Comparative pharmacokinetics of verapamil and norverapamil in normal and ulcerative colitis rats after oral administration of low and high dose verapamil by UPLC-MS/MS

Abstract

1. In this study, UC rat model was established by administration of 5% (w/v) dextran sulfate sodium, and the pharmacokinetics of verapamil and norverapamil were evaluated in normal and UC rats using UPLC-MS/MS after oral administration of 5 mg/kg and 50 mg/kg verapamil.

2. The peak concentration (C_max) and the area under plasma concentration–time curves (AUC) of verapamil in UC rats after oral administration of 5 mg/kg were significantly greater (2.5 times and 2 times, respectively) than those in normal rats, but the clearance rate (Cl) was significantly lower (by 50%). For norverapamil, C_max and AUC were significantly greater (2.8 times and 2.5 times, respectively), and Cl was significantly lower (by 45%). But, pharmacokinetic parameters of verapamil and norverapamil after oral administration of 50 mg/kg were no significant differences between UC and normal rats.

3. The better absorption and poor excretion for low-dose verapamil may be attributed to down-regulation of P-gp expression in the intestine and kidney. No significant differences of pharmacokinetic parameters for high-dose verapamil may be explained as the saturation of an efflux mechanism.

4. The findings of this study suggested that in UC patients, doses of verapamil should be decreased when low-dose verapamil was orally administrated.

Keywords:

• Pharmacokinetics
• P-glycoprotein
• verapamil
• norverapamil
• ulcerative colitis rats

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was financially supported by the National Natural Science Foundation of China [grant numbers 81673397].