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Drug-Disease Interactions: Losartan Effect Is Not Downregulated by Rheumatoid Arthritis

From the Faculty of Pharmacy (Dr Daneshtalab, Dr Jamali) and Pharmaceutical Sciences and Faculty of Medicine (Dr Lewanczuk, Dr Russell), University of Alberta, Edmonton, Alberta, Canada. Financial support provided by the Canadian Institute for Health Research and Novartis Pharmaceuticals, Switzerland.

Inflammatory conditions, such as rheumatoid arthritis, reduce response to calcium channel and ß-adrenergic antagonists but not the angiotensin II type 1 receptor (AT₁R) antagonist valsartan. Inflammation also reduces clearance of some drugs or active metabolite, thereby reducing response. Active (n = 14) and controlled rheumatoid arthritis (n = 12) and healthy subjects (n = 12) received losartan (100 mg). Blood pressures were measured, and samples were taken for pharmacokinetic and inflammatory mediator concentration determination. Active disease significantly increased arthritic index, nitric oxide, and Creactive protein. Although no between-group difference in plasma losartan concentration-time curves was observed, concentrations of the active metabolite, EXP 3174, were significantly reduced by arthritis. This, however, was not accompanied by reduced clinical response. One subject produced no detectable concentrations of EXP 3174 likely due to insufficient CYP2C9 activity. Despite reduced concentrations of the active metabolite, AT₁R antagonists potency does not appear to be reduced by inflammation.

Key Words: Inflammation • receptor downregulation • angiotensin II type 1 receptor • inflammatory mediators • C-reactive protein

Address for reprints: Fakhreddin Jamali, PhD, #3118 Dentistry/Pharmacy Building, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada, T6G-2N8; e-mail: fjamali{at}ualberta.ca.

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