EFFECT OF FOOD ON THE BIOAVAILABILITY OF SDZ DJN-608, AN ORAL HYPOGLYCEMIC AGENT, FROM A TABLET AND A LIQUID-FILLED CAPSULE IN THE DOG

Purpose. The effect of food on the bioavailability of SDZ DJN 608, a D -phenylalanine derivative, was investigated in three mature, male beag le dogs. Methods. Each dog received, under fasting and postprandial co nditions, a 30 mg oral dose as a tablet (T) and a liquid-filled capsul e (LC). Additionally, a 5 mg intravenous dose was given in the fasting state. Doses in the same dog were separated by 1-week washout periods . Serial plasma samples were collected for 24 h postdose and analyzed for SDZ DJN 608 using HPLC. Model-independent pharmacokinetic paramete rs were compared between treatments by 3-way ANOVA. In vitro dissoluti on profiles of T and LC were generated using the USP paddle method. In addition, the transport of SDZ DJN 608 through a Caco-2 cell monolaye r was examined at concentrations of 0.1 and 1 mM, in the absence and p resence of an aromatic amino acid, L-alpha-methyldopa, the transport o f which is mediated by the large neutral amino acid (LNAA) carrier. Re sults. In the dog, SDZ DJN 608 was rapidly absorbed. The peak plasma c oncentration (C-max) averaged higher, and the peak time (t(max)) short er, after LC than T, though the differences were not statistically sig nificant. This finding is consistent with in vitro dissolution data sh owing that, at both pH 1.2 and pH 6.8, the dissolution rate of LC was faster than that of T. No significant difference in the area under cur ve (AUG) was observed between LC and T, the absolute bioavailability o f both being complete in the fasting state. Whereas the presence of fo od showed little effect on the t(max) and C-max of either dosage form, it significantly reduced the AUC, the effect (ca -20%) being not diff erent between LC and T. In the Caco-2 model, the mucosal-to-serosal pe rmeability of SDZ DJN 608 was independent of concentration and unaffec ted by L-alpha-methyldopa, suggesting passive diffusion of the former. Conclusions. Food had little effect on the absorption rate but signif icantly reduced the bioavailability of SDZ DJN 608 regardless of the d osage form. This effect is unlikely to be caused by inhibition of the transepithelial transport of SDZ DJN 608 by amino acids in the diet.