Lammers Laureen A, Achterbergh Roos, Romijn Johannes A, Mathôt Ron A A
Department of Hospital Pharmacy, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Eur J Drug Metab Pharmacokinet. 2018 Dec;43(6):751-767. doi: 10.1007/s13318-018-0487-5.
Previous studies have shown that nutritional status can alter drug metabolism which may result in treatment failure or untoward side effects. This study assesses the effect of two nutritional conditions, short-term fasting, and a short-term high fat diet (HFD) on cytochrome P450 3A4 (CYP3A4) and uridine 5'-diphospho-glucuronosyltransferase (UGT) mediated drug metabolism by studying the pharmacokinetics of midazolam and its main metabolites.
In a randomized-controlled cross-over trial, nine healthy subjects received a single intravenous administration of 0.015 mg/kg midazolam after: (1) an overnight fast (control); (2) 36 h of fasting; and (3) an overnight fast after 3 days of a HFD consisting of 500 ml of cream supplemented to their regular diet. Pharmacokinetic parameters were analyzed simultaneously using non-linear mixed-effects modeling.
Short-term fasting increased CYP3A4-mediated midazolam clearance by 12% (p < 0.01) and decreased UGT-mediated metabolism apparent 1-OH-midazolam clearance by 13% (p < 0.01) by decreasing the ratio of clearance and the fraction metabolite formed (ΔCL/f). Furthermore, short-term fasting decreased apparent clearance of 1-OH-midazolam-O-glucuronide (CL/(f × f)) by 20% (p < 0.01). The HFD did not affect systemic clearance of midazolam or metabolites.
Short-term fasting differentially alters midazolam metabolism by increasing CYP3A4-mediated metabolism but by decreasing UGT-mediated metabolism. In contrast, a short-term HFD did not affect systemic clearance of midazolam.
既往研究表明，营养状况可改变药物代谢，这可能导致治疗失败或出现不良副作用。本研究通过研究咪达唑仑及其主要代谢产物的药代动力学，评估两种营养状况，即短期禁食和短期高脂饮食（HFD）对细胞色素P450 3A4（CYP3A4）和尿苷5'-二磷酸葡萄糖醛酸转移酶（UGT）介导的药物代谢的影响。
在一项随机对照交叉试验中，9名健康受试者在以下情况下接受单次静脉注射0.015 mg/kg咪达唑仑：（1）过夜禁食（对照）；（2）禁食36小时；（3）在常规饮食基础上补充500 ml奶油的高脂饮食3天后过夜禁食。使用非线性混合效应模型同时分析药代动力学参数。
短期禁食使CYP3A4介导的咪达唑仑清除率提高了12%（p<0.01），并通过降低清除率与代谢产物生成分数之比（ΔCL/f），使UGT介导的1-羟基咪达唑仑代谢表观清除率降低了13%（p<0.01）。此外，短期禁食使1-羟基咪达唑仑-O-葡萄糖醛酸苷的表观清除率（CL/(f×f)）降低了20%（p<0.01）。高脂饮食对咪达唑仑或其代谢产物的全身清除率没有影响。
短期禁食通过增加CYP3A4介导的代谢，但降低UGT介导的代谢，从而差异性地改变咪达唑仑的代谢。相比之下，短期高脂饮食不影响咪达唑仑的全身清除率。
