Blakey G E, Lockton J A, Perrett J, Norwood P, Russell M, Aherne Z, Plume J
Department of Experimental Medicine, AstraZeneca R & D, Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK.
Br J Clin Pharmacol. 2004 Feb;57(2):162-9. doi: 10.1046/j.1365-2125.2003.01973.x.
The primary objectives of the present study were to establish whether there was a pharmacokinetic or pharmacodynamic interaction between the probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), debrisoquine (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4), when administered in combination as a cocktail. Furthermore, the tolerability of these probe drugs, both alone and in combination as a cocktail was assessed.
Twelve healthy volunteer subjects (age range 22-48 years) were entered into an open, fixed sequence, 6-limb, single centre study. The randomization was such that all drugs were given individually followed by the full "cocktail" as the last treatment limb. The phenotypic index used to assess the intrinsic activity of the CYP isoforms included metabolite/parent ratios in plasma and urine (CYPs 1A2, 2E1 & 2C9), parent/metabolite ratios in urine (CYP2D6) and plasma AUClast (CYP3A4). Blood pressure and blood glucose measurements were used to assess pharmacodynamic interactions. Tolerability was assessed through reporting of adverse events
Overall, there was little evidence that the probe drugs interacted metabolically when co-administered as the cocktail. The ratio of the geometric mean (and 90% confidence interval) of the phenotypic index, obtained after administration of the probe as part of the cocktail and when given alone were: caffeine, 0.86 (0.67-1.10), midazolam, 0.96 (0.74-1.24), tolbutamide, 0.86 (0.72-1.03), debrisoquine 1.04 (0.97-1.12) and chlorzoxazone, 0.95 (0.86-1.05). There was no difference in blood pressure and blood glucose concentrations following the cocktail and dosing of the individual probes. There was no effect on ECG recordings at any time-point. The adverse events reported for individual drug administrations were mild, transient and expected. Overall no more adverse events were reported on the cocktail study days than on the days when the drugs were administered alone.
The five probe drugs when coadministered, in this dosing regimen, demonstrated no evidence of either a metabolic or pharmacodynamic interaction that might confound the conclusions drawn during a cocktail study. The present cocktail methodology has the potential to become a useful tool to aid the detection of clinically important drug-drug interactions during drug development.
本研究的主要目的是确定作为鸡尾酒组合给药时，探针药物咖啡因（CYP1A2）、甲苯磺丁脲（CYP2C9）、异喹胍（CYP2D6）、氯唑沙宗（CYP2E1）和咪达唑仑（CYP3A4）之间是否存在药代动力学或药效学相互作用。此外，还评估了这些探针药物单独使用以及作为鸡尾酒组合使用时的耐受性。
12名健康志愿者受试者（年龄范围22 - 48岁）进入一项开放、固定顺序、6阶段、单中心研究。随机分组方式为所有药物先单独给药，最后一个治疗阶段给予完整的“鸡尾酒”组合。用于评估CYP同工酶内在活性的表型指标包括血浆和尿液中的代谢物/母体比率（CYP1A2、2E1和2C9）、尿液中的母体/代谢物比率（CYP2D6）以及血浆最后一次给药浓度 - 时间曲线下面积（AUC）（CYP3A4）。通过测量血压和血糖来评估药效学相互作用。通过报告不良事件来评估耐受性。
总体而言，几乎没有证据表明作为鸡尾酒组合给药时探针药物之间存在代谢相互作用。作为鸡尾酒组合一部分给药后与单独给药时获得的表型指标几何均值（及90%置信区间）之比为：咖啡因，0.86（0.67 - 1.10）；咪达唑仑，0.96（0.74 - 1.24）；甲苯磺丁脲，0.86（0.72 - 1.03）；异喹胍，1.04（0.97 - 1.12）；氯唑沙宗，0.95（0.86 - 1.05）。鸡尾酒组合给药与单独给予各探针药物后，血压和血糖浓度没有差异。在任何时间点对心电图记录均无影响。单独给药时报告的不良事件轻微、短暂且在预期范围内。总体而言，鸡尾酒组合研究日报告的不良事件并不比单独给药日更多。
在这种给药方案下，五种探针药物共同给药时，没有证据表明存在可能混淆鸡尾酒研究结论的代谢或药效学相互作用。目前的鸡尾酒方法有潜力成为药物研发过程中辅助检测临床重要药物 - 药物相互作用的有用工具。
