Mechanisms of efflux for fluoroquinolone antibiotics from the vitreous humor of rabbits

Purpose. Previous studies showed that the ocular penetration of systemically administered (IV) fluoroquinolones (FQ) correlated with lipophilicity. Different mechanisms of FQ translocation were suggested based upon the pharmacokinetic modeling (PK) of entry and efflux in rabbits that received IV FQs. We sought to determine if there are different mechanisms of efflux following direct intravitreal injection (IO). In particular, is lipophilicity correlated with FQ elimination half-lives (β t1/2), and what is the effect of probenecid (PBEN) and inflammation on the rate of efflux ? Methods: Serial samples of vitreous humor were obtained from NZW rabbits using a recently described ocular PK model. One eye received IO ciprofloxacin, ofloxacin, sparfloxacin or fleroxacin (FX). The contralateral eye received the same FQ plus IO PBEN. Additionally, for FX the effects of IV PBEN and IO heat killed S. epidermidis (SE) were independently studied. Drug concentrations were determined using a microbiological assay. Lipophilicity was determined by octanol/water partitioning. PK was determined using RSTRIP. Results: IO PBEN increased the β t1/2 for all FQs; the relative increase in the β t1/2s were similar for all the FQs. IV PBEN had no effect on FX elimination. The β t1/2 in eyes receiving HKSE was similar to that in eyes that received IO PBEN. The correlation between the β t1/2 and lipophilicity was linear, r² =0.99. Conclusions: IO PBEN and SE significantly prolong the β t1/2 of the FQs tested. IV PBEN has no effect. These studies strongly suggest that there are several routes of transport for FQs across ocular membrane barriers. One, diffusion is proportional to lipophilicity. Another, active transport, occurs via a (protein) pump that can be blocked by probenecid and by inflammation. These studies also demonstrate the advantages of our serial sampling approach to ocular PK.