Department of Physics, Grand Valley State University , Allendale, Michigan 49401, United States.
Mol Pharm. 2017 Dec 4;14(12):4661-4674. doi: 10.1021/acs.molpharmaceut.7b00798. Epub 2017 Nov 20.
The potential use of poly(dimethylsiloxane) (PDMS) as an in vitro biomimetic analogue of the passive drug absorption process in the human gastrointestinal tract (GI) is assessed. PDMS is biomimetic because of similarities in small molecule transport, such as mechanism, ionization selectivity, lipophilicity. Nine molecular probes are used to evaluate the transport pathways and properties used to predict human oral absorption rates. The transport pathways through PDMS (bulk/pore) are analogous to transcellular (TCDT) and paracellular (PCDT) drug transport pathways. PDMS PCDT is assessed using positronium annihilation lifetime spectroscopy (PALS) and partition experiments; TCDT using diffusion and partition experiments. PALS determined that PDMS pores were uniform (D ∼ 0.85 nm), isolated, and void volume was unaffected by drug accumulation after equilibrium partitioning. Therefore, there is no PCDT or convective flow through PDMS. A strong linear correlation exists between predicted octanol-water partition coefficients and PDMS partition coefficients (LogK = 0.736 × LogP - 0.971, R = 0.981). The pH-partition hypothesis is confirmed in PDMS using ibuprofen over pH 2-12. Diffusivity through PDMS is a function of lipophilicity and polar surface area K × D = 4.46 × 10 × e(R = 0.963) and [Formula: see text] (R = 0.973). Varying the mass% of curing agent changed the lipophilicity and diffusivity (p < 0.02), but not practically (K × D = 2.23 × 10cms vs 2.60 × 10cms), and does affect elastic modulus (3.2% = 0.3 MPa to 25% = 3.2 MPa).
评估了聚二甲基硅氧烷（PDMS）作为人类胃肠道（GI）被动药物吸收过程体外仿生模拟物的潜在用途。PDMS 具有仿生特性，因为小分子运输的机制、离解选择性、亲脂性等方面存在相似性。使用九种分子探针来评估用于预测人体口服吸收率的运输途径和性质。PDMS 中的运输途径（本体/孔）类似于细胞间（TCDT）和细胞旁（PCDT）药物运输途径。使用正电子湮没寿命谱（PALS）和分配实验评估 PDMS 的 PCDT；使用扩散和分配实验评估 TCDT。PALS 确定 PDMS 孔是均匀的（D∼0.85nm）、孤立的，并且药物积累后平衡分配对空体积没有影响。因此，PDMS 中不存在 PCDT 或对流。预测的辛醇-水分配系数与 PDMS 分配系数之间存在很强的线性相关性（LogK=0.736×LogP-0.971，R=0.981）。在 PDMS 中，使用布洛芬在 pH 2-12 范围内证实了 pH-分配假说。PDMS 中的扩散系数是疏水性和亲水表面积的函数 K×D=4.46×10×e（R=0.963）和[Formula: see text]（R=0.973）。改变固化剂的质量%会改变疏水性和扩散系数（p<0.02），但实际上不会（K×D=2.23×10cms 与 2.60×10cms），并且确实会影响弹性模量（3.2%=0.3MPa 至 25%=3.2MPa）。
