| Objectives: To characterize the intestinal transport and mechanism of MET in rats, thus to estimate its absorption property in human and further to provide theoretical basis for the design and preparation of the drug in sustained release system. Another objective is to study the relative bioavailability of MET sustained-release tablets in healthy male volunteers, and to evaluate the bioequivalence of the drug made in two formulations (test drugs, T1, T2) to MET sustained-release tablets already for sale (reference product, R).Methods: 1. The effective intestinal permeability of MET was investigated using single-pass intestinal perfusion (SPIP) technique in male, Wistar rats. (1)SP1P was performed in three isolated intestinal segments (duodenum, jejunum and ileum) at same concentration of MET (50μgmL-1) to test if the intestinal transport of MET exhibited site-dependent changes. (2)And the experiment was performed in the same isolated intestinal segment (duodenal segment) at three different concentrations of MET (10, 50, 200μgmL-1) to test if the intestinal transport of MET exhibited concentration-dependent changes. (3)Besides, P-gp inhibitor VER (400μg-mL-1) was co-perfused with MET (50μgmL-1) in the duodenum segment to find out if the intestinal absorption of MET was affected by P-gp exiting along the gastrointestinal track. Stability studies were conducted to ensure that the loss of MET could be only attributed to intestinal absorption. (4)Based on the Peff values obtained in the present study and using established relationships, the effective intestinal permeability of MET in human Peff,man ) and fraction dose absorbed(fa,man) in vivo for MET was estimated. 2. An open-label, single-dose, randomized, three-way crossover clinical trial and an open-label, multiple-doses, randomized, two-way crossover clinical trial both recruited thesame 18 healthy volunteers were carried out to study single-dose administration of MET test drugs (Tj and T2) and reference drug (R), and multiple-doses administration of test drug (Ti) and reference drug(R), respectively. Venous blood samples were collected among 024h (single-dose) and 72-168h (multiple-doses) after drug administration. The plasma drug concentrations were determined using HPLC method. Calculate the relative bioavailability of test drugs to reference drug, and evaluate bioequivalence between test drugs and reference drug.Results: 1. Intestinal absorption experiment: (l)Intestinal absorption site dependent changes in permeability were found in the jejunum and ileum where the /\,# values at 50ugmL"' (3.3795 ± 0.5447 xlO"5cm-s"' and 3.2100 ± 0.1752 xlO"5 cms"1) were significantly lower than the value in the duodenum at the same concentration (5.8837±0.9287xl0"5cnvs"', P<0.0l). (2) Furthermore, concentration dependent changes in permeability values were also found in the duodenum where the Peffvalue at 200(j,gmL"' (2.7086 ± 0.2595xl0"5cnvs"') was significantly lower than the values at two lower concentrations (5.1324 ± 0.5137xl0'5cms"' at lOugmL"' and 5.8837 ± 0.9287xl0"5cm-s"1 at 50ugmL"\ P0.05). (4)The Peff, ,,wn and fa,man were estimated to be in the range of 1.005lxlO"42.1481 xlO'4 cms"1 and 74.25%94.50%, repectively. 2. Various pharmacokinetic parameters were determined from plasma MET concentrations. (l)After single-dose administration (T|, T2, R), there was no statistical significant difference in AUC, Cmax and tmax either among the three treatments or formulations by ANOVA after log-transformation of the data and two one-sided t-test, and the relative bioavailabilities for test drugs to the reference drug, were 98.8% ± 13.0% and6...
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