Bioequivalence assessment of pioglitazone hydrochloride oral preparation by limited sampling strategy / 药学学报

<p><b>AIM</b>To develop limited sampling strategy (LSS) for estimation of C(max) and AUC(0-t) and assessing the bioequivalence of two pioglitazone hydrochloride (PGT) preparations.</p><p><b>METHODS</b>Healthy subjects (n = 20), enrolled in a bioequivalence study, were received 30 mg PGT po of reference or test formulation. The plasma concentration of PGT was determined by the validated HPLC method. A multiple linear regression analysis of the Cmax and AUC(0-t) against the PGT concentration for the reference formulation was carried out to develop LSS models to estimate these parameters. The models were internally validated by the Jackknife method and externally validated using simulated sets generated by Monte Carlo method. The best model was employed to assess bioequivalence of the two PGT formulations.</p><p><b>RESULTS</b>The linear relationship between pharmacokinetics parameters and single concentration point was poor. Several models for these parameters estimation met the predefined criteria (r2 > 0.9). The Jackknife validation procedure revealed that LSS models based on two sampling times (C1, C2.5 and C1.5, C2.5 for C(max); C1.5, C9 and C2.5, C9 for AUC(0-t) predict accurately. Mean prediction errors (MPE) were less than 3%, and mean absolute prediction error (MAE) were less than 9%. The prediction error (PE) beyond 20% was less than 5% of total samples. Model external validation by Monte Carlo simulated data indicated that the most informative sampling combinations were C1.5, C2.5 for C(max), and C1.5, C9 for AUC(0-t), respectively. MPE and MAE of the proposed models were less than 5% , and 9% respectively. The PE beyond 20% was less than 5% of the total. Bioequivalence assessment of the two PGT formulations, based on the best LSS models, provided results similar to those obtained using all the observed concentration-time data points, and indicated that the two PGT formulations were bioequivalent.</p><p><b>CONCLUSION</b>The LSS method for bioequivalence assessment of PGT formulations was established and proved to be applicable and accurate. Thus, it could be considered appropriate for PGT bioequivalence study with inexpensive cost of sampling acquisition and analysis. Key words: pioglitazone hydrochloride; limited sampling strategy; Monte Carlo simulation; bioequivalence</p>

Preparation and evaluation of self-microemulsifying drug delivery systems containing atorvastatin / 药学学报

<p><b>AIM</b>To prepare self-microemulsifying drug delivery system (SMEDDS) containing atorvastatin,and decrease its size to improve the solubility in the stomach. And to study the effect of the resultant microemulsion in reducing the presystemic clearance in the gastrointestinal mucosa and hepatic first-pass metabolism, improving the oral bioavailability, and reducing side effect and expenditure.</p><p><b>METHODS</b>Pseudoternary phase diagrams were used to evaluate the self-microemulsification existence area. The HPLC analyses in vitro and in vivo were set up. Solubility in various vehicles was determined. The self-microemulsification efficiency was assessed, such as self-microemulsification time, stability, particle size and zeta potential. SMEDDS containing atorvastatin, non-ionic surfactant and lipid were prepared. Droplet size/distributions and zeta potential of the resultant microemulsion were determined. Photos were taken with transmission electron microscope. Oral bioavailability was studied on prepared SMEDDS hard capsules and compared with that of the conventional tablet in Beagle dogs in vivo.</p><p><b>RESULTS</b>The optimal formulations had wide microemulsion existent field and had good self-microemulsifying efficiency. Droplet size was within 100 nm and showed Gaussian distribution. After oral administration of SMEDDS capsules and the conventional tablet to fasted Beagle dogs, the Cmax from SMEDDS was greater than that of the conventional tablet. AUC from zero to 24 h of SMEDDS was about 1.5-fold higher than that of the conventional tablet. Oral bioavailability of atorvastatin SMEDDS was greater than that of the conventional tablet.</p><p><b>CONCLUSION</b>The results indicated the potential use of SMEDDS for the delivery of atorvastatin to increase its oral bioavailability.</p>

Effect of MDR1 polymorphic expression on oral disposition of cyclosporine A / 药学学报

<p><b>AIM</b>To determine the relationship between C3435T mutation in exon 26 of the human multidrug resistant 1 gene and cyclosporine (CsA) pharmacokinetic (PK) parameters among healthy Chinese volunteers by nonlinear mixed effect model (NONMEM).</p><p><b>METHODS</b>Twenty healthy subjects were given orally a single dose of 500 mg CsA in microemulsion solution. Blood CsA concentrations were measured with HPLC and the genotype for the C3435T polymorphism of MDR1 gene was determined with the PCR and restriction fragment length polymorphism. The results were further confirmed by sequencing. NONMEM was performed to assess the effect of genotype on CsA PK profile.</p><p><b>RESULTS</b>MDR1 C3435T genotype was identified as the best predictor of CsA systemic exposure. The relative bioavailability of CsA was 40% higher in subjects who carried at least one 3435C allele compared to that of TT type individuals in the study population.</p><p><b>CONCLUSION</b>The MDR1 C3435T genotype offers a potential basis of mechanism to explain inter-subject differences in CsA oral bioavailability.</p>