Comparison of the Permeability Surface Product (PS) of the Blood Capillary Wall in Skeletal Muscle Tissue of Various Species and In Vitro Porous Membranes Using Hydrophilic Drugs

Abstract

The aim of this study was twofold: Firstly, to compare the PS, the permeability surface product or organ clearance, of various hydrophilic molecules in the muscle blood capillary wall of different animal species, including humans and, secondly, to design an in vitro diffusion cell to identify similar PS values using the respective membranes. The flux rates of solutes with a wide range of molecular weights measured across porous membranes (Millipore® VM (MVM), and Nadir® UFC (NUFC)) was associated with high reproducibility (<±10% SD). The findings were as follows: (1) For the first time ever it was demonstrated that the log molecular weight dependency (between 180 and 10,000 Dalton) of the log of the PS product of the animal muscle capillary wall (slope = −0.51 ± 0.16, and a regression coefficient r2 = 0.90) reported in the literature was similar to that observed by various authors in humans (slope = −0.50 ± 0.25 r2 = 0.77). (2) PS of the MVM membrane with a surface area of 3.8 cm2 recorded for the newly developed diffusion cell ranged at approximately 50% below (slope −0.58 ± 0.12, r2 = 0.85) the value observed in the in vivo human experiments after intramuscular injection. No linear relationship was established for the NUFC membrane due to solute exclusion effects of the membrane. (3) The diameter of the inner donor chamber (resembling the interstice between the muscle fiber membrane and the capillary wall membrane) was calculated to be sufficiently small to eliminate the possibility of creating a statistically significant diffusion barrier to the test membranes, which was corroborated by theoretical modeling. The structure of the in vitro diffusion cell prevents any significant contribution from the unstirred water layer (UWL) to overall resistance, thus reflecting in vivo diffusion properties of hydrophilic solutes deposited intramuscularly to enter the systemic circulation. It may be concluded, that MVM membrane in the vitro diffusion cell mimics the in vivo blood capillary PS for hydrophilic solutes of up to 10,000 Da. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 115–127, 2000