Prediction of drug-membrane interactions by IAM-HPLC: effects of different phospholipid stationary phases on the partition of bases.
The chromatographic capacity factors of 39 neutral and basic compounds were measured on an immobilized artificial membrane-phosphatidylcholine-drug discovery (IAM-PC-DD) HPLC column, and the values compared with both octanol/water partition coefficients and capacity factors previously obtained on an IAM-PC-MG column. These two columns differ in their lipidic phase, since the IAM-PC-MG phase is made of phosphatidylcholine as found in biomembranes, whereas the glycerol linker is absent in the IAM-PC-DD phase. We found that the two phases interact differently with basic compounds at different degrees of ionization. On the IAM-PC-MG column, ionized compounds are as strongly or more strongly retained than isolipophilic neutral compounds. In contrast, their retention on the IAM-PC-DD column is less strong than, or at most as strong as, that of isolipophilic neutral compounds. The IAM-PC-MG data appear as better predictors of the interactions between drugs and biological membranes. Indeed, they correlate better than the IAM-PC-DD data with partitioning in both biological membrane and liposomes; moreover, they are better correlated with biological activities from the literature. These results suggest that even modest modifications in the structure of IAM phospholipids can have a major effect on the retention of basic compounds. We conclude that an acceptable IAM-HPLC estimate of the interactions between biomembranes and basic compounds should rely on stationary phases that reproduce the structure of natural phospholipids.
Barbato
F
F
Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli Federico II, Via D. Montesano, 49, I-80131 Naples, Italy. fbarbato@unina.it
di Martino
G
G
Grumetto
L
L
La Rotonda
M I
MI
D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002853:Chromatography, Liquid; D007700:Kinetics; D008567:Membranes, Artificial; D008968:Molecular Conformation; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D010713:Phosphatidylcholines / Q000737:chemistry*; D010743:Phospholipids / Q000737:chemistry*; D013329:Structure-Activity Relationship
D008567:Membranes, Artificial; D004364:Pharmaceutical Preparations; D010713:Phosphatidylcholines; D010743:Phospholipids