Werner Dierk, Werner Ulrike, Meybaum Annett, Schmidt Boris, Umbreen Sumaira, Grosch Anton, Lestin Heiko G, Graf Bernhard, Zolk Oliver, Fromm Martin F
Department of Cardiology, Helios-Hospital Schwerin, Schwerin, Germany.
Clin Pharmacokinet. 2008;47(5):323-32. doi: 10.2165/00003088-200847050-00003.
Torasemide is frequently used for the treatment of hypertension and heart failure. However, the determinants of torasemide pharmacokinetics in patients during steady-state conditions are largely unknown. We therefore explored the impact of genetic polymorphisms of cytochrome P450 (CYP) 2C9 (CYP2C9) and organic anion transporting polypeptide (OATP) 1B1 (SLCO1B1), gender, and the effects of losartan and irbesartan comedication on the interindividual variability of steady-state pharmacokinetics of torasemide.
Twenty-four patients receiving stable medication with torasemide 10 mg once daily and with an indication for additional angiotensin II receptor blocker (ARB) treatment to control hypertension or to treat heart failure were selected. Blood samples were taken before torasemide administration and 0.5, 1, 2, 4, 8, 12 and 24 hours after administration. After this first study period, patients received either irbesartan 150 mg (five female and seven male patients aged 69+/-8 years) or losartan 100 mg (two female and ten male patients aged 61+/-8 years) once daily. After 3 days of ARB medication, eight blood samples were again collected at the timepoints indicated above. The patients' long-term medications, which did not include known CYP2C9 inhibitors, were maintained at a constant dose during the study. All patients were genotyped for CYP2C9 (*1/*1 [n=15]; *1/*2 [n = 4]; *1/*3 [n=5]) as well as for SLCO1B1 (c.521TT [n=13]; c.521TC [n=11]).
Factorial ANOVA revealed an independent impact of the CYP2C9 genotype (dose-normalized area under the plasma concentration-time curve during the 24-hour dosing interval at steady state [AUC(24,ss)/D]: *1/*1 375.5+/-151.4 microg x h/L/mg vs *1/*3 548.5+/-271.6 microg x h/L/mg, p=0.001), the SLCO1B1 genotype (AUC(24,ss)/D: TT 352.3+/-114 microg x h/L/mg vs TC 487.6+/-218.4 microg x h/L/mg, p<0.05) and gender (AUC(24,ss)/D: males 359.5+/-72.2 microg x h/L/mg vs females 547.3+/-284 microg x h/L/mg, p<0.01) on disposition of torasemide. Coadministration of irbesartan caused a 13% increase in the AUC(24,ss)/D of torasemide (p=0.002), whereas losartan had no effect.
This study shows that the CYP2C9*3 and SLCO1B1 c.521TC genotype and female gender are significant and independent predictors of the pharmacokinetics of torasemide. Coadministration of irbesartan yields moderate but significant increases in the torasemide plasma concentration and elimination half-life.
托拉塞米常用于治疗高血压和心力衰竭。然而，在稳态条件下患者体内托拉塞米药代动力学的决定因素尚不清楚。因此，我们探讨了细胞色素P450（CYP）2C9（CYP2C9）和有机阴离子转运多肽（OATP）1B1（SLCO1B1）的基因多态性、性别以及氯沙坦和厄贝沙坦联合用药对托拉塞米稳态药代动力学个体间差异的影响。
选取24例每日一次稳定服用10 mg托拉塞米且有额外使用血管紧张素II受体阻滞剂（ARB）治疗指征以控制高血压或治疗心力衰竭的患者。在托拉塞米给药前及给药后0.5、1、2、4、8、12和24小时采集血样。在第一个研究期后，患者每日一次服用厄贝沙坦150 mg（5例女性和7例男性患者，年龄69±8岁）或氯沙坦100 mg（2例女性和10例男性患者，年龄61±8岁）。ARB用药3天后，再次在上述时间点采集8份血样。在研究期间，患者的长期用药（不包括已知的CYP2C9抑制剂）维持恒定剂量。对所有患者进行CYP2C9（*1/*1 [n = 15]；*1/*2 [n = 4]；*1/*3 [n = 5]）以及SLCO1B1（c.521TT [n = 13]；c.521TC [n = 11]）基因分型。
析因方差分析显示CYP2C9基因型（稳态时24小时给药间隔期间血浆浓度-时间曲线下剂量标准化面积[AUC(24,ss)/D]：*1/*1 375.5±151.4 μg·h/L/mg vs *1/*3 548.5±271.6 μg·h/L/mg，p = 0.001）、SLCO1B1基因型（AUC(24,ss)/D：TT 352.3±114 μg·h/L/mg vs TC 487.6±218.4 μg·h/L/mg，p < 0.05）和性别（AUC(24,ss)/D：男性359.5±72.2 μg·h/L/mg vs女性547.3±284 μg·h/L/mg，p < 0.01）对托拉塞米处置有独立影响。厄贝沙坦联合给药使托拉塞米的AUC(24,ss)/D增加13%（p = 0.002），而氯沙坦无影响。
本研究表明CYP2C9*3和SLCO1B1 c.521TC基因型以及女性性别是托拉塞米药代动力学的重要且独立的预测因素。厄贝沙坦联合给药使托拉塞米血浆浓度和消除半衰期适度但显著增加。
