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Drug‐disease interaction:effect of rheumatoid arthritis (RA) on the pharmacodynamics (PD) and pharmacokinetics (PK) of AT1 receptor antagonists
Author(s) -
Daneshtalab N. M.,
Lewanczuk R. Z.,
Russell A. S.,
Jamali F.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.313
Subject(s) - active metabolite , rheumatoid arthritis , pharmacokinetics , pharmacology , medicine , losartan , downregulation and upregulation , pharmacodynamics , valsartan , angiotensin ii receptor type 1 , arthritis , metabolite , receptor , endocrinology , angiotensin ii , blood pressure , chemistry , biochemistry , gene
Inflammatory conditions decrease cardiovascular response to β and Ca 2+ channel blockers despite elevated drug levels due to downregulation of the receptors by inflammatory mediators. Whether downregulation is also evident with AT 1 R antagonists in RA was tested. The subjects were 14 active RA, 12 controlled RA and 12 healthy. Joint swelling, NO and C‐reactive protein were measured. Valsartan (VAL) or losartan (LOS) was dosed orally, with a one‐week washout period. VAL, LOS and its active metabolite EXP 3174 (EXP) were analyzed from blood samples. Systolic, diastolic and mean arterial pressure were recorded. Area under the % effect‐time curve (AUEC) and the maximum change from baseline (E max ) were calculated. Inflammatory mediators were significantly higher in patients with active RA as compared with controlled RA and healthy. PK parameters indicated no significant difference between the 3 groups for VAL and LOS. However AUC of EXP was significantly lower in RA indicating its reduced formation caused by the disease. Arthritis had no significant effect on AUEC or E max . However, there was a trend towards increased response to VAL in RA as compared to healthy subjects, perhaps due to receptor upregulation. This was not observed with LOS due, possibly to reduced active metabolite concentration. Since there was no receptor downregulation, AT 1 R antagonists may serve as alternative antihypertensive agents to β or Ca 2+ channel blockers for patients with inflammatory conditions. Clinical Pharmacology & Therapeutics (2004) 75 , P82–P82; doi: 10.1016/j.clpt.2003.11.313