Pharmacokinetics of sparfloxacin in the serum and vitreous humor of rabbits: physicochemical properties that regulate penetration of quinolone antimicrobials

Abstract

We have used a recently described animal model to characterize the ocular pharmacokinetics of sparfloxacin in vitreous humor of uninfected albino rabbits following systemic administration and direct intraocular injection. The relationships of lipophilicity, protein binding, and molecular weight to the penetration and elimination of sparfloxacin were compared to those of ciprofloxacin, fleroxacin, and ofloxacin. To determine whether elimination was active, elimination rates following direct injection with and without probenecid or heat-killed bacteria were compared. Sparfloxacin concentrations were measured in the serum and vitreous humor by a biological assay. Protein binding and lipophilicity were determined, respectively, by ultrafiltration and oil-water partitioning. Pharmacokinetic parameters were characterized with RSTRIP, an iterative, nonlinear, weighted, least-squares-regression program. The relationship between each independent variable and mean quinolone concentration 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. Penetration of sparfloxacin, ciprofloxacin, fleroxacin, and ofloxacin into, and elimination from, the vitreous humor correlated with lipophilicity (r2 > 0.999). The linear-regression equation describing this relationship was not improved by including the inverse of the square root of the molecular weight and/or the degree of protein binding. Elimination rates for each quinolone were decreased by the intraocular administration of probenecid. Heat-killed Staphylococcus epidermidis decreased the rate of elimination of fleroxacin. Penetration of sparfloxacin into the noninflamed vitreous humor was greater than that of any quinolone previously examined. There was an excellent correlation between lipophilicity and vitreous entry or elimination for sparfloxacin as well as ciprofloxacin, fleroxacin, and ofloxacin. There are two modes of quinolone translocation into and out of the vitreous humor: diffusion into the eye and both diffusion and carrier-mediated elimination out of the vitreous humor.

FIG. 1

Mean concentrations of sparfloxacin in the serum and vitreous humor of six rabbits following a single intravenous dose (40 mg/kg). The left graph shows the data plotted arithmetically, and the right graph shows the data plotted semilogarithmically.

FIG. 2

(A) Relationship between the partition coefficients for ciprofloxacin (•), fleroxacin (⧫), ofloxacin (▴), and sparfloxacin (▪) and levels of penetration into the vitreous humor. (B) Relationship between the partition coefficients for these quinolones (same symbols) and the elimination rate half-lives following direct intravitreal injection.

FIG. 3

Effect of probenecid on the elimination of sparfloxacin (A), fleroxacin (B), ofloxacin (C), and ciprofloxacin (D) with (•) and without (▴) the coadministration of probenecid; both probenecid and the quinolones were given intravitreally. The inset shows the effect of heat-killed S. epidermidis (•) on the elimination of fleroxacin alone (▴).