Drug-Phospholipid Interactions. 2. Predicting the Sites of Drug Distribution Using n-Octanol/Water and Membrane/Water Distribution Coefficients

Abstract

The in vivo tissue distribution of seventeen drugs has been modeled by using estimated n-octanol/water and membrane/water distribution coefficients. In this study, the membrane affinities are estimated using the new technique of immobilized artificial membrane (IAM) column chromatography. delta (log D(n-octanol/water-membrane/water)), which measures a hypothetical equilibrium of the drug between of n-octanol and membrane phase, is a better model of in vivo tissue distribution, as measured by Adipose Tissue Storage Index (ASI), than either n-octanol/ water or membrane/water distribution coefficients alone. This demonstrates the importance of membrane distribution coefficients as a complementary descriptor of lipophilicity to n-octanol/water distribution coefficients, in modeling in vivo distribution of drugs. This rapid method for predicting in vivo distribution of drugs, based on n-octanol and membrane/water distribution coefficients, may be a useful tool to aid the selection of drugs with beneficial pharmacokinetic profiles.

The retention properties of nucleobases in alkyl C8-/C18- and IAM-chromatographic systems in relation to log Pow

“…Accordingly, several phospholipid-modified biomembrane-like systems based on the major eukaryotic phospholipid phosphatidylcholine (PC) have been developed for the remedy. Immobilized-artificialmembrane (IAM) stationary phase [3,[6][7][8], which is prepared by phospholipids covalently bonded to a propylamino-silica support, has been popular for its high-throughput screening potential [3], and is useful as a physico-chemical model of drug-membrane partitioning similarly as liposome membranes [6][7][8][9][10][11]. The logarithmic capacity factor using IAM (log k IAM ) has been correlated well with log P ow statistically and some other bioactivities [8][9][10][11].…”

Induced Correlations in the Use of Unbound/Intrinsic Pharmacokinetic Parameters in Quantitative Structure-Pharmacokinetic Relationships with Lipophilicity

“…Associations between these properties and drug distribution are usually assessed in terms of correlation coef®cients. Such structurepharmacokinetic relationships have been established for clearance [2], renal clearance [3], volume of distribution [4], adipose storage [5] and brain penetration [6], and tissue af®nity [7].…”

Determination of liposome partitioning of ionizable drugs by titration

“…[1][2][3][4] In contrast to octanol and other water-immiscible solvents no bulk phase separation between aqueous and organic component occurs in liposome systems. Therefore, standard spectrophotometric techniques cannot be routinely applied to measure drug partitioning in liposomes.…”