Distribution of Small Molecular Weight Drugs intothe Porcine Lens: Studies on Imaging Mass Spectrometry PartitionCoefficients and Implicationsin Ocular Pharmacokinetics

摘要

Lens is the avascular tissue in the eye between the aqueous humor and vitreous. Drug binding to the lens might affect ocular pharmacokinetics, and the binding may also have a pharmacological role in drug-induced cataract and cataract treatment. Drug distribution in the lens has been studied in vitro with many compounds; however, the experimental methods vary, no detailed information on distribution between the lens sublayers exist, and the partition coefficients are reported rarely. Therefore, our objectives were to clarify drug localization in the lens layers and establish partition coefficients for a wide range of molecules. Furthermore, we aimed to illustrate the effect of lenticular drug binding on overall ocular drug pharmacokinetics. We studied the distribution of 16 drugs and three fluorescent dyes in whole porcine lenses in vitro with imaging mass spectrometry and fluorescence microscopy techniques. Furthermore, we determined lens/buffer partition coefficients with the same experimental setup for 28 drugs with mass spectrometry. Finally, the effect of lenticular bindingof drugs on aqueous humor drug exposure was explored with pharmacokineticsimulations. After 4 h, the drugs and the dyes distributed only tothe outermost lens layers (capsule and cortex). The lens/buffer partitioncoefficients for the drugs were low, ranging from 0.05 to 0.8. Onthe basis of the pharmacokinetic simulations, a high lens-aqueoushumor partition coefficient increases drug exposure in the lens butdoes not significantly alter the pharmacokinetics in the aqueous humor.To conclude, the lens seems to act mainly as a physical barrier fordrug distribution in the eye, and drug binding to the lens affectsmainly the drug pharmacokinetics in the lens.