title: Effect of early phase adjuvant arthritis on hepatic P450 enzymes and pharmacokinetics of verapamil: an alternative approach to the use of an animal model of inflammation for pharmacokinetic studies.
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 alpha (TNFalpha). 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 TNFalpha 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.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Spencer
authors.initials: S
authors.lastname: Ling
authors.forename: Fakhreddin
authors.initials: F
authors.lastname: Jamali
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology / Q000378:metabolism* / Q000382:microbiology; D001798:Blood Proteins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009161:Mycobacterium; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D014700:Verapamil / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D001798:Blood Proteins; D003577:Cytochrome P-450 Enzyme System; D014700:Verapamil