Varma Manthena V S, Panchagnula Ramesh
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Phase X, SAS. Nagar, Mohali, Punjab 160062, India.
Eur J Pharm Sci. 2005 Jul-Aug;25(4-5):445-53. doi: 10.1016/j.ejps.2005.04.003.
Solubility and permeability being important determinants of oral drug absorption, this study was aimed to investigate the effect of D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) on the solubility and intestinal permeability of paclitaxel in vitro, in situ and in vivo, in order to estimate the absorption enhancement ability of TPGS. Aqueous solubility of paclitaxel is significantly enhanced by TPGS, where a linear increase was demonstrated above a TPGS concentration of 0.1 mg/ml. Paclitaxel demonstrated asymmetric transport across rat ileum with significantly greater (26-fold) basolateral-to-apical (B-A) permeability than that in apical-to-basolateral (A-B) direction. Presence of P-glycoprotein (P-gp) inhibitor, verapamil (200 microM), diminished asymmetric transport of paclitaxel suggesting the role of P-gp-mediated efflux. TPGS showed a concentration-dependent increase in A-B permeability and decreased B-A permeability. The maximum efflux inhibition activity was found at a minimum TPGS concentration of 0.1 mg/ml, however, further increase in TPGS concentration resulted in decreased A-B permeability with no change in B-A permeability. Thus, the maximum paclitaxel permeability attained with 0.1 mg/ml TPGS was attributed to the interplay between TPGS concentration dependent P-gp inhibition activity and miceller formation. In situ permeability studies in rats also demonstrated the role of efflux in limiting permeability of paclitaxel and inhibitory efficiency of TPGS. The plasma concentration of [14C]paclitaxel following oral administration (25 mg/kg) was significantly increased by coadministration of TPGS at a dose of 50 mg/kg in rats. Bioavailability is enhanced about 4.2- and 6.3-fold when [14C]paclitaxel was administrated with verapamil (25 mg/kg) and TPGS, respectively, as compared to [14C]paclitaxel administered alone. The effect of verapamil on oral bioavailability of [14C]paclitaxel was limited relative to the TPGS, consistent with the in vitro solubility and permeability enhancement ability of TPGS. In conclusion, the current data suggests that the coadministration of TPGS may improve the bioavailability of BCS class II-IV drugs with low solubility and/or less permeable as a result of significant P-gp-mediated efflux.
溶解度和渗透性是口服药物吸收的重要决定因素，本研究旨在考察聚乙二醇1000维生素E琥珀酸酯（TPGS）在体外、原位和体内对紫杉醇溶解度和肠道渗透性的影响，以评估TPGS的吸收促进能力。TPGS显著提高了紫杉醇的水溶性，在TPGS浓度高于0.1mg/ml时呈线性增加。紫杉醇在大鼠回肠的转运呈现不对称性，其基底外侧到顶端（B-A）的渗透性显著高于顶端到基底外侧（A-B）方向（26倍）。P-糖蛋白（P-gp）抑制剂维拉帕米（200μM）的存在减少了紫杉醇的不对称转运，提示P-gp介导的外排作用。TPGS使A-B方向的渗透性呈浓度依赖性增加，而B-A方向的渗透性降低。在TPGS最低浓度为0.1mg/ml时发现最大外排抑制活性，然而，TPGS浓度进一步增加导致A-B方向的渗透性降低，而B-A方向的渗透性无变化。因此，0.1mg/ml TPGS时达到的最大紫杉醇渗透性归因于TPGS浓度依赖性P-gp抑制活性与胶束形成之间的相互作用。大鼠原位渗透性研究也证明了外排在限制紫杉醇渗透性方面的作用以及TPGS的抑制效率。在大鼠中，口服给药（25mg/kg）[14C]紫杉醇后，同时给予50mg/kg剂量的TPGS可显著提高其血浆浓度。与单独给予[14C]紫杉醇相比，[14C]紫杉醇分别与维拉帕米（25mg/kg）和TPGS联合给药时，生物利用度分别提高了约4.2倍和6.3倍。维拉帕米对[14C]紫杉醇口服生物利用度的影响相对于TPGS有限，这与TPGS在体外的溶解度和渗透性增强能力一致。总之，目前的数据表明，由于显著的P-gp介导的外排作用，联合给予TPGS可能会提高BCS II-IV类低溶解度和/或低渗透性药物的生物利用度。
