Ramesh Mullangi, Mamidi Rao N V S, Jagannath Kota, Singh Sunil Kumar, Rao Kalleda Srinivasa, Rao Yeleswarapu Koteswar, Seshagirirao Casturi, Rajagopalan Ramanujam, Srinivas Nuggehally R
Research Bioanalysis, Metabolism and Pharmacokinetic Laboratories, Discovery Research, Dr. Reddy's Laboratories Ltd., Miyapur, Hyderabad, India.
Eur J Drug Metab Pharmacokinet. 2003 Apr-Jun;28(2):137-41. doi: 10.1007/BF03190502.
The pharmacokinetic characterization of DRF-4367 (a new diaryl pyrazole derivative), a potent selective COX-2 inhibitor was performed in Wistar rats. In the first study, a single dose of 2, 5, 10, 30 or 100 mg/kg DRF-4367 was given orally to rats for investigating the dose proportionality and/or linearity in the pharmacokinetics. In the second study, a single intravenous bolus dose of DRF-4367 was given at a dose of 10 mg/kg to calculate the absolute oral bioavailability, clearance and volume of distribution parameters. Blood samples were drawn at predetermined intervals up to 24 h post-dose. The concentrations of DRF-4367 in various plasma samples were determined by a validated HPLC method. Plasma concentration versus time data was generated following oral and i.v dosing and subjected to a noncompartmental pharmacokinetic analysis. Following oral administration, maximum concentrations of DRF-4367 were achieved at about 3 h and were unchanged with incremental doses. Both Cmax and AUC0-infinity appeared to increases less than proportional to the administered oral doses. While the doses increased in the ratio of 1.0 : 2.5 : 5.0 : 15.0 : 50.0, the mean AUC0-infinity and Cmax increased in the ratios of 1.0 : 2.8 : 4.5 : 8.6 : 14.5 and 1 : 2.4 : 4.1 : 6.2 : 8.3, respectively. Following i.v. administration, the concentration of DRF4367 declined in a monoexponential fashion with terminal elimination half-life of 5.7 h. The systemic clearance and volume of distribution of DRF-4367 in rats were 0.36 L/h/Kg and 2.2 L/Kg respectively after i.v administration. Elimination half-life was unchanged with route of administration and with increase in oral doses. Absolute oral bioavailability of DRF-4367 in the efficacy dose range was 70-80%.
对一种强效选择性COX - 2抑制剂DRF - 4367（一种新型二芳基吡唑衍生物）进行了Wistar大鼠体内的药代动力学特征研究。在第一项研究中，给大鼠口服2、5、10、30或100mg/kg的单剂量DRF - 4367，以研究药代动力学中的剂量比例关系和/或线性关系。在第二项研究中，以10mg/kg的剂量给大鼠静脉注射单剂量DRF - 4367，以计算绝对口服生物利用度、清除率和分布容积参数。在给药后长达24小时的预定时间间隔采集血样。通过经过验证的高效液相色谱法测定各种血浆样品中DRF - 4367的浓度。口服和静脉给药后生成血浆浓度与时间的数据，并进行非房室药代动力学分析。口服给药后，DRF - 4367在约3小时达到最大浓度，且随剂量增加无变化。Cmax和AUC0-无穷大似乎与口服给药剂量的增加不成正比增加。当剂量以1.0 : 2.5 : 5.0 : 15.0 : 50.0的比例增加时，平均AUC0-无穷大和Cmax分别以1.0 : 2.8 : 4.5 : 8.6 : 14.5和1 : 2.4 : 4.1 : 6.2 : 8.3的比例增加。静脉给药后，DRF4367的浓度以单指数方式下降，终末消除半衰期为5.7小时。静脉给药后，大鼠体内DRF - 4367的全身清除率和分布容积分别为0.36L/h/Kg和2.2L/Kg。消除半衰期不随给药途径和口服剂量增加而改变。DRF - 4367在有效剂量范围内的绝对口服生物利用度为70 - 80%。
