Šíma Martin, Bobek Daniel, Cihlářová Petra, Ryšánek Pavel, Roušarová Jaroslava, Beroušek Jan, Kuchař Martin, Vymazal Tomáš, Slanař Ondřej
Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, 128 00 Prague, Czech Republic.
Forensic Laboratory of Biologically Active Substances, Department of Chemistry of Natural Compounds, University of Chemistry and Technology, 166 28 Prague, Czech Republic.
Pharmaceutics. 2022 Aug 4;14(8):1627. doi: 10.3390/pharmaceutics14081627.
The objective of this prospective study was to examine the exposure to the main active metabolites of ciprofloxacin in critically ill patients and to examine the factors (demographic, laboratory and genetic) that could potentially affect the drug metabolic conversion of ciprofloxacin. The secondary aim was to develop a population pharmacokinetic model for the metabolite showing the most associations with the abovementioned factors. A total of 29 patients were treated with intravenous infusion of ciprofloxacin and enrolled on this trial. Blood samples for pharmacokinetic analysis were taken at 1, 4, and 11.5 h following the completion of the infusion. Sex, age, body weight, height, serum creatinine and bilirubin levels, and creatinine clearance (CL) were recorded, and polymorphisms rs2032582 and rs1045642 in the gene, rs4148977 in the gene and rs762551 in the gene were analyzed. A three-stage parent drug-metabolite population pharmacokinetic model was developed. Median (IQR) metabolite/parent ratios of the desethylene ciprofloxacin, formyl ciprofloxacin and oxociprofloxacin were 5.86 (4.09-9.87)%, 4.08 (3.38-6.92)% and 5.91 (3.42-13.65)%, respectively. The desethylene ciprofloxacin metabolic ratio was positively associated with height (r = 0.2277, = 0.0089) and CL (r = 0.2023, = 0.0144) and negatively associated with age (r = 0.2227, = 0.0112). Males had a significantly higher oxociprofloxacin metabolic ratio than females (9.14 vs 3.42%, = 0.0043). In the desethylene ciprofloxacin population PK model, the volume of distribution decreased with age, the parent drug-metabolite transfer rate constant increased with CL, and the metabolite elimination rate constant decreased with age and is increased in rs762551 variant allele carriers. We therefore hypothesized that the CYP1A2 inhibition by ciprofloxacin is mediated by its metabolite desethylene ciprofloxacin.
这项前瞻性研究的目的是检测重症患者中对环丙沙星主要活性代谢物的暴露情况，并研究可能影响环丙沙星药物代谢转化的因素（人口统计学、实验室和遗传学因素）。次要目的是为与上述因素关联最多的代谢物建立群体药代动力学模型。共有29例患者接受了环丙沙星静脉输注并纳入本试验。在输注结束后的1小时、4小时和11.5小时采集用于药代动力学分析的血样。记录性别、年龄、体重、身高、血清肌酐和胆红素水平以及肌酐清除率（CL），并分析基因中的rs2032582和rs1045642、基因中的rs4148977以及基因中的rs762551多态性。建立了一个三阶段的母体药物-代谢物群体药代动力学模型。去乙基环丙沙星、甲酰基环丙沙星和氧环丙沙星的代谢物/母体比值中位数（IQR）分别为5.86%（4.09 - 9.87%）、4.08%（3.38 - 6.92%）和5.91%（3.42 - 13.65%）。去乙基环丙沙星代谢比值与身高呈正相关（r = 0.2277，P = 0.0089），与CL呈正相关（r = 0.2023，P = 0.0144），与年龄呈负相关（r = 0.2227，P = 0.0112）。男性的氧环丙沙星代谢比值显著高于女性（9.14%对3.42%，P = 0.0043）。在去乙基环丙沙星群体药代动力学模型中，分布容积随年龄减小，母体药物-代谢物转化速率常数随CL增加，代谢物消除速率常数随年龄减小且在rs762551变异等位基因携带者中增加。因此，我们推测环丙沙星对CYP1A2的抑制作用是由其代谢物去乙基环丙沙星介导的。
