Peter J D, Jehl F, Pottecher T, Dupeyron J P, Monteil H
Département d'Anesthésiologie, Hôpital Civil, Strasbourg, France.
Antimicrob Agents Chemother. 1993 Mar;37(3):501-6. doi: 10.1128/AAC.37.3.501.
The pharmacokinetics of fusidic acid and 3-ketofusidic acid were investigated in cholestatic and noncholestatic patients after intravenous administration of single and multiple doses of 500 mg of sodium fusidate. The patients, all with low serum albumin levels, were divided into three groups. Group I consisted of six noncholestatic patients; group II consisted of nine mildly cholestatic patients with mild hepatic impairment (conjugated bilirubin, 47 mumol liter-1; alkaline phosphatase, 280 IU liter-1; gamma-glutamyltranspeptidase, 190 IU liter-1); group III consisted of six benign intrahepatic cholestatic patients with high isolated conjugated hyperbilirubinemia (98.1 mumol liter-1). Assays were performed by high-pressure liquid chromatography. At steady state, the mean peak concentrations in serum were 63.7, 44.9, and 92.2 micrograms ml-1 in groups I, II, and III, respectively; over a dosage interval, areas under the concentration-time curve were 411.1, 238.7, and 603.4 micrograms.h ml-1 and the mean body clearances were 0.34, 0.53, and 0.25 ml min kg-1 in groups I, II, and III, respectively. The accumulation ratio of fusidic acid increased from 2.8 and 2.4 in groups I and II to 4.2 in group III. At steady state, the ratios of the areas under the concentration-time curve from 0 to 8 h for 3-ketofusidic acid/fusidic acid were 0.11, 0.09, and 0.10 in the three groups, respectively. Only very small amounts of fusidic acid and 3-ketofusidic acid were found in urine. These results substantiate the following hypotheses. In group I and II patients the clearance is higher than that in healthy volunteers because of the increased free, unbound fraction of fusidic acid, a consequence of lower serum albumin concentrations, resulting in increased distribution in tissue and hepatic metabolism. In group III patients, the higher bilirubinemia results in competition with fusidic acid for the limited glucuronidation, thus compensating for the increased elimination with fusidic acid because of the low serum albumin concentration. These results suggest that fusidic acid can be administered normally even to patients with high bilirubinemia because the postoperative serum albumin concentration is usually low.
在静脉注射单剂量和多剂量500mg夫西地酸钠后，对胆汁淤积和非胆汁淤积患者中夫西地酸和3-酮基夫西地酸的药代动力学进行了研究。所有患者血清白蛋白水平均较低，被分为三组。第一组由6名非胆汁淤积患者组成；第二组由9名轻度胆汁淤积且伴有轻度肝功能损害的患者组成（结合胆红素，47μmol/L；碱性磷酸酶，280IU/L；γ-谷氨酰转肽酶，190IU/L）；第三组由6名良性肝内胆汁淤积且伴有高孤立性结合胆红素血症（98.1μmol/L）的患者组成。通过高压液相色谱法进行测定。在稳态时，第一组、第二组和第三组血清中的平均峰浓度分别为63.7、44.9和92.2μg/ml；在一个给药间隔内，浓度-时间曲线下面积分别为411.1、238.7和603.4μg·h/ml，第一组、第二组和第三组的平均机体清除率分别为0.34、0.53和0.25ml·min·kg-1。夫西地酸的蓄积比从第一组和第二组的2.8和2.4增加到第三组的4.2。在稳态时，三组中3-酮基夫西地酸/夫西地酸从0至8小时的浓度-时间曲线下面积之比分别为0.11、0.09和0.10。在尿液中仅发现极少量的夫西地酸和3-酮基夫西地酸。这些结果证实了以下假设。在第一组和第二组患者中，由于夫西地酸游离、未结合部分增加，导致清除率高于健康志愿者，这是血清白蛋白浓度较低的结果，导致组织分布和肝脏代谢增加。在第三组患者中，较高的胆红素血症导致与夫西地酸竞争有限的葡萄糖醛酸化，从而弥补了由于血清白蛋白浓度低而导致的夫西地酸消除增加。这些结果表明，即使是高胆红素血症患者也可以正常给予夫西地酸，因为术后血清白蛋白浓度通常较低。
