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Partition and distribution coefficients (log P, log D) into rat small intestinal brush border membrane (BBM) were measured for a variety of ionizable and non-ionizable drugs and solutes using a novel technique. The log P values were compared with those determined with model solvents, octanol and propylene glycol dipelargonate (PGDP). Non-ionizable solutes with log P values up to 3.0 showed that octanol was a better model for partition into the BBM than PGDP. With one exception, BBM partition coefficients of greater than 3 were not observed, even for solutes with log P values in model solvents that were greater than 5. Liposomes prepared from BBM lipids, or synthetic lipid mixtures of similar composition to BBM, demonstrated similar trends in partition coefficients to the intact BBM. Two cationic drugs, Atenolol and Xamoterol were investigated for partition into BBM lipid liposomes. An apparent enhancement of log D with respect to octanol was attributed to a "surfactant-like" orientation in the membrane and an interaction of the ionized drug with anionic phospholipid head groups. The anionic drug Proxicromil shows the expected decrease in log D with increasing pH, at low NaCl concentrations. Changes in electrophoretic mobility of liposomes after incorporation of Proxicromil into them were consistent with the negative charge of the ionized drug being at the membrane surface. It was concluded that Proxicromil also associates with membranes in a "surfactant-like" orientation and that increased extraction with increasing NaCl concentrations is a result of ionic strength effects. Partition of solutes into BBM vesicles is more complex than into organic solvents and probably represents an important step in overall intestinal permeation of solutes.

Brush border membrane vesicles (BBMV) were isolated from rat small intestine and characterized in terms of relative enrichment of specific organelle marker enzymes (20-fold enrichment; 20% yield), contamination by other subcellular organelles (less than 1%) and functional integrity (Na(+)-dependent glucose uptake). Using these vesicles, techniques were developed for the determination of partition and distribution coefficients for the model solutes, nitrobenzene, toluene and benzoic acid. No gender, age or regional variation along the small intestine in partition coefficient (log P) values was detected. There was no temperature (10-40 degrees) or pH (4.5-8.0) dependence in partition coefficients of nitrobenzene and toluene. Fair agreement was obtained for log P and log D values for these two solutes determined with BBMV and those reported with octanol and propylene glycol dipelargonate. Selective removal of proteins, both ecto-brush border and micro-villus core proteins, did not alter the partition coefficients of the three model solutes. In contrast, depletion of the BBMV of non-esterified fatty acids significantly decreased the partition coefficients. Liposomes prepared from BBMV lipid extracts were also used for partition coefficient determinations and gave similar values to intact BBMV; addition of increasing amounts of cholesterol to the lipid extract caused small increases in the partition coefficients of the model solutes in the liposomes. It was concluded that the partition coefficients of the BBMV were related to the lipid and not to the protein composition of the vesicles. The method offers a rapid and reliable means of measuring the partition coefficient of non-protein bound drugs and nutrients in isolated intestinal BBMV and should assist in the subsequent modelling and prediction of intestinal absorption in vivo.