Effects of Pathological Conditions on Ocular Pharmacokinetics of Antimicrobial Drugs

Abstract

A diffusion model of ocular pharmacokinetics was used to estimate the effects of pathological conditions on ocular pharmacokinetics. In vivo rabbit data after topical instillation of ciprofloxacin and ofloxacin were compared with the simulated concentrations in the aqueous and vitreous humors. The barrier capacity of the surrounding membranes such as the retina/choroid/sclera (RCS) membrane and the cornea was characterized by dimensionless Sherwood number derived by the pseudo-steady state approach (PSSA). We assumed the barrier capacity decreased by inflammation; when the barrier capacity of the RCS membrane and the cornea was assumed to be one-tenth for the RCS membrane and a half for the cornea respectively, the in vivo data agreed with the simulated profile without contradiction. The drug concentration gradient simulated in the vitreous body near the RCS membrane was more significant in the inflamed eyes than in the normal eyes, suggesting that the elimination of the drugs from the RCS membrane was enhanced by inflammation. The present diffusion model can better describe the ocular pharmacokinetics in both normal and diseased conditions.

Drug Penetration of the Posterior Eye Tissues after Topical Instillation: In Vivo and in Silico Simulation

“…7,[13][14][15] The diffusion coefficients in the eye were determined from the previous in vitro penetration experiments by a time-lag method. 7,14,15) The tear compartment is assumed to be perfectly mixed by blinking and tear flow.…”

“…These rates are characterized by the Sherwood number SH, which is defined as follows 7,13) : (10) where D m is the diffusion coefficient in the barrier membrane (cm 2 /s).…”

“…In Silico Pharmacokinetic Study Ofloxacin has a molecular weight of 361.37, 13) and an octanol/buffer partition coefficient of 0.33. 16) Model parameters, such as the coefficient of elimination rate and the Sherwood numbers, were determined as follows.…”

“…The initial tear concentration on the surface of the cornea was 45% of the formulation concentration due to the instantaneous dilution by tear fluid. 13) Thus, the concentration in the tear fluid was assumed to be 1350 mg/ml. 13) Model parameters for evaluating Eq.…”

“…10, such as the diffusion coefficient and the partition coefficient in the eye tissue, were determined from the membrane penetration experiments. 7,13) The value of the membrane thickness of the eye tissue was calculated from the dimensionless ratio of the actual membrane thickness to the spherical radius (12 mm). 17) Accordingly, the Sherwood numbers of the vitreous body and the posterior chamber were defined as 6.17ϫ10 Ϫ4 and 7.24, respectively.…”