Benzodiazepine localisation at the lipid-water interface: effect of membrane composition and drug chemical structure

The effect of membrane chemical composition and drug chemical structure on the localisation of several benzodiazepines (BZDs) (DZ, diazepam; CZ, clona zepam; CX, chlordiazepoxide) within model membranes was investigated. We us ed a spectrophotometric method presented in a previous paper (B.A. Garcia, M.A. Perillo, Biochim. Biophys. Acta 1324 (1997) 76-84) based on the study of BZD acid-base equilibrium. 'Intrinsic pK' values (pK(i)) were calculated according to the theory of M.S. Fernandez and P. Fromherz (J. Phys. Chem. 81 (1977) 1755-1761). Homogeneous media of known dielectric constant (dioxa ne 0-80% v/v in water) were used to construct a curve of Delta pK(i) (pK(i) -pK(w)) vs. dielectric constant (D) where Delta pK(i) values obtained in li pidic dispersions were interpolated. In heterogeneous media consisting of a queous dispersions of Triton X-100 micelles we determined the relative loca lisation depth of BZDs according to their D-Triton values (36, 37 and 62 fo r DZ, CX and CZ respectively) taking into account that lower D values corre spond to deeper localisation. pK(i) determined in dispersions of dipalmitoy lphosphatidylcholine (dpPC) and egg phosphatidylcholine (egg-PC) mixed mult ilamellar vesicles showed that, when cholesterol content increased from 0 t o 20 mole%, D values decreased (from 59 to 40) in dpPC vesicles and increas ed (from 51 to 72) in egg-PC vesicles, indicating a tendency of BZDs to pen etrate deeper into less ordered interfaces. These results should be conside red to understand the non-specific pharmacological effects of BZDs as well as to evaluate the actual relevance of their pharmacological concentrations . (C) 1999 Elsevier Science B.V. All rights reserved.