Prediction of blood levels following oral administration of weakly acidic drug particles such as sulfa drugs in rabbits from the in vitro dissolution behavior.
Prediction of blood levels following oral administration of weakly acidic drug particles such as sulfa drugs from data obtained in in vitro dissolution tests of drug suspensions was studied in the rabbit. The relationship between in vivo and in vitro dissolution rates or between absorption rate and in vitro dissolution rate was investigated. The drug absorption from aqueous solution was suggested to be rate-limited by the gastric emptying rate because the initial absorption rate constant in a biexponential time course of aqueous solution for the amount unabsorbed vs. time plot was almost the same among 9 of the 10 drugs [sulfadimethoxine, sulfadiazine, sulfisoxaxole, sulfathiazole, sulfamethizole, sulfisomidine, aspirin, sulfacetamide, sulfanilamide and acetaminophen] tested, except for sulfacetamide. This indicated that when the in vivo dissolution rate constant is much slower than the initial absorption rate constant of aqueous solution, the time course of blood levels for the solid drug will deviate from that of aqueous solution. Based on the consideration, the critical in vitro dissolution rate constant corresponding to the initial absorption rate constants of aqueous solution was calculated by means of statistical analysis using the relationship between in vivo and in vitro parameters. The validity of this prediction was examined using 4 high-solubility drugs. The prediction could be done whether the in vitro dissolution medium was distilled water or 0.1 N HCl solution. Although the experiment was done using an aqueous suspension form in the rabbit, the applicability of this prediction method to other dosage forms and to the case of humans is discussed.