The effect of molecular weight/lipophilicity on clearance of organic compounds from lungs

The objective of this study was to test the hypothesis that lipophilicity (as measured by the octanol/water partition coefficient, P) and/or molecular weight are determining factors in the rate of clearance of organic compounds from the lung. Previous work in our laboratory has shown that organic-soluble compounds such as pyrene, benzo[a]pyrene, 1-nitropyrene, 2-aminoanthracene, phenanthridone, dibenzo[c,g]carbazole, 1,3-dichloropropene, and methyl bromide, all of which have a log P less than 6.1, clear the lung rapidly (t 1/2 less than 12 hr). In the present study, organic compounds (mainly anthraquinone dyes) having a wider range of log P's (1.95-8.65) were instilled into rat lungs and the percentage of the compound retained in the lungs at 24 hr was determined. A positive correlation between the log of the theoretical P and the percentage of the compound retained in lungs at 24 hr was found. The lipophilicity of the series of compounds studied was highly dependent on the molecular weight, so that there was also a positive correlation between the molecular weight of the compounds and the percentage of the compound retained in the lung at 24 hr. To help understand the relative importance of lipophilicity and molecular weight in determining lung retention, an additional compound with a high molecular weight but containing a polar functional group [1,5-di(2-sulfo-p-toluidino)anthraquinone] was studied. The results indicated that the lipophilicity was the more important factor in whether the material was retained in the lung. On the basis of the results of this study, organic-soluble compounds with molecular weights less than 300 Da can be expected to clear the lungs rapidly. Nonpolar, organic-soluble compounds with a molecular weight greater than 300 Da can be expected to clear the lungs more slowly.