Correlation of the bioavailability of diazepam from uncoated tablets in beagle dogs with its dissolution rate and bioavailability in humans.
The bioavailability of diazepam (I) in uncoated tablets in beagles was tested using tablets tested previously in humans. The correlations of the dissolution rates and bioavailabilities of these tablets in humans and beagles were examined. The plasma level of N-desmethyldiazepam (II), the main metabolite of I, was used as an index of bioavailability after p.o. administration of uncoated tablets of I, because I is rapidly metabolized. Thus the plasma level of I is very low, and AUCs (areas under plasma level-time curves) calculated from plasma levels of II were related to the dose of I (2-10 mg). With different tablets, the rates and extents of bioavailability of I differed significantly in beagles, but only the rate of bioavailability showed significant differences in humans. The rank orders of tablets, based on the blood levels of II soon after p.o. administration of the tablets were the same, but other parameters of bioavailability of I in the tablets were quite different in beagles and humans. Consequently, there was no significant correlation between the bioavailabilities of I in beagles and humans. The gastric fluid of beagles is almost neutral, and the bioavailabilities of the tablets in beagles correlated well with the dissolution rates of I determined at pH 4.6, but not at pH 1.2. The differences in the bioavailabilities of I in humans and beagles were attributed to differences in transit time in the gastrointestinal tract and/or in the volume of the gastrointestinal fluid.
D000818:Animals; D001682:Biological Availability; D001835:Body Weight / Q000187:drug effects; D003975:Diazepam / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D006863:Hydrogen-Ion Concentration; D003708:Nordazepam / Q000378:metabolism; D012995:Solubility; D013045:Species Specificity; D013607:Tablets
D013607:Tablets; D003708:Nordazepam; D003975:Diazepam