Pharmacokinetics of ofloxacin in serum and vitreous humor of albino and pigmented rabbits. Antimicrob Agents Chemother

Department of Medicine, Albany Medical College, New York 12208, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 07/1995; 39(7):1493-8. DOI: 10.1128/AAC.39.7.1493
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The purpose of this study was to evaluate the pharmacokinetics of ofloxacin in serum and vitreous humor samples from albino and pigmented rabbits by using a recently described animal model which permits robust estimation of parameter values. The drug was administered to rabbits intravenously, multiple vitreous humor and serum samples were taken from each rabbit, and the vitreous humor and serum samples were assayed by high-pressure liquid chromatography. The pharmacokinetic parameters were determined with RSTRIP, an iterative, nonlinear, weighted, least-squares regression program. Eight New Zealand White rabbits and eight Dutch Belted rabbits (split into single-dose and multiple-dose groups) were investigated in this study. The value of penetration into the vitreous humor of albino rabbits (n = 6) was 32.6% +/- 2.12%, with terminal-elimination half-life values of 3.21 and 2.39 h, respectively, for vitreous humor and serum. In pigmented rabbits after a single dose (n = 3) and with a steady-state concentration of drug in serum (n = 4), penetration values were similar, at 30.4% +/- 2.98% and 30.0% +/- 4.12%, respectively (P > 0.10). Following a single dose of ofloxacin, pigmented animals had elimination half-life values from serum and vitreous humor of 2.64 and 4.32 h, respectively. After steady state was achieved, half-life values for serum and vitreous humor were 3.12 and 6.05 h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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    • "The importance of drug melanin binding in pharmacology was demonstrated decades earlier (Potts, 1962; Salazar et al., 1976). Literature supports altered pharmacokinetics and/or pharmacodynamics due to the presence of melanin pigment for drugs including gentamicin (Kane et al., 1981), ofloxacin (Perkins et al., 1995), pefloxacin (Cochereau-Massin et al., 1991), grepafloxacin (Solans et al., 2004), beta-blockers (Araie et al., 1982), celecoxib (Amrite et al., 2010; Cheruvu et al., 2008), ganciclovir, and acyclovir (Durairaj et al., 2009b; Hughes et al., 1996). Since ocular drug product development relies heavily on preclinical studies, choosing an animal model with melanin pigmentation similar to humans is most desirable in obtaining valid preclinical data. "
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    ABSTRACT: The purpose of this study was to quantify the melanin pigment content in sclera, choroid-RPE, and retina, three tissues encountered during transscleral drug delivery to the vitreous, in human, rabbit, monkey, minipig, and dog models. Strain differences were assessed in NZW × NZR F1 and Dutch belted rabbits and Yucatan and Gottingen minipigs. The choroid-RPE and retina tissues were divided into central (posterior pole area) and peripheral (away from posterior pole) regions while the sclera was analyzed without such division. Melanin content in the tissues was analyzed using a colorimetric assay. In all species the rank order for pigment content was: choroid-RPE >retina ≥ sclera, except in humans, where scleral melanin levels were higher than retina and central choroid. The melanin content in a given tissue differed between species. Further, while the peripheral tissue pigment levels tended to be generally higher compared to the central regions, these differences were significant in human in the case of choroid-RPE and in human, monkey, and dogs in the case of retina. Strain difference was observed only in the central choroid-RPE region of rabbits (NZW × NZR F1 >Dutch Belted). Species, strain, and regional differences exist in the melanin pigment content in the tissues of the posterior segment of the eye, with Gottingen minipig being closest to humans among the animals assessed. These differences in melanin content might contribute to differences in drug binding, delivery, and toxicity.
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    ABSTRACT: Ofloxacin (OFLX) is a fluoroquinolone-antibiotic with a broad antimicrobial spectrum that may have a potential role in the treatment of bacterial endophthalmitis. However, its elimination half life after intravitreal injection is short. To prolong the intravitreal antibacterial level OFLX was incorporated into liposomes. This study was performed to investigate the retinal toxicity of liposome-incorporated and free OFLX. OFLX was incorporated into multilamellar large vesicles. 0.1 ml of this suspension (= 180.2 microg OFLX) was injected into the midvitreous of rabbit eyes (n = 6). Free OFLX in doses of 100 microg, 500 microg and 1,000 microg was injected into the midvitreous of a second group of rabbit eyes (n = 18). The other eye served as a control and received empty liposomes or normal saline solution, respectively. Before injection and at the end of follow-up an ERG was obtained. After a follow-up of 1 day, 14 and 28 days the animals were perfused with glutaraldehyde and the eyes were examined by light- and transmission electron microscopy. The ERG as well as the histologic studies did not reveal any pathological changes after injection of liposome-incorporated OFLX compared to the control eyes. Significant reduction of the ERG was observed after 500 microg free OFLX in 2 out of 6 eyes after 1 and 14 days, respectively, and in 2 eyes 1 day after 1,000 microg free OFLX. Three days after injection of 1,000 microg OFLX the retina showed focal destruction in 1 out of 6 eyes. In another eye with the same dose 14 days after injection the photoreceptor outer segments showed disorganisation. This study shows that liposome-incorporated OFLX did not have any retinal toxicity in this animal model. Free OFLX appears to have no retinal toxicity in rabbit eyes at a dose of 100 microg after intravitreal injection. Injection of higher doses resulted in ERG changes and marked retinal damage.
    International Ophthalmology 01/1998; 22(3):133-43. DOI:10.1023/A:1006137100444 · 0.55 Impact Factor
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    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.
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