PHARMACOKINETICS OF SPARFLOXACIN IN THE SERUM AND VITREOUS-HUMOR OF RABBITS - PHYSICOCHEMICAL PROPERTIES THAT REGULATE PENETRATION OF QUINOLONE ANTIMICROBIALS

We have used a recently described animal model to characterize the ocu lar pharmacokinetics of sparfloxacin in vitreous humor of uninfected a lbino rabbits following systemic administration and direct intraocular injection. The relationships of lipophilicity, protein binding, and m olecular weight to the penetration and elimination of sparfloxacin wer e compared to those of ciprofloxacin, fleroxacin, and ofloxacin. To de termine whether elimination was active, elimination rates following di rect injection with and without probenecid or heat-killed bacteria wer e compared. Sparfloxacin concentrations were measured in the serum and vitreous humor by a biological assay. Protein binding and lipophilici ty were determined, respectively, by ultrafiltration and oil-water par titioning. Pharmacokinetic parameters were characterized with RSTRIP, an iterative, nonlinear, weighted, least-squares-regression program. T he relationship between each independent variable and mean quinolone c oncentration or elimination rate in the vitreous humor was determined by multiple linear regression. The mean concentration of sparfloxacin in the vitreous humor was 59.4% +/- 12.2% of that in serum. Penetratio n of sparfloxacin, ciprofloxacin, fleroxacin, and ofloxacin into, and elimination from, the vitreous humor correlated with lipophilicity (r( 2) > 0.999). The linear-regression equation describing this relationsh ip was not improved by including the inverse of the square root of the molecular weight and/or the degree of protein binding. Elimination ra tes for each quinolone were decreased by the intraocular administratio n of probenecid. Heat-killed Staphylococcus epidermidis decreased the rate of elimination of fleroxacin. Penetration of sparfloxacin into th e noninflamed vitreous humor was greater than that of any quinolone pr eviously examined. There was an excellent correlation between lipophil icity and vitreous entry or elimination for sparfloxacin as well as ci profloxacin, fleroxacin, and ofloxacin. There are two modes of quinolo ne translocation into and out of the vitreous humor: diffusion into th e eye and both diffusion and carrier-mediated elimination out of the v itreous humor.