Solubilization of Cationic Drugs in Lung Surfactant

Abstract

Purpose. The association of hydrophobic, cationic drugs with lung surfactant was determined to assess the pharmacokinetic implications on drug disposition and retention in the lung.

Methods. The distribution coefficients, K, were determined at 25 and 37° in normal saline solution buffered at pH 7.4 for a series of structurally related, cationic drugs. Drugs were dispersed into lung surfactant, equilibrated, and then centrifuged to separate the aqueous phase from the surfactant pellet. Drug concentrations in the supernatant and pellet were determined following dilution using spectrophotometric assays. In addition, the apparent acid dissociation constant of quinacrine in the presence and absence of surfactant was determined by measuring the pH-dependent absorption spectra. The effect of stereochemistry on the distribution of drugs into surfactant was examined with (R)- and (S)-propranolol.

Results. The mole fraction distribution coefficients for amitriptyline, promethazine, promazine, ethopropazine, imipramine, R-propranolol, and S-propranolol at 25°C were 6,560 ± 500, 28,400 ± 1,500, 12,100 ± 840, 5,480 ± 330, 4,490 ± 250, 8,680 ± 260, 8,190 ± 530, respectively. At 37°C, the distribution coefficients were generally smaller indicating a significant exothermic heat of transfer for these solutes from aqueous solution to the lung surfactant. The pKa of quinacrine was 7.43 ± 0.04 in aqueous solution and was shifted to 7.62 ± 0.06 in the presence of lung surfactant. From this shift, the double layer potential for quinacrine-lung surfactant was estimated to be −0.012 V assuming a dielectric constant equivalent to that of water.

Conclusions. Cationic drugs have very favorable distributions from an aqueous solution to the lipid phase of lung surfactant. The transfer process generally has both a large entropic and enthalpic contribution. The latter thermodynamic aspect may be related to the charge interaction between the solute and the negatively charged surfactant. Finally, no significant effect of stereochemistry was evident with the distribution of (R)- and (S)-propranolol.