Bilayer Composition, Temperature, Speciation Effects and the Role of Bilayer Chain Ordering on Partitioning of Dexamethasone and its 21-Phosphate

• Published in: Pharmaceutical research 2013-12, Vol.30 (12), p.3154-3169
• Main Authors: Modi, Sweta, Anderson, Bradley D.
• Format: Article
• Language: English
• Subjects: Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacokinetics; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Dexamethasone - chemistry; Dexamethasone - pharmacokinetics; Lipid Bilayers - chemistry; Lipid Bilayers - metabolism; Lipids; Liposomes - chemistry; Liposomes - metabolism; Medical Law; Membranes; Permeability; Pharmaceutical sciences; Pharmacology/Toxicology; Pharmacy; Phosphates - chemistry; Phosphates - pharmacokinetics; Phosphatidylcholines - chemistry; Phosphatidylcholines - metabolism; Research Paper; Steroids; Temperature
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-013-1143-z

ABSTRACT Purpose Models to predict membrane-water partition coefficients (K p ) as a function of drug structure, membrane composition, and solution properties would be useful. This study explores the partitioning of dexamethasone (Dex) and its ionizable 21-phosphate (Dex-P) in liposomes varying in acyl chain length, physical state, and pH. Methods DMPC:mPEG DMPE, DPPC:mPEG DPPE, and DSPC:mPEG DSPE (95:5 mol%) liposomes were prepared by thin film hydration. K p values for Dex and Dex-P were determined from pH 1.5–8 by equilibrium dialysis and equilibrium solubility (Dex). Results Dex K p values at 25°C were 705 ± 24, 106 ± 11, and 58 ± 9 in DMPC, DPPC, and DSPC, increasing to 478 ± 20 in DPPC liposomes at 45°C. Both neutral and anionic species contributed to the K p of Dex-P versus solution pH (1.5–8). A linear correlation was found between the natural logarithm of K p and the inverse of bilayer free surface area (1/a free ) where a free is a parameter reflecting chain ordering that depends on bilayer composition and temperature. Conclusions Models of the pH dependence of partitioning of ionizable compounds must include contributions of both neutral and ionized species. Bilayer free surface area may be an important variable to predict K p of drug molecules versus lipid composition and temperature.