伊曲康唑对全反式维甲酸药动学的影响

Effect of itraconazole on the pharmacokinetics of all-trans-retinoic acid in rabbits

目的 研究伊曲康唑对全反式维甲酸 (ATRA)药动学的影响 ,探讨联合用药方法 ,解决ATRA治疗中耐药问题的可能性。方法 将动物按交叉试验方法给药 ,先后按单用维甲酸和合用维甲酸与伊曲康唑两种方案给药 ,以高效液相色谱法测定维甲酸血药浓度 ,研究两种给药方案的药动学差异。结果 维甲酸在动物体内的药动学过程符合单室开放模型 ,单用及合用的药动学参数cmax分别为 (113.83± 6 2 .6 5 ) ,(2 81.91± 75 .40 )ng·mL-1(P <0 .0 1) ;tmax分别为 (3.6 7± 0 .5 0 ) ,(2 .11± 0 .6 0 )h(P <0 .0 1) ;MRT分别为 (4 .34± 0 .83) ,(2 .89± 0 .34 )h(P <0 .0 1) ;AUC0～∞ 分别为 (374.9± 179.5 ) ,(6 75 .5± 2 12 .6 )ng·h·mL-1(0 .0 1<P <0 .0 5 ) ;t1/ 2ke分别为 (2 .40± 0 .98) ,(1.91± 1.2 6 )h(P >0 .0 5 )。结论 合用伊曲康唑可以升高ATRA血药峰浓度和维持有效治疗浓度 ,提示并用伊曲康唑可能是解决维甲酸耐药的一种方法 。

OBJECTIVE: To investigate the effect of itraconazole on the pharmacokinetics of all-trans-retinoic acid (ATRA). METHODS: ATRA (10 mg) alone and simutaneously with itraconazole (10 mg + 30 mg) were administered orally in a randomized, cross-over way. A reversed-phase high performance liquid chromatographic method was established for the determination of ATRA in serum. RESULTS: The pharmacokinetics of ATRA conformed to a one-compartment open model. The main pharmacokinetic parameters after the oral administration alone and combination were as follows: cmax were (113.83 ± 62.65) ng&middotmL-1 and (281.91 ± 75.40) ng&middotmL-1 (Pmax were (3.67 ± 0.50) h and (2.11 ± 0.60) h (P0∼∞ were (374.9 ± 179.5) ng&middoth&middotmL-1 and (675.5 ± 212.6) ng&middoth&middotmL-1 (0.011/2ke were (2.40 ± 0.98) h and (1.91 ± 1.26) h (P>0.05), respectively. CONCLUSION: There was significant effect of itraconazole on the pharmacokinetics of ATRA, the cmax and AUC of ATRA were increased by the combination. The use of ATRA in combination with itraconazole merits further investigation.