twice daily decreased 14 and 15%, respectively, upon lovastatin coadministration.
Lovastatin and metabolite exposure is increased only by up to 2-fold when cilostazol is coadministered, which is considerably less than that observed for potent CYP3A inhibitors such as itraconazole and grapefruit juice. Absorption of cilostazol decreased approximately 15% when it was given with lovastatin. No dosage adjustments are necessary for cilostazol when coadministered with lovastatin, whereas lovastatin dose reductions may be needed when the 2 drugs are given together.
评估西洛他唑对洛伐他汀药代动力学的影响。
这是一项单中心、开放标签、多剂量、序贯治疗研究。参与者在第1、7和9天接受单次口服80 mg洛伐他汀，在第2至8天每天两次口服100 mg西洛他唑，随后在第9天接受单次口服150 mg西洛他唑。
招募了15名健康、不吸烟的男性或女性志愿者（年龄18至60岁），12人完成了研究。
使用洛伐他汀及其β-羟基代谢物以及西洛他唑及其代谢物的血浆浓度计算药代动力学参数。通过方差分析评估每种药物单独给药或联合给药时药代动力学的差异。
单独给予洛伐他汀和与100 mg西洛他唑联合给药时，洛伐他汀或其代谢物的最大观察血浆浓度（Cmax）无显著差异。与单独给予洛伐他汀相比，与100 mg西洛他唑联合给药时，洛伐他汀从零到最后可测量浓度时间的血浆浓度-时间曲线下面积（AUCt）的平均比值，洛伐他汀为1.6，其代谢物为1.7。给予150 mg西洛他唑时，洛伐他汀的Cmax不变，而其代谢物的Cmax增加了2.2倍。与单独给予洛伐他汀相比，与150 mg西洛他唑联合给药时，洛伐他汀及其代谢物的平均AUCt比值分别为1.6和2.0。洛伐他汀及其代谢物AUC的所有增加均具有统计学意义，但150 mg西洛他唑使洛伐他汀AUC增加1.6倍的情况除外。每天两次给予100 mg西洛他唑时，稳态血浆药物最大浓度（Cssmax）和给药间隔期间的AUC（AUC tau）在与洛伐他汀联合给药时分别降低了14%和15%。
联合使用西洛他唑时，洛伐他汀及其代谢物的暴露量仅增加至2倍，远低于伊曲康唑和葡萄柚汁等强效CYP3A抑制剂的情况。与洛伐他汀一起给药时，西洛他唑的吸收降低了约15%。与洛伐他汀联合给药时，西洛他唑无需调整剂量，而两种药物一起给药时可能需要降低洛伐他汀的剂量。
