González-Martin G, Domínguez A R, Guevara A
Department of Pharmacy, Faculty of Chemistry, Catholic University of Chile, Santiago, Chile.
Biomed Pharmacother. 1997;51(4):170-5. doi: 10.1016/s0753-3322(97)85586-2.
Pharmacokinetics and hepatotoxicity of diclofenac was studied in a recirculating model of isolated perfused rat liver. Ten male Sprague-Dawley rat (weighing 230-330 g) livers were perfused for 2 h with 250 mL Krebs-Henseleit bicarbonate buffer that contained 10.75 mg (group A, n = 5) and 1.075 mg (group B, n = 5) of diclofenac (approximately 100 and 10 times the therapeutic dose in man, respectively). Samples were collected from the efflux at regular time intervals for the determination of diclofenac concentrations by a high performance liquid chromatography (HPLC) method. Pharmacokinetic analyses were carried out using a computer program. To establish viability of the liver and toxicity of the drug, enzyme activity measurements of lactate dehydrogenase (LDH), aspartate aminotransferase (SGOT) and piruvate aminotransferase (SGPT) were performed by a spectrophotometric method. Oxygen consumption was also recorded during the entire perfusion period. Both groups presented bicompartmental kinetics. Concentration profiles showed that group B had a better metabolizing capacity, reflected in a 85.54 +/- 37.05 min half-life, a 0.52 +/- 0.19 mL min-1 g-1 liver clearance and a 0.517 +/- 0.188 extraction ratio, compared to group A, which presented a 123.95 +/- 88.13 min half-life, a 0.1164 +/- 0.067 mL min-1 g-1 liver clearance (P < 0.002) and a 0.116 +/- 0.680 extraction ratio (P < 0.002). LDH activity showed a significant increase in group A at 90 min in comparison with the control group, while in group B this increase was significantly higher at 10 min (P < 0.004). The aminotransferase levels did not show a significant increase. According to these results, diclofenac would not have a direct hepatotoxic effect, even at doses 100 times higher than therapeutic ones.
在离体灌注大鼠肝脏的再循环模型中研究了双氯芬酸的药代动力学和肝毒性。用含有10.75毫克（A组，n = 5）和1.075毫克（B组，n = 5）双氯芬酸（分别约为人治疗剂量的100倍和10倍）的250毫升Krebs-Henseleit碳酸氢盐缓冲液灌注10只雄性Sprague-Dawley大鼠（体重230 - 330克）的肝脏2小时。定期从流出液中采集样品，通过高效液相色谱（HPLC）法测定双氯芬酸浓度。使用计算机程序进行药代动力学分析。为了确定肝脏的活力和药物的毒性，通过分光光度法测量乳酸脱氢酶（LDH）、天冬氨酸转氨酶（SGOT）和丙酮酸转氨酶（SGPT）的酶活性。在整个灌注期间也记录了耗氧量。两组均呈现双室动力学。浓度曲线表明，B组具有更好的代谢能力，其半衰期为85.54±37.05分钟，肝脏清除率为0.52±0.19毫升·分钟⁻¹·克⁻¹，提取率为0.517±0.188；相比之下，A组的半衰期为123.95±88.13分钟，肝脏清除率为0.1164±0.067毫升·分钟⁻¹·克⁻¹（P < 0.002），提取率为0.116±0.680（P < 0.002）。与对照组相比，A组在90分钟时LDH活性显著增加，而B组在10分钟时这种增加显著更高（P < 0.004）。转氨酶水平没有显著增加。根据这些结果，即使剂量比治疗剂量高100倍，双氯芬酸也不会产生直接的肝毒性作用。
