Uptake of basic drugs into rat lung granule fraction in vitro

Although basic drugs are distributed widely in various tissues, they are characteristically concentrated in the lung granule fraction. We examined the uptake of seven lipophilic basic drugs into rat lung granule fraction (P₂) in vitro and investigated the contributions of drug lipophilicity and lysosomal trapping to the characteristic lung P₂ distribution. The uptake of each drug into P₂ was examined at various pH values. The drug concentration in P₂ was determined by gas chromatography. Biperiden (BP) was rapidly taken up into P₂, reaching a maximal concentration within 1 min at pH 7.4 at both 4 °C and 37 °C. Both BP and chlorpromazine uptake into P₂ was biphasic. Though the uptake rates of the seven drugs into P₂ increased with rising pH, the rate of increase varied for each drug. There was a good correlation between the octanol-water partition coefficient of the non-ionized form (P(oct)) of each drug and the uptake into P₂ in the presence or absence of NH₄Cl, which inhibits lysosomal trapping. However, uptake into P₂ in the presence of NH₄Cl showed a stronger P(oct)-dependency. We conclude that the distribution of basic drugs into lung P₂ is dependent on both drug lipophilicity and lysosomal uptake.