Puozzo C, Pozet N, Deprez D, Baille P, Ung H L, Zech P
Institut de Recherche Pierre Fabre, Department de Pharmacokinetique, Castres, France.
Eur J Drug Metab Pharmacokinet. 1998 Apr-Jun;23(2):280-6. doi: 10.1007/BF03189352.
The pharmacokinetics of a single 50 mg dose of milnacipran, a new non tricyclic antidepressant drug, were compared in 8 chronic renal failure subjects (Clc(reat) between 9 to 84.5 ml.min(-1)) and in 6 healthy volunteers. Concentrations of unchanged (F2207 racemate and F2695 and F2696, enantiomers) and glucuroconjugated drug (main metabolite) were measured using HPLC and GC-MS. As for drugs mainly eliminated via renal route, the pharmacokinetics of milnacipran were markedly affected by impaired renal function with the elimination half-life of severely impaired subject being approximately three times that of the control group. Milnacipran apparent total clearance and renal clearance were positively correlated with glomerular filtration rate, while non-renal clearance and apparent volume of distribution were unaffected by renal impairment. Plasma concentrations of the glucuroconjugate were gradually increased in plasma, while its total urine excretion remained unchanged. As for the racemate, pharmacokinetics of each enantiomer were modified by renal failure, although, as predictable from its higher renal clearance value, it was more marked for F2696 than for F2695. Considering that modifications were shown to be proportional to the degree of renal impairment and that milnacipran presents low variability, the necessary dose adjustment is therefore easy to predict.
在8名慢性肾衰竭患者（肌酐清除率在9至84.5 ml·min⁻¹之间）和6名健康志愿者中比较了单剂量50 mg新型非三环类抗抑郁药米那普明的药代动力学。使用高效液相色谱法（HPLC）和气相色谱-质谱联用仪（GC-MS）测定了未变化的药物（F2207外消旋体以及F2695和F2696对映体）和葡萄糖醛酸结合型药物（主要代谢物）的浓度。对于主要经肾脏途径消除的药物，米那普明的药代动力学受到肾功能损害的显著影响，严重肾功能损害患者的消除半衰期约为对照组的三倍。米那普明的表观总清除率和肾脏清除率与肾小球滤过率呈正相关，而非肾脏清除率和表观分布容积不受肾功能损害的影响。葡萄糖醛酸结合物的血浆浓度在血浆中逐渐升高，而其总尿排泄量保持不变。对于外消旋体，肾衰竭会改变各对映体的药代动力学，尽管从其较高的肾脏清除率值可预测，F2696的变化比F2695更明显。鉴于已表明这些变化与肾功能损害程度成正比，且米那普明的变异性较低，因此所需的剂量调整很容易预测。
