Population pharmacokinetics of metformin in late pregnancy
Population pharmacokinetics of metformin in late pregnancy
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DOI：
10.1097/01.ftd.0000184161.52573.0e
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发表时间：
2006-02-01
影响因子：
2.5
通讯作者：
Hague, W
中科院分区：
文献类型：
--
作者：
Charles, B;Norris, R;Hague, W
研究了二甲双胍在妊娠晚期的药代动力学，以及胎儿出生时的暴露水平。血样取自妊娠晚期糖尿病或2型糖尿病患者，其中5人曾被诊断为多囊卵巢综合征。在其中一些妇女分娩时，以及在怀孕期间一直在服用二甲双胍但没有采血的其他妇女分娩时，也采集了脐带血样本。用一种新的、有效的反相高效液相色谱法测定了二甲双胍的血药浓度，数据符合两室、经胎盘将药物分配到胎儿室的血管外母体模型。在NONMEM中使用带相互作用的FOCE进行了非线性混合效应建模。用对数、个体间和相加残差方差模型估计变异性，同时模拟林隙和蓄积量之间的协方差。脐带血和孕妇血浆中二甲双胍的平均浓度分别为0.81(范围0.1-2.6)mg/L和1.2(范围0。1~2.9 mg/L。异速生长母体清除和分布量的典型种群数值(个体间变异，CV%)分别为28 L/h/70公斤(17.1%)和190 L/70 ka(46.3%)，由此推算的种群半衰期为5.1h。二甲双胍的胎盘分配系数为1.07(36.3%)。孕妇年龄和体重对药代动力学均无显著影响。模型预测血药浓度的变异系数(SD)为0.32 mg/L。药代动力学与非妊娠患者相似，因此不需要调整剂量。二甲双胍很容易通过胎盘，使胎儿暴露在接近母体循环中的浓度中。这种暴露的后遗症EA对新生儿肥胖和胰岛素抵抗的影响尚不清楚。
The pharmacokinetic disposition of metformin in late pregnancy was studied together with the level of fetal exposure at birth. Blood samples were obtained in the third trimester of pregnancy from women with gestational diabetes or type 2 diabetes, 5 had a previous diagnosis of polycystic ovary syndrome. A cord blood sample also was obtained at the delivery of some of these women, and also at delivery of others who had been taking metformin during pregnancy but from whom no blood had been taken. Plasma metformin concentrations were assayed by a new, validated, reverse-phase HPLC method, A 2-compartment, extravascular maternal model with transplacental partitioning of drug to a fetal compartment was fitted to the data. Nonlinear mixed-effects modeling was performed in'NONMEM using FOCE with INTERACTION. Variability was estimated using logarithmic interindividual and additive residual variance models; the covariance between clearance and volume was modeled simultaneously. Mean (range) metformin concentrations in cord plasma and in maternal plasma were 0.81 (range, 0.1-2.6) mg/L and 1.2 (range, 0. 1-2.9) mg/L, respectively. Typical population values (interindividual variability, CV%) for allometrically scaled maternal clearance and volume of distribution were 28 L/h/70 kg (17.1%) and 190 L/70 ka (46.3%), giving a derived population-wide half-life of 5.1 hours. The placental partition coefficient for metformin was 1.07 (36.3%). Neither maternal age nor weight significantly influenced the pharmacokinetics. The variability (SD) of observed concentrations about model-predicted concentrations was 0.32 mg/L. The pharmacokinetics were similar to those in nonpregnant patients and, therefore, no dosage adjustment is warranted. Metformin readily crosses the placenta, exposing the fetus to concentrations approaching those in the maternal circulation. The sequelae to such exposure, ea, effects on neonatal obesity and insulin resistance, remain unknown.