Comparative bioavailability of josamycin, a macrolide antibiotic, from a tablet and solution and the influence of dissolution on in vivo release.

摘要

The bioavailability of josamycin from a tablet formulation (2 x Josacine 500 mg tablets) was investigated and compared with the bioavailability of a solution (containing 1 g drug and buffered at pH 4.0) following administration to six healthy human volunteers. Bioavailability profiles for the solution indicated that the drug was inherently rapidly absorbed with a mean Cmax of 1.64 +/- 0.67 mg L-1 attained at a mean tmax of 0.39 +/- 0.08 h. The AUC0-last was 1.510 +/- 0.687 mg h L-1. Bioavailability was significantly lower from the tablets than from the solution. Highly variable serum concentration-time profiles were obtained from the tablets and Cmax values ranged from 0.05 to 0.71 mg L-1 with a tmax range of 0.33-2.0 h. AUC0-last values ranged from 0.03 to 0.95 mg h L-1. Dissolution of josamycin from the tablets was generally unaffected at low pH (pH 1.2-5.0), but, rather, limited predominantly by tablet disintegration. However, dissolution was increasingly limited as the pH increased from 5.0 to 9.0. Besides poor disintegration, the particularly low intrinsic dissolution rate and solubility of josamycin at these pH values is likely to further reduce the dissolution rate. Comparison of the solution and tablet serum concentration-time profiles suggests that the absorption of josamycin from the tablets was dissolution rate limited. This is supported by the in vitro dissolution-pH topogram, which suggests that dissolution will be particularly rate limiting if dissolution of whole or parts of tablets occurs in gastro-intestinal fluid above pH 5.0.