吉非贝齐对吡格列酮及其主要活性代谢产物的药物动力学影响

Effect of gemfibrozil on the pharmacokinetics of pioglitazone

目的研究吉非贝齐对吡格列酮及其主要活性代谢产物药物动力学的影响，为临床合理用药提供参考。方法12名健康男性受试者随机分为2组，分别服用吉非贝齐（GEM）或安慰剂（PLA）600mg，2次·d^-1，连续1周；第3日在服用吉非贝齐或安慰剂1h后口服单剂量吡格列酮（PIO）30mg；第2周期2组交叉服用安慰剂或吉非贝齐，其余给药方案不变。采用HPLC-MS法测定吡格列酮及其代谢产物M-Ⅲ和M-Ⅳ的血药浓度，HPLC-RIF法测定吉非贝齐的血药浓度。结果与安慰剂组相比，合用吉非贝齐后：PIO的AUC0-∞增加239％（P〈0．01），而M-Ⅲ和M-Ⅳ的AUG0—∞均无显著性改变，M-Ⅲ和M-Ⅳ与PIO的AUG0～∞比值分别减小71％和65％（P〈0．01）；PIO的Gmax在两组间无显著性差别，M-Ⅲ的Cmax减小51％（P〈0．05），M-Ⅳ的Cmax也有减小趋势；三者的半衰期均延长约1倍；总活性成分（TAC）的AUC0～∞增加59％（P〈0．01）；Gmax无显著变化，t1／2由24．3h延长至30．2h（P〈0．01）。结论吉非贝齐可同时抑制吡格列酮活性代谢产物M-Ⅲ和M-Ⅳ的生成和进一步代谢。吉非贝齐使吡格列酮及其总活性成分的AUC显著增加、清除减慢，因此临床上两药合用需谨慎，必要时需减少吡格列酮剂量。

OBJECTIVE To determine the effect of gemfibrozil on the pharmacokinetics of pioglitazone.METHODS A randomized, single blind, placebo-controlled crossover study with two phases and a washout period of 2 weeks was carried out. Twelve male volunteers took the drug twice daily （at 7 a. m. and 7 p. m. ） for a week either 600 mg gemfibrozil （GEM） or placebo （PLA）. On day 3, after an overnight fast, they received 600 mg gemfibrozil or placebo at 7 a.m. At 8 a. m. , each ingested a single dose of 30 mg pioglitazone （PIO） orally. At the second phase they were given placebo or gemfibrozil crossly, with the other design unchanged. Timed venous blood samples were collected before the gemfibrozil, pioglitazone administration and up to 12 hours and 120 hours Plasma concentration of PIO and its active metabolites M-Ⅲ and M-Ⅳ were detemained by HPLC-MS. Plasma concentration of GEM was determined by HPLC with fluorescence detector. RESULTS Gemfibrozil increased the mean total area under concentration-time curve （AUC0-∞） of parent pioglitazone and the total active compounds by 239% and 59% （P〈0. 001）. No statistically significant changes were seen in the total AUC of M-Ⅲ and M- Ⅳ after gemfibrozil pretreatment. Gemfibrozil reduced the M-Ⅲ/pioglitazone and M-Ⅳ/pioglitazone AUC0-∞ratio by 71% （P〈0. 001） and 65% （P〈0. 001）, strikingly prolonging their t1/2. Gemfibrozil decreased the Cmax of M-Ⅲ by 51%, and diminishing tendency was observed in that of M-Ⅳ. But no notable changes were found in Cmax of pioglitazine and TAC. CONCLUSIONS Gemfibrozil inhibited both the formation and luther metabolism of pioglitazon metabolite M-Ⅲ and M-Ⅳ. The AUCs of parent pioglitazone and the total active compounds were markedly increased by gemfibrozil, so careful blood sugar monitoring and dosage adjustment are suggested during the co-administration of pioglitazone and gemfibrozik.