Penetration of Dimyristoylphosphatidylcholine Monolayers and Bilayers by Model β-Blocker Agents of Varying Lipophilicity

Penetration of model ß-blockers, propranolol, oxprenolol, metaprolol, and nadolol, into dimyristoylphosphatidylcholine (DMPC) monolayers cast on a pH7.4 phosphate buffer (μ=0.155 adjusted with NaCI) at 25°C was monitored using a film balance equipped with a Wilhelmy plate for measuring changes in surface pressure. Drug solution (pH7.4) is injected below the surface of the monolayer. The difference in surface pressure, Δπ, for each drug concentration added to the monolayer was measured at equilibrium. Δπ increased with increasing drug concentration. Consistent with the relative lipophilicities, the Δπ vs drug concentration slopes were as follows: propranolol>metaprolol>oxprenolol>nadolol. The intrinsic surface activity of the ß-blockers was also determined in the absence of the lipid. Differential scanning calorimetry (DSC) measurements were also made on DMPC bilayers in the above buffer. DMPC suspended in buffered drug solutions were scanned over a temperature range of 5° to 40°C at a scan rate of 0.091ºC/min. The DSC studies indicate that the DMPC thermotropic phase behavior is modulated by these compounds as follows: propranolol » metaprolol ≅>nadolol which agrees with reported partition coefficients as well as the above Δπ observations. However, an accounting of the intrinsic surface activity of these compounds results in a lower than expected affinity for the DMPC monolayer.