F L Tse1, D Labbadia, K Habucky, A Karara, S Au. 1. Department of Drug Metabolism and Pharmacokinetics, Sandoz Pharmaceuticals Corporation, Hanover, New Jersey 07936, USA.
Abstract
PURPOSE: The effect on food on the bioavailability of SDZ DJN 608, a D-phenylalanine derivative, was investigated in three mature, male beagle dogs. METHODS: Each dog received, under fasting and postprandial conditions, a 30 mg oral dose as a tablet (T) and a liquid-filled capsule (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 parameters were compared between treatments by 3-way ANOVA: In vitro dissolution 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 monolayer was examined at concentrations of 0.1 and 1 mM, in the absence and presence of an aromatic amino acid, L-alpha-methyldopa, the transport of which is mediated by the large neutral amino acid (LNAA) carrier. RESULTS: In the dog, SDZ DJN 608 was rapidly absorbed. The peak plasma concentration (Cmax) averaged higher, and the peak time (tmax) shorter, after LC than T, though the differences were not statistically significant. This finding is consistent with in vitro dissolution data showing 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 curve (AUC) was observed between LC and T, the absolute bioavailability of both being complete in the fasting state. Whereas the presence of food showed little effect on the tmax and Cmax of either dosage form, it significantly reduced the AUC, the effect (ca -20%) being not different between LC and T. In the Caco-2 model, the mucosal-to-serosal permeability of SDZ DJN 608 was independent of concentration and unaffected by L-alpha-methyldopa, suggesting passive diffusion of the former. CONCLUSIONS: Food had little effect on the absorption rate but significantly reduced the bioavailability of SDZ DJN 608 regardless of the dosage form. This effect is unlikely to be caused by inhibition of the transepithelial transport of SDZ DJN 608 by amino acids in the diet.
PURPOSE: The effect on food on the bioavailability of SDZ DJN 608, a D-phenylalanine derivative, was investigated in three mature, male beagle dogs. METHODS: Each dog received, under fasting and postprandial conditions, a 30 mg oral dose as a tablet (T) and a liquid-filled capsule (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 parameters were compared between treatments by 3-way ANOVA: In vitro dissolution 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 monolayer was examined at concentrations of 0.1 and 1 mM, in the absence and presence of an aromatic amino acid, L-alpha-methyldopa, the transport of which is mediated by the large neutral amino acid (LNAA) carrier. RESULTS: In the dog, SDZ DJN 608 was rapidly absorbed. The peak plasma concentration (Cmax) averaged higher, and the peak time (tmax) shorter, after LC than T, though the differences were not statistically significant. This finding is consistent with in vitro dissolution data showing 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 curve (AUC) was observed between LC and T, the absolute bioavailability of both being complete in the fasting state. Whereas the presence of food showed little effect on the tmax and Cmax of either dosage form, it significantly reduced the AUC, the effect (ca -20%) being not different between LC and T. In the Caco-2 model, the mucosal-to-serosal permeability of SDZ DJN 608 was independent of concentration and unaffected by L-alpha-methyldopa, suggesting passive diffusion of the former. CONCLUSIONS: Food had little effect on the absorption rate but significantly reduced the bioavailability of SDZ DJN 608 regardless of the dosage form. This effect is unlikely to be caused by inhibition of the transepithelial transport of SDZ DJN 608 by amino acids in the diet.
Authors: H Shinkai; M Nishikawa; Y Sato; K Toi; I Kumashiro; Y Seto; M Fukuma; K Dan; S Toyoshima Journal: J Med Chem Date: 1989-07 Impact factor: 7.446