Abstract
The objective of this study was to evaluate the suitability of the early phase of adjuvant arthritis (pre-AA) as a model of inflammation for pharmacokinetic studies. Pre-AA is associated with little or no pain and discomfort as compared with fully developed adjuvant arthritis. Pre-AA was induced in male Sprague-Dawley rats with a tail base injection of Mycobacterium butyricum. Animals were monitored for symptoms of arthritis and levels of the proinflammatory mediators, serum nitrite, C-reactive protein (CRP), and tumor necrosis factor α (TNFα). On day 6, rats were administered single i.v. (2 mg/kg) or oral (20 mg/kg) doses of racemic verapamil, and S- and R-verapamil concentrations were determined by high-performance liquid chromatography. Hepatic cytochrome P450 (P450) content and verapamil protein binding were also measured. All experiments were carried out in both pre-AA and control rats. Serum nitrite, CRP, and TNFα levels were significantly elevated in pre-AA rats while signs of pain and arthritis were absent. Pre-AA also significantly elevated plasma concentrations of S- and R-verapamil after both i.v. and oral doses, due, likely, to decreased drug clearance. This was accompanied by a significant reduction in hepatic cytochrome P450, CYP3A, and CYP1A content as well as significantly reduced verapamil free fraction in pre-AA. The early phase of AA is marked by increased proinflammatory mediators and reduced verapamil clearance, as well as decreased hepatic P450 enzymes. Hence, pre-AA is a suitable model of inflammation for pharmacokinetic studies that avoids unnecessary exposure of animals to the pain and distress of fully developed adjuvant arthritis.
Footnotes
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This work was supported by a research grant from the Canadian Institutes of Health Research, the National Science and Engineering Research Council, and the Canadian Foundation for Innovation. S.L. was supported by an Rx&D/HRFCIHR Graduate Research Scholarship in Pharmacy.
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This work was presented in part as an abstract at the 7th Annual Symposium of the Canadian Society for Pharmaceutical Sciences, June 9–12, 2004, Vancouver, BC, Canada.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.104.002360.
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ABBREVIATIONS: AA, adjuvant arthritis; pre-AA, early phase adjuvant arthritis; CRP, C-reactive protein; HPLC, high-performance liquid chromatography; AAG, α1-acid glycoprotein; HRP, horseradish peroxidase; NO, nitric oxide; AUC, area under the plasma concentration-time curve.
- Received September 15, 2004.
- Accepted January 14, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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