Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan.
Biopharm Drug Dispos. 2019 Nov;40(9):350-357. doi: 10.1002/bdd.2209. Epub 2019 Nov 21.
We previously analysed the serum concentrations of dihydrocodeine in a 1-month-old infant with respiratory depression after being prescribed dihydrocodeine phosphate 2.0 mg/day divided t.i.d. for 2 days. The purpose was to develop a full physiologically based pharmacokinetic (PBPK) model that could account for these and other drug monitoring results. Based on experiments in Caco-2 cell monolayers, the effective permeability of dihydrocodeine in human jejunum was established as 1.28 × 10 cm/s. The in vitro V /K values for dihydrocodeine demethylation mediated by recombinant cytochrome P450 2D6 and 3A4 were 0.19 and 0.066 μl/min/pmol, respectively, and for dihydrocodeine 6-O-glucuronidation mediated by recombinant UGT2B4 and 2B7, the V /K values were 0.14 and 0.22 μl/min/mg protein, respectively. Renal clearance was calculated as 5.37 L/h on the total clearance value multiplied by the fraction recovered in urine. The reported plasma concentration-time profiles of dihydrocodeine after intravenous administration in healthy volunteers were used to adjust the tissue partitioning ratios. The developed model simulated the pharmacokinetic profiles of dihydrocodeine after single and multiple oral administrations reasonably well in the same population. Subsequently, the validated model was used to simulate pharmacokinetic profiles for five pediatric cases, including the 1-month-old Japanese boy and a 14-year-old Japanese girl who took an overdose of dihydrocodeine phosphate (37 mg). The simulated pharmacokinetic profiles for five virtual pediatric subjects matching the age, gender, and P450 2D6 phenotype of each case approximately reflected the observed values. These results suggested that our dihydrocodeine PBPK model reproduced the results of clinical cases reasonably well for subjects.
我们之前分析了一个 1 个月大的婴儿在服用磷酸二氢可待因 2.0mg/天，每日 3 次，共 2 天后出现呼吸抑制时的血清二氢可待因浓度。目的是建立一个能够解释这些和其他药物监测结果的全生理学基于药代动力学（PBPK）模型。基于 Caco-2 细胞单层的实验，确定了人空肠中二氢可待因的有效渗透系数为 1.28×10cm/s。重组细胞色素 P450 2D6 和 3A4 介导的二氢可待因去甲基化的体外 V/K 值分别为 0.19 和 0.066 μl/min/pmol，重组 UGT2B4 和 2B7 介导的二氢可待因 6-O-葡萄糖醛酸结合的 V/K 值分别为 0.14 和 0.22 μl/min/mg 蛋白。肾清除率通过尿中回收分数乘以总清除率计算得出，为 5.37 L/h。该模型使用在健康志愿者中静脉内给予二氢可待因后的报告血浆浓度-时间曲线来调整组织分配比。该模型在同一人群中单次和多次口服给药后能够很好地模拟二氢可待因的药代动力学特征。随后，使用验证的模型模拟了五个儿科病例的药代动力学特征，包括服用磷酸二氢可待因过量（37mg）的 1 个月大和 14 岁的日本男孩和女孩。五个虚拟儿科受试者的模拟药代动力学特征与每个病例的年龄、性别和 P450 2D6 表型相匹配，大致反映了观察值。这些结果表明，我们的二氢可待因 PBPK 模型能够很好地模拟患者的临床病例结果。
