Effects of Inflammation and the Severity of Disease on the Action and Disposition of Drugs

• Author / Creator

  Sanaee,Forughalsadat

• Inflammation is involved in the pathogenesis of some cardiovascular diseases and contributes to the observed increased overall mortality rate. It also influences the action and disposition of drugs including some of the cardiovascular agents that are commonly used by patients with inflammatory conditions. This may result in reduced response to pharmacotherapy. Previous studies have demonstrated that inflammatory conditions such as rheumatoid arthritis, old age and obesity result in altered response to verapamil as measured by the PR prolongation despite increased plasma drug concentration. Interestingly, the action and disposition of verapamil are restored in patients, whose rheumatoid arthritis is in remission, pointing to the possibility that the degree of disease severity may have a role in the above observation. Both the reduced clearance, hence, increased plasma drug concentration and diminished pharmacological response caused by inflammatory conditions have been attributed to down-regulations of target proteins, i.e., drug metabolizing enzymes and receptors, respectively. As our first objective, we investigated the effect of disease severity on the pharmacokinetic and pharmacodynamics of verapamil, a well-studied representative of the calcium channel blockers. As a model of inflammation, we chose Crohn’s disease. We observed that increased disease severity decreased response to the drug while elevating its plasma concentration. As our second objective, we studied the action and disposition of nebivolol in rat adjuvant arthritis. Nebivolol is a third generation β-blocker and is thought to be exclusively metabolized in the liver. It is administered as a racemate of equal ratios of the D- (S,R,R,R) and the L- (R,S,S,S) isomers. It has some unique mechanisms of action including a high selectivity for β1 and β3-adrenoceptors. Nebivolol has the ability to release nitric oxide from the cardiovascular endothelium and possesses antioxidant properties which can increase the level of NO by reducing its oxidative inactivation. These benefits suggest nebivolol as the drug of choice in patients with cardiovascular complications when inflammatory conditions exist. As our third objective, we investigated the pharmacokinetics of nebivolol with the aim of finding whether its intestinal metabolism contributes to its first-pass metabolism in the rat. We also investigated the stereospecific pharmacokinetics of nebivolol to determine factors which cause stereoselectivity in its disposition. Our results revealed that the pharmacological response to nebivolol remained unchanged in the presence of inflammation and the gut rather than liver is responsible for drug’s first pass metabolism. The drug’s pharmacokinetic profile is stereoselective due to its stereoselective binding to plasma proteins. This study revealed that neither the pharmacokinetics nor pharmacodynamics of nebivolol are influenced by inflammation, making it unique among the thus far investigated β-blockers such as propranolol and sotalol.

• Subjects / Keywords

  • Inflammation
  • Disease severity
  • Pharmacodynamics
  • Pharmacokinetics

• Graduation date

  Spring 2014

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3901ZP12

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.