Predicting drug-membrane interactions by HPLC: structural requirements of chromatographic surfaces

Abstract

Drug-membrane interactions have recently been studied by immobilized artificial membrane (IAM) chromatography (Pidgeon, C.; et al. J. Med. Chem. 1995, 38, 590-595. Ong, S.; et al. Anal. Chem. 1995, 67, 755-762), and the molecular recognition properties of IAM surfaces toward drug binding/partitioning appear to be remarkably close to the molecular recognition properties of fluid membranes. The structural requirements of chromatography surfaces to emulate biological partitioning are unknown. To begin to elucidate the surface structural requirements needed to predict drug partitioning into membranes, three bonded phases were prepared. The chromatography bonded phases were prepared by immobilizing (i) a single-chain analog containing the phosphocholine (PC) headgroup (IAM.PC.DD), (ii) a long-chain alcohol containing polar OH groups protruding from the surface (12-OH-silica), and (iii) a long-chain fatty acid containing OCH3 groups protruding from the surface (12-MO-silica). The 12-OH-silica surface can be considered as an immobilized "octanol" phase with OH groups protruding from the surface and is therefore a solid phase model of octanol/water partitioning systems. As expected, improved capability of predicting solute-membrane interactions as found for the chromatographic surface containing the PC polar head-group because the PC headgroup is also found in natural cell membranes. For instance, the IAM.PC.DD column predicted drug partitioning into dimyristoylphosphatidylcholine liposomes (r = 0.864) better than 12-OH-silica (r = 0.812), and 12-MO-silica (r = 0.817). IAM. PC.DD columns also predicted intestinal drug absorption (r = 0.788) better than 12-OH-silica (r = 0.590) and 12-MO-silica (r = 0.681); reversed phase octadecylsilica (ODS) columns could not predict intestinal absorption (r = 0.10). Collectively, these results suggest that chromatographic surfaces containing interfacial polar groups, i.e., PC, OH, and OCH3, model drug-membrane interactions, but surfaces lacking interfacial polar functional groups (e.g., ODS surface) are poor models. Most interestingly, drug partitioning into octanol/water systems does not correlate with drug binding to the immobilized octanol phase. However, drug partitioning into immobilized octanol correlates with drug partitioning into liposomes (r = 0.812).