Ott P, Ranek L, Young M A
Medical Department A, Copenhagen University Hospital, Rigshospitalet, Denmark.
Eur J Clin Pharmacol. 1998 Sep;54(7):567-71. doi: 10.1007/s002280050514.
Troglitazone is an agonist of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), which has been shown to improve the metabolic control of type 2 diabetes. Troglitazone undergoes hepatic metabolism to an inactive sulphate conjugate and an oxidative quinone metabolite with minor activity. The objective of this study was to compare the pharmacokinetics of troglitazone in patients with hepatic insufficiency and normal subjects.
Three groups of eight subjects with normal liver function and moderate or severe hepatic impairment (Pugh-Child classification) completed this open study. Subjects received a single 400-mg dose of troglitazone 30 min after breakfast. Plasma concentrations of troglitazone and its metabolites were measured and standard pharmacokinetic parameters derived.
A 46% increase in area under the plasma concentration-time curve (AUClast) was observed for troglitazone, together with a 154% increase for the quinone metabolite in the patients with moderate hepatic impairment compared with normal subjects, but these did not reach statistical significance. Corresponding increases of 18% and 53% in the severe group also failed to reach statistical significance. For the sulphate conjugate, the AUClast values for both moderate and severe hepatic impairment were in the order of fourfold higher than those in the normal group. There were reductions in the maximum observed plasma concentration (Cmax) of troglitazone to 61% of the normal group in the severe group for troglitazone, and twofold increases in sulphate metabolite Cmax in the moderate and severe groups. There was an approximately threefold increase in the half-life of the sulphate conjugate in subjects with both moderate and severe impairment of liver function compared with normal individuals. First times to maximum concentrations of troglitazone, its sulphate conjugate and the quinone metabolite were significantly longer in all severely impaired subjects compared with those with normal hepatic function, although the range was wide in all cases. Plasma protein binding was high in all subjects measured (mean unbound fraction range 0.7-5.1%), but there were insufficient samples to compare across groups.
The formation of metabolites of troglitazone following a single dose is not impaired in the presence of reduced liver function although the capacity to eliminate the metabolites is altered. The clinical significance of the effect of liver disease on the conjugates is not clear.
曲格列酮是过氧化物酶体增殖物激活受体γ（PPAR-γ）的激动剂，已被证明可改善2型糖尿病的代谢控制。曲格列酮在肝脏代谢为无活性的硫酸结合物和活性较弱的氧化醌代谢物。本研究的目的是比较曲格列酮在肝功能不全患者和正常受试者中的药代动力学。
三组，每组八名肝功能正常和中度或重度肝功能损害（Child-Pugh分级）的受试者完成了这项开放性研究。受试者在早餐后30分钟单次服用400毫克曲格列酮。测定曲格列酮及其代谢物的血浆浓度，并得出标准药代动力学参数。
与正常受试者相比，中度肝功能损害患者的曲格列酮血浆浓度-时间曲线下面积（AUClast）增加了46%，醌代谢物增加了154%，但这些均未达到统计学显著性。重度组相应增加18%和53%也未达到统计学显著性。对于硫酸结合物，中度和重度肝功能损害的AUClast值均比正常组高约四倍。重度组曲格列酮的最大观察血浆浓度（Cmax）降至正常组的61%，中度和重度组硫酸代谢物Cmax增加了两倍。与正常个体相比，肝功能中度和重度损害受试者的硫酸结合物半衰期增加了约三倍。所有重度肝功能损害受试者中，曲格列酮、其硫酸结合物和醌代谢物达到最大浓度的首次时间均明显长于肝功能正常者，尽管所有情况下范围都很广。所有测量的受试者血浆蛋白结合率都很高（平均未结合分数范围为0.7-5.1%），但样本量不足无法进行组间比较。
尽管肝功能降低时代谢物的消除能力发生了改变，但单剂量给药后曲格列酮代谢物的形成并未受到损害。肝病对结合物影响的临床意义尚不清楚。
