COMPARATIVE BIOAVAILABILITY OF JOSAMYCIN, A MACROLIDE ANTIBIOTIC, FROM A TABLET AND SOLUTION AND THE INFLUENCE OF DISSOLUTION ON IN-VIVO RELEASE

The bioavailability of josamycin from a tablet formulation (2 x Josaci ne(R) 500 mg tablets) was investigated and compared with the bioavaila bility of a solution (containing 1 g drug and buffered at pH 4.0) foll owing administration to six healthy human volunteers. Bioavailability profiles for the solution indicated that the drug was inherently rapid ly absorbed with a mean C-max of 1.64 +/- 0.67 mg L-1 attained at a me an t(max) of 0.39 +/- 0.08 h. The AUC(0-last) was 1.510 +/- 0.687 mg h L-1. Bioavailability was significantly lower from the tablets than fr om the solution. Highly variable serum concentration-time profiles wer e obtained from the tablets and C-max values ranged from 0.05 to 0.71 mg L-1 with a t(max) range of 0.33-2.0 h. AUC(0-last) values ranged fr om 0.03 to 0.95 mg h L-1. Dissolution of josamycin from the tablets wa s generally unaffected at low pH (pH 1.2-5.0), but, rather, limited pr edominantly by tablet disintegration. However, dissolution was increas ingly limited as the pH increased from 5.0 to 9.0. Besides poor disint egration, the particularly low intrinsic dissolution rate and solubili ty of josamycin at these pH values is likely to further reduce the dis solution rate. Comparison of the solution and tablet serum concentrati on-time profiles suggests that the absorption of josamycin from the ta blets was dissolution rate limited. This is supported by the in vitro dissolution-pH topogram, which suggests that dissolution will be parti cularly rate Limiting if dissolution of whole or parts of tablets occu rs in gastro-intestinal fluid above pH 5.0. (C) 1998 John Wiley & Sons , Ltd.