Effect of adjuvant arthritis on the disposition of acebutolol enantiomers in rats

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Abstract
Disease states such as arthritis may interact with the kinetics of β-blockers. Acebutolol (AC) is a chiral β-blocker which is available as a racemate. The beneficial properties of AC, however, is attributed mainly to theS-(+)-enantiomer. The disposition of AC enantiomers and their active, chiral metabolites, diacetolol (DC) were examined after oral administration to healthy and adjuvant-induced arthritic (AA) female Sprague-Dawley rats. Arthritis was induced by tail base injection ofMycobacterium butyricum. Swelling of hind and forepaws were apparent in 10–16 days in AA but not controls. Control and AA rats were sacrificed at 0.5, 1, 2, 4, 6 and 8 h after a 25 mg/kg oral AC dose and blood was collected (n=6). Significant three to tenfold increases in the initial plasma concentrations (0.5–2h) of AC were observed in AA. Enantiomers were equally affected, thus ACS∶R ratio was not changed. Higher plasma concentrations of the metabolite were only significant at 2h. The ratio of DC∶AC, however, was unaffected by AA. The DCS∶R ratio was significantly decreased at 0.5 and 1 h in AA. The limited protein binding of AC (10%) was neither stereoselective nor affected by AA. Reduced intrinsic clearance in AA may be responsible for these observations.