Lenticular Uptake and Distribution of Xenobiotics and Amino Acids

ABSTRACT

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, (Clens section/C_m).

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/C_m value of polar compounds, being less than one, did not further increase by prolonging the incubation period. Only compounds with log P_o/w values between 3 and 6 had C_nucleus/C_m values exceeding unity. The maximal values of C_cortex/C_m and C_nucleus/C_m, approximately 15 and 4, respectively, for anthracene (log P_o/w = 4.5) and diethylstilbestrol (log P_o/w = 5.1), were observed in this study. A bell-shaped relationship was observed between the lenticular uptake rate and drug lipophicity, of which the maximum occurred around log P_o/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 C_nucleus/C_m 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 V_max and Km values of 18.3 μmol/gm/hr and 49.8 mM, respectively.

In summary, a relationship between lenticular uptake and drug lipophilicity was demonstrated. The optimal log P_o/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.