Prasad V Gangadhara N V, Achanta Satyanarayana, Tammineni Yathiraja Rao, Alla Gopala Reddy, Thirtham Madhava Rao, Rao G S
Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science, Hyderabad, 500 030, India.
Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27701, USA.
Eur J Drug Metab Pharmacokinet. 2016 Dec;41(6):733-741. doi: 10.1007/s13318-015-0302-5.
Infection and inflammation are known to cause wide variability in disposition of drugs through modulation of drug transporters. However, the effects of inhibition of multidrug resistance protein 4 (MRP4) on pharmacokinetics and pharmacodynamics are poorly understood in normal and inflamed conditions. We hypothesized that inflammation alters the pharmacokinetic parameters of ciprofloxacin; and Pharmacokinetic/Pharmacodynamic indices, such as ratio of peak plasma concentration to minimum inhibitory concentration (C /MIC) and ratio of area under the plasma drug concentration-time curve to minimum inhibitory concentration (AUC/MIC) of ciprofloxacin will be improved with the co-administration of a MRP4 inhibitor, dipyridamole, in inflammatory conditions.
In this study, the role of MRP4 on the pharmacokinetic and pharmacodynamic parameters of ciprofloxacin was investigated by the co-administration of dipyridamole in rats with or without lipopolysaccharide (LPS)-induced inflammation. The pharmacokinetic parameters for ciprofloxacin were calculated by non-compartmental approach. MIC of ciprofloxacin was determined using broth microdilution technique.
Induction of inflammation in rats resulted in marked reduction in C and AUC; and an increase in the volume of distribution (V /F) and clearance (Cl/F) of ciprofloxacin, compared to normal rats. Co-administration of dipyridamole with ciprofloxacin in inflamed rats resulted in a threefold increase in AUC, a twofold decrease in V /F and a threefold decrease in Cl/F of ciprofloxacin with significantly prolonged half-life compared to inflamed rats who received ciprofloxacin alone. Co-administration of dipyridamole enhanced AUC/MIC values of ciprofloxacin in both normal and inflamed rats.
The results suggest that MRP4 inhibition increases the systemic exposure of ciprofloxacin in both normal and inflammatory conditions.
已知感染和炎症可通过调节药物转运体导致药物处置的广泛变异性。然而，在正常和炎症条件下，多药耐药蛋白4（MRP4）抑制对药代动力学和药效学的影响了解甚少。我们假设炎症会改变环丙沙星的药代动力学参数；并且在炎症条件下，联合使用MRP4抑制剂双嘧达莫会改善环丙沙星的药代动力学/药效学指标，如血浆峰浓度与最低抑菌浓度之比（C /MIC）以及血浆药物浓度-时间曲线下面积与最低抑菌浓度之比（AUC/MIC）。
在本研究中，通过在有或无脂多糖（LPS）诱导炎症的大鼠中联合使用双嘧达莫，研究MRP4对环丙沙星药代动力学和药效学参数的作用。采用非房室方法计算环丙沙星的药代动力学参数。使用肉汤微量稀释技术测定环丙沙星的最低抑菌浓度。
与正常大鼠相比，大鼠炎症诱导导致环丙沙星的C 和AUC显著降低；分布容积（V /F）和清除率（Cl/F）增加。在炎症大鼠中，双嘧达莫与环丙沙星联合给药导致环丙沙星的AUC增加三倍，V /F降低两倍，Cl/F降低三倍，半衰期与单独接受环丙沙星的炎症大鼠相比显著延长。在正常和炎症大鼠中，双嘧达莫联合给药均提高了环丙沙星的AUC/MIC值。
结果表明，MRP4抑制在正常和炎症条件下均增加了环丙沙星的全身暴露。
