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 (r 2 > 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-killedStaphylococcus 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.

Ocular Penetration and Pharmacokinetics of Topical Gatifloxacin 0.3% and Moxifloxacin 0.5% Ophthalmic Solutions After Keratoplasty

“…23,29 Higher lipophilicity has been shown to correlate with greater ocular penetration in several fluoroquinolones, including ciprofloxacin and ofloxacin. 30 In addition to greater penetration of the cornea and aqueous humor as shown by high C max and AUC 0-2 values, an optimal antibiotic agent would have higher potency-ie, lower MICs-and a wider spectrum of coverage against common ocular pathogens. Results of previously reported in vitro tests showed that gatifloxacin and moxifloxacin were more potent than the second-and third-generation fluoroquinolones, suggesting that these agents could provide advantages over the early-generation agents for treating and preventing ocular infections caused by Gram-positive organisms and atypical mycobacteria.…”

Prediction of Vitreal Half-Life Based on Drug Physicochemical Properties: Quantitative Structure–Pharmacokinetic Relationships (QSPKR)

“…A systematic study was carried out by Miller (26) to correlate the physicochemical properties and drug elimination from vitreous following intravitreal injection. These authors had shown an excellent correlation between lipophilicity (Log D at pH 7.2) and vitreal elimination half-life following intravitreal injection in albino rabbits.…”

“…(26) had previously reported a linear correlation between the lipophilicity (Log D at pH 7.2) and beta half-life using a small group (four) of structurally similar quinolones. How-…”

Antibiotics in Endophthalmitis: Microbiological and Pharmacokinetic Considerations

“…As a result of the poor vascularization and the small diffusion surface, the ocular globe shows an abscess-like behaviour, with a very limited diffusion of antibiotics, especially those with a high protein binding rate and/or low liposolubility [20]. The main consequences of this fact are: (i) the drug concentration peak in vitreous humour is lower than the drug concentration peak in plasma, and (ii) the maximum drug concentration is reached with some hours of delay between plasma and vitreous humour.…”