The objective of this study was to explore the relationship between lipophilicity and the lenticular uptake of radiolabeled xenobiotics. The lenticular uptake of amino acids was also investigated. An organ-culture technique was employed and the partitioning of compounds into the rabbit lens was measured for compounds with log octanol/water partition coefficients (log P o/w) ranging from -1 to 7.3. Drug distribution in the lens was expressed as the concentration ratio of that in the lenticular section (capsule/epithelium, cortex, and nucleus) to that in the incubation medium, (C(lens) section/Cm). The drug partitioning into the lens capsule was facile for all of the compounds tested. The drug concentrations in the lens capsule were higher than those in the cortical and nuclear regions. For compounds with low partition coefficients (such as sulfacetamide and cimetidine), an apparent distribution equilibrium was achieved during a 5-hr period. The C(lens)/Cm value of polar compounds, being less than one, did not further increase by prolonging the incubation period. Only compounds with log Po/w values between 3 and 6 had Cnucleus/Cm values exceeding unity. The maximal values of Ccortex/Cm and Cnucleus/Cm, approximately 15 and 4, respectively, for anthracene (log Po/w = 4.5) and diethylstilbestrol (log Po/w = 5.1), were observed in this study. A bell-shaped relationship was observed between the lenticular uptake rate and drug lipophilicity, of which the maximum occurred around log Po/w of 4. These results indicate the existence of a lipophilicity window for favorable drug distribution into the deeper region of the lens. For several lipophilic compounds, such as padimate-O, values of Cnucleus/Cm increased steadily over a 24-hour incubation period. This suggests that the nucleus behaved as a deep compartment for these compounds. L-Cysteine and L-serine were actively taken up by the lens and the lenticular absorption of L-cysteine was concentration-dependent with Vmax and Km values of 18.3 mumol/gm/hr and 49.8 mM, respectively. In summary, a relationship between lenticular uptake and drug lipophilicity was demonstrated. The optimal log Po/w value for drug uptake into the lens was between 4 and 5. The slowness of reaching significant drug concentrations in the nucleus necessitates a chronic dosing regimen to deliver therapeutic drug levels inside the lens.