Vermerie N, Kusielewicz D, Tod M, Nicolas P, Perret G, Fauvelle F, Petitjean O
Département de Pharmaco-Toxicologie Clinique, Hôpital Avicenne, Bobigny, France.
Fundam Clin Pharmacol. 1992;6(4-5):197-203. doi: 10.1111/j.1472-8206.1992.tb00112.x.
Pharmacokinetic parameters were evaluated in 12 patients with alcoholic cirrhosis and 12 healthy volunteers after a single 400 mg oral dose of glafenine. Glafenine (G) and its major active metabolite glafenic acid (GA) were measured at regular intervals using a specific high performance liquid chromatographic method. Glafenine absorption was significantly delayed in cirrhotic patients (CP) (Tmax = 2.8 +/- 1.3 hvs 1.5 +/- 0.4 h, p less than 0.01) and was dramatically reduced in 3 patients. The large hepatic 'first pass' effect observed in healthy volunteers was markedly reduced in CP (ratio Cmax GA/Cmax G = 3.6 +/- 2.9 vs 18.9 +/- 9.8, p less than 0.001; ratio areas under the curves AUC GA/AUC G = 2.3 +/- 2.3 vs 18.2 +/- 11.2, p less than 0.001). The elimination half-life of G was prolonged in the CP (13.0 +/- 13.1 h vs 1.5 +/- 0.5 h, p less than 0.01). In CP, GA elimination half-life was increased (12.0 +/- 13.4 h vs 4.3 +/- 1.3 h, NS) but the difference did not reach statistical significance because of large variability. The significant rise of G plasma concentrations (Cmax = 2.2 +/- 2.1 mg/L vs 0.7 +/- 0.2 mg/L, p less than 0.05) and its longer half-life would lead to an accumulation if the usual dosage regimen was prescribed for CP and could result in nephrotoxicity. On the other hand, lower dosage would be ineffective because only GA is active and nephrotoxic. Hence, G should be given with great caution to CP.
在12例酒精性肝硬化患者和12名健康志愿者单次口服400mg格拉非宁后评估其药代动力学参数。采用特定的高效液相色谱法定期测定格拉非宁（G）及其主要活性代谢物格拉非酸（GA）。肝硬化患者（CP）中格拉非宁的吸收明显延迟（达峰时间Tmax = 2.8±1.3小时 vs 1.5±0.4小时，p<0.01），且3例患者吸收显著降低。在健康志愿者中观察到的显著的肝脏“首过”效应在CP中明显降低（最大血药浓度比Cmax GA/Cmax G = 3.6±2.9 vs 18.9±9.8，p<0.001；曲线下面积比AUC GA/AUC G = 2.3±2.3 vs 18.2±11.2，p<0.001）。CP中G的消除半衰期延长（13.0±13.1小时 vs 1.5±0.5小时，p<0.01）。在CP中，GA的消除半衰期增加（12.0±13.4小时 vs 4.3±1.3小时，无统计学意义），但由于变异性大，差异未达到统计学显著性。G的血浆浓度显著升高（Cmax = 2.2±2.1mg/L vs 0.7±0.2mg/L，p<0.05）及其较长的半衰期，如果对CP采用常规给药方案会导致蓄积，并可能导致肾毒性。另一方面，较低剂量将无效，因为只有GA具有活性且有肾毒性。因此，给CP患者使用G时应极其谨慎。
