Influence of severity of inflammation on the disposition kinetics of propranolol enantiomers in ketoprofen-treated and untreated adjuvant arthritis
Piquette-Miller, M.; Jamali, F.
Drug Metabolism and Disposition the Biological Fate of Chemicals 23(2): 240-245
1995
ISSN/ISBN: 0090-9556 PMID: 7736918 Document Number: 449787
Clearance of the beta-blocker, propranolol (PR), is decreased in inflammatory conditions such as arthritis, in both humans and rats. However, inflammation in arthritic patients is often controlled by drugs such as the nonsteroidal antiinflammatory drugs (NSAIDs). Therefore, it is possible that arthritic-induced changes in drug disposition are minimized or suppressed in subjects receiving NSAIDs. To examine this hypothesis, we induced mild and severe adjuvant arthritis (AA) in rats and daily doses of the NSAID, ketoprofen (KT), were given to half of these rats. The pharmacokinetics of PR were thus examined in nontreated (MILD-control and SEVERE-control) and KT-treated (MILD-KT and SEVERE-KT) arthritic rats. Treatment with KT significantly reduced the arthritic index (Al) in the severe model of AA. In AA, the AUC-0-8 of R- and S-PR were not significantly different in MILD-KT rats (R, 15.8 +- 9.5; S, 1.72 +- 9.1 mg cntdot hr/liter) as compared with MILD-control rats (R, 16.2 +- 12; S, 1.76 +- 1.2 mg cntdot hr/liter). On the other hand, the AUC-0-8 of both enantiomers were significantly lower in SEVERE-KT (R, 39.2 +- 13.2; S, 2.92 +- 1.2 mg cntdot hr/liter) as compared with SEVERE-control (R, 79.9 +- 17; S, 6.88 +- 2.1 mg cntdot hr/liter). A high correlation between disease severity (Al) and the AUC-0-8 of R- (r = 0.82) and S-PR (r = 0.81) was observed in all groups. Furthermore, the relationship between the Al and protein binding of R- and S-PR was significant in severe AA. Therefore, increased plasma concentrations of PR in arthritis are related to the degree of inflammation. As the severity of arthritis is reduced by NSAID treatment, arthritic-induced changes in PR disposition are also diminished. This may explain in part the intersubject variation in pharmacokinetics of drugs in disease states and underlines the importance of considering disease activity when examining drug-disease interactions.