Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
Mol Pharm. 2021 Apr 5;18(4):1768-1778. doi: 10.1021/acs.molpharmaceut.1c00015. Epub 2021 Mar 17.
The aim of this study was to evaluate the effect of lipid digestion on the permeability and absorption of orally administered saquinavir (SQV), a biopharmaceutics classification system (BCS) class IV drug, in different lipid-based formulations. Three LBFs were prepared: a mixed short- and medium-chain lipid-based formulation (SMCF), a medium-chain lipid-based formulation (MCF), and a long-chain lipid-based formulation (LCF). SQV was loaded into these LBFs at 26.7 mg/g. To evaluate the pharmacokinetics of SQV , drug-loaded formulations were predispersed in purified water at 3% w/w and orally administered to rats. A low dose (0.8 mg/rat) was employed to limit confounding effects on drug solubilization, and consistent with this design, presolubilization of SQV in the LBFs did not increase exposure compared to a control suspension formulation. The areas under the plasma concentration-time curve were, however, significantly lower after administration of SQV as MCF and LCF compared to SMCF. To evaluate the key mechanisms underpinning absorption, each LBF containing SQV was digested, and the flux of SQV from the digests across a dialysis membrane was evaluated in permeation experiments. This study revealed that the absorption profiles were driven by the free concentration of SQV and that this varied due to differences in SQV solubilization in the digestion products generated by LBF digestion. The apparent first-order permeation rate constants of SQV () were estimated by dividing the flux of SQV in the dialysis membrane experiments by the concentration of total SQV on the donor side. values strongly correlated with AUC. The data provide one of the first studies of the effect of digestion products on the free concentration of a drug in the GI fluid and oral absorption. This simple permeation model may be a useful tool for the evaluation of the impact of lipid digestion on apparent drug permeability from lipid-based formulations. These effects should be assessed alongside, and in addition to, the more well-known effects of lipids on enhancing intestinal solubilization of poorly water-soluble drugs.
本研究旨在评估脂质消化对不同脂质基制剂中口服给予的沙奎那韦（SQV）（生物药剂学分类系统（BCS）分类 IV 类药物）的通透性和吸收的影响。制备了三种 LBF：混合短链和中链脂质基制剂（SMCF）、中链脂质基制剂（MCF）和长链脂质基制剂（LCF）。将 SQV 以 26.7mg/g 的剂量载入这些 LBF 中。为了评估 SQV 的药代动力学，将载药制剂以 3%w/w 的浓度预分散在纯化水中并口服给予大鼠。采用低剂量（0.8mg/rat）以限制药物增溶对药物暴露的混杂影响，并且根据这一设计，与对照混悬剂相比，在 LBF 中预溶解 SQV 并没有增加暴露。然而，与 SMCF 相比，给予 MCF 和 LCF 后 SQV 的血浆浓度-时间曲线下面积显著降低。为了评估吸收的关键机制，每种含有 SQV 的 LBF 均进行了消化，并在渗透实验中评估了 SQV 从消化产物穿过透析膜的通量。本研究表明，吸收谱由 SQV 的游离浓度驱动，而这一浓度由于 LBF 消化产生的消化产物中 SQV 的溶解度不同而发生变化。通过将透析膜实验中 SQV 的通量除以供体侧总 SQV 的浓度，估算了 SQV 的表观一级渗透速率常数（）。值与 AUC 强烈相关。该数据提供了关于消化产物对胃肠道液中药物游离浓度和口服吸收影响的首批研究之一。这种简单的渗透模型可能是评估脂质消化对脂质基制剂中药物表观渗透性的影响的有用工具。除了更众所周知的脂质对增强亲脂性差的药物在肠道中的增溶作用之外，还应评估这些影响。
