Influence of severity of inflammation on the disposition kinetics of propranolol enantiomers in ketoprofen-treated and untreated adjuvant arthritis.
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 (MILDcontrol and SEVEREcontrol) and KT-treated (MILDKT and SEVEREKT) arthritic rats. Treatment with KT significantly reduced the arthritic index (AI) in the severe model of AA. In AA, the AUC0-8 of R- and S-PR were not significantly different in MILDKT rats (R, 15.8 +/- 9.5; S, 1.72 +/- 9.1 mg.hr/liter) as compared with MILDcontrol rats (R, 16.2 +/- 12; S, 1.76 +/- 1.2 mg.hr/liter). On the other hand, the AUC0-8 of both enantiomers were significantly lower in SEVEREKT (R, 39.2 +/- 13.2; S, 2.92 +/- 1.2 mg.hr/liter) as compared with SEVEREcontrol (R, 79.9 +/- 17; S, 6.88 +/- 2.1 mg.hr/liter). A high correlation between disease severity (AI) and the AUC0-8 of R- (r = 0.82) and S-PR (r = 0.81) was observed in all groups. Furthermore, the relationship between the AI 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Piquette-Miller
M
M
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Jamali
F
F
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism*; D007660:Ketoprofen / Q000494:pharmacology*; D011433:Propranolol / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D011917:Rats, Inbred Lew; D013237:Stereoisomerism
D001798:Blood Proteins; D007660:Ketoprofen; D011433:Propranolol