Effects of cholesterol and model transmembrane proteins on drug partitioning into lipid bilayers as analysed by immobilized-liposome chromatography

Abstract

We have analysed how cholesterol and transmembrane proteins in phospholipid bilayers modulate drug partitioning into the bilayers. For this purpose we determined the chromatographic retention of drugs on liposomes or proteoliposomes entrapped in gel beads. The drug retention per phospholipid amount (the capacity factor Ks) reflects the drug partitioning. Cholesterol in the bilayers decreased the Ks value and hence the partitioning into the membrane in proportion to the cholesterol fraction. On average this cholesterol effect decreased with increasing temperature. Model transmembrane proteins, the glucose transporter GLUT1 and bacteriorhodopsin, interacted electrostatically with charged drugs to increase or decrease the drug partitioning into the bilayers. Bacteriorhodopsin proteoliposomes containing cholesterol combined the effects of the protein and the cholesterol and approached the partitioning properties of red blood cell membranes. For positively charged drugs the correlation between calculated intestinal permeability and log Ks was fair for both liposomes and bacteriorhodopsin-cholesterol proteoliposomes. Detailed modeling of solute partitioning into biological membranes may require an extensive knowledge of their structures.

Comparing the Lipid Membrane Affinity and Permeation of Drug-like Acids: The Intriguing Effects of Cholesterol and Charged Lipids

“…Several studies (16,(32)(33)(34) revealed a significant decrease of the membrane affinity of a variety of acidic, basic and neutral drugs when Chol was present in phospholipid bilayers. This was assigned to motion restrictions of the fatty acyl chain regions close to the lipid head groups and to the higher rigidity of the membrane induced by Chol in general, leading to an impeded integration of the drug molecules into the lipid bilayer.…”

Lipid Bilayer Fragments and Disks in Drug Delivery

“…Sterically stabilized liposomes prepared from phospholipids with covalently attached poly(ethylene glycol) (PEG lipids) are commonly used for the preparation of long based methods for the determination of drug partitioning such as potentiometric [55][56][57], chromatographic [58][59][60][61][62][63][64], electrophoretic [65][66][67] and calorimetric methods [68,69]. From Lundhal and coworkers technique [58,59] liposomes and disks were immobilized in chromatographic gel beads so that the partition of a large set of drugs was quickly and conveniently assessed [54].…”

Co-delivery of Doxorubicin and PSC 833 (Valspodar) by Stealth Nanoliposomes for Efficient Overcoming of Multidrug Resistance

“…Incorporation of higher Chol concentration in liposomal formulations increased the PSC 833 release rate. The planar and rigid ring system of Chol is thought to reside in outer layer part of the fatty acyl chain region where it tends to restrict the motion of chains in liquid crystalline bilayers (55,56) which may increase tendency of PSC 833 to partition in the release medium. We have previously reported phospholipids concentration-dependent drug release from liposomes (28).…”