Liu W, Liu Q F, Perkins R, Drusano G, Louie A, Madu A, Mian U, Mayers M, Miller M H
Division of Infectious Disease, Albany Medical College, New York 12208, USA.
Antimicrob Agents Chemother. 1998 Jun;42(6):1417-23. doi: 10.1128/AAC.42.6.1417.
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.
我们使用了一种最近描述的动物模型，来表征全身给药和直接眼内注射后，未感染的白化兔玻璃体液中司帕沙星的眼内药代动力学。将司帕沙星的亲脂性、蛋白结合率和分子量与环丙沙星、氟罗沙星和氧氟沙星的穿透及消除情况进行了比较。为确定消除是否为主动过程，比较了直接注射司帕沙星后，在有和没有丙磺舒或热灭活细菌的情况下的消除率。通过生物测定法测量血清和玻璃体液中的司帕沙星浓度。分别通过超滤和油水分配法测定蛋白结合率和亲脂性。使用RSTRIP（一种迭代、非线性、加权、最小二乘回归程序）来表征药代动力学参数。通过多元线性回归确定每个自变量与玻璃体液中喹诺酮平均浓度或消除率之间的关系。玻璃体液中司帕沙星的平均浓度为血清中浓度的59.4%±12.2%。司帕沙星、环丙沙星、氟罗沙星和氧氟沙星在玻璃体液中的穿透及消除与亲脂性相关（r2>0.999）。通过纳入分子量平方根的倒数和/或蛋白结合程度，描述这种关系的线性回归方程并未得到改善。眼内给予丙磺舒可降低每种喹诺酮的消除率。热灭活的表皮葡萄球菌可降低氟罗沙星的消除率。司帕沙星进入非炎症性玻璃体液的穿透性高于之前检测的任何喹诺酮。司帕沙星以及环丙沙星、氟罗沙星和氧氟沙星的亲脂性与进入玻璃体液或从玻璃体液中消除之间存在极好的相关性。喹诺酮进出玻璃体液有两种转运模式：扩散进入眼内以及扩散和载体介导的消除从玻璃体液中排出。
