双氯芬酸在有和无格列本脲的大鼠体内的药代动力学。

Pharmacokinetic of diclofenac in the presence and absence of glibenclamide in the rat.

机构信息

Sección de Estudios de Postgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México, D.F., Mexico.

出版信息

J Pharm Pharm Sci. 2009;12(3):280-7. doi: 10.18433/j3s597.

DOI:10.18433/j3s597

PMID:20067705

Abstract

PURPOSE

There is evidence that the sulfonylurea antidiabetic agent glibenclamide reduces the analgesic action of non-steroidal anti-inflammatory drugs (NSAIDs), opioids and neuromodulators in animal models. Therefore, in view of the vast clinical uses and interactions of NSAIDs with commonly used therapeutic agents, the interaction of the NSAID diclofenac and glibenclamide was investigated about pharmacokinetic profile and antinociceptive effect in rats.

METHODS

Antinociception was assessed using the formalin test. Fifty microliters of diluted formalin was injected s.c. into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60 min after injection. Rats were treated with oral administration of vehicle or increasing doses of diclofenac (3-18 mg/kg) before formalin injection. To determine the pharmacodynamic interaction between diclofenac and glibenclamide, the effect of oral administration of glibenclamide (1-30 mg/kg) on the antinociceptive effect induced by diclofenac (18 mg/kg, p.o.) was assessed. To evaluate the pharmacokinetic interaction between diclofenac and glibenclamide, the effect of glibenclamide (10 mg/kg, p.o.) on the pharmacokinetic of diclofenac (18 mg/kg, p.o.) was studied in the rat. Blood samples were taken over 8 h and analyzed using a validated high-performance liquid chromatography method to generate the pharmacokinetic profile of diclofenac. Pharmacokinetic parameters were estimated using noncompartmental analysis.

RESULTS

Systemic administration of diclofenac produced a dose-dependent antinociceptive effect in the formalin test. Systemic treatment with glibenclamide prevented diclofenac-induced antinociception. In pharmacokinetic interaction study, no significant (P>0.05) change in diclofenac concentration-time profiles in the presence of glibenclamide was detected.

CONCLUSION

The experimental findings suggest that systemic glibenclamide is able to block the diclofenac-induced antinociception in the rat formalin test. Besides, this antagonism was not produced by diminution in the bioavailability of diclofenac. Likewise, the validated assay had sufficient accuracy and precision for pharmacokinetic determination of diclofenac in the rat.

摘要

目的

有证据表明，磺酰脲类降糖药格列本脲会降低非甾体抗炎药（NSAIDs）、阿片类药物和神经调节剂在动物模型中的镇痛作用。因此，鉴于 NSAIDs 与常用治疗药物的广泛临床用途和相互作用，研究了 NSAID 双氯芬酸和格列本脲的药代动力学特征和在大鼠中的镇痛作用的相互作用。

方法

采用福尔马林试验评估镇痛作用。将 50μl 稀释的福尔马林皮下注射到右后爪的背部表面。注射后 60 分钟内，通过注射爪的退缩次数来量化痛觉行为。在福尔马林注射前，大鼠通过口服给予载体或增加剂量的双氯芬酸（3-18mg/kg）进行治疗。为了确定双氯芬酸和格列本脲之间的药效学相互作用，评估了口服给予格列本脲（1-30mg/kg）对双氯芬酸（18mg/kg，po）诱导的镇痛作用的影响。为了评估双氯芬酸和格列本脲之间的药代动力学相互作用，研究了格列本脲（10mg/kg，po）对双氯芬酸（18mg/kg，po）药代动力学的影响。在大鼠中，采集 8 小时的血样，并使用经过验证的高效液相色谱法进行分析，以生成双氯芬酸的药代动力学特征。使用非房室分析估算药代动力学参数。