A comprehensive insight on ocular pharmacokinetics

Abstract

The eye is a distinctive organ with protective anatomy and physiology. Several pharmacokinetics compartment models of ocular drug delivery have been developed for describing the absorption, distribution, and elimination of ocular drugs in the eye. Determining pharmacokinetics parameters in ocular tissues is a major challenge because of the complex anatomy and dynamic physiological barrier of the eye. In this review, pharmacokinetics of these compartments exploring different drugs, delivery systems, and routes of administration is discussed including factors affecting intraocular bioavailability. Factors such as precorneal fluid drainage, drug binding to tear proteins, systemic drug absorption, corneal factors, melanin binding, and drug metabolism render ocular delivery challenging and are elaborated in this manuscript. Several compartment models are discussed; these are developed in ocular drug delivery to study the pharmacokinetics parameters. There are several transporters present in both anterior and posterior segments of the eye which play a significant role in ocular pharmacokinetics and are summarized briefly. Moreover, several ocular pharmacokinetics animal models and relevant studies are reviewed and discussed in addition to the pharmacokinetics of various ocular formulations.

Keywords: Animal models; Anterior chamber; Compartment models; Ocular pharmacokinetics; Posterior chamber; Simulation study; Transporter.

Fig. 1

Schematic illustration of the main structure of the eye and the ocular barriers. The primary physiologic blockage against installed drugs is the tear film. Cornea is the main route for drug transport to the anterior chamber (I). The retinal pigment epithelium and the retinal capillary endothelium are the main barriers for systemically administered drugs (II). Intravitreal injection is an invasive strategy to reach the vitreous (III). The administered drugs can be carried from the anterior chamber away either by venous blood flow after diffusing across the iris surface (1) or by the aqueous humor outflow (2). Drugs can be removed from the vitreous away through diffusion into the anterior chamber (3), or by the blood–retinal barrier (4). The image was adapted with permission from Reference .

Fig 2

Schematic representation of ocular absorption through topical administration. The image was adapted with permission from Reference .

Fig 3

Schematic of one compartment pharmacokinetic model

Fig 4

Schematic of two compartment pharmacokinetic model

Fig 5

Schematic of three compartment pharmacokinetic model

Fig 6

Schematic of four compartment pharmacokinetic model

Fig 7

Schematic of four compartment pharmacokinetic model

Fig 8

Compartmental model for drug distribution from systemic circulation to the ocular vitreous. Reproduced with permission (Ref. 40)

Fig. 9

Experimental (solid line) and simulated (dashed line) concentrations of the drugs in systemic circulation (plasma or serum) of rabbits after intravenous administration. The drugs ciprofloxacin, cytarabine, fleroxacin, fluconazole, and foscarnet are presented in panel A and mercaptopurine,methotrexate, ofloxacin, sparfoxacin, and topotecan in panel B. Reproduced with permission (Ref. 40)

Fig. 10

Besifloxacin concentration versus time profiles in tear fluid from cynomolgus monkeys, pigmented rabbits, and humans following single topical ocular administration of besifloxacin ophthalmic suspension (0.6%) (58).

Fig. 11

Pharmacokinetic profile of loteprednoletabonate in rabbit aqueous humor, cornea and conjunctiva. The value shown for each time point is the mean ± SEM for six samples. Reproduced with permission from Ref.

Fig. 12

Bevacizumab is distributed from the aqueous humor into the serum and vitreous humor. It is also distributed from the serum into the aqueous and vitreous humor, and excreted. CL1 = distribution from the serum intothe aqueous humor; CL2 = distribution from the aqueous humor into theserum; CL3 = distribution from the serum into the vitreous humor; CL4 = distribution from the vitreous humor into the serum; CL5 = distributionbetween the vitreous and aqueous humor; K10 = elimination rate constant;VAH = volume of the aqueous humor; VVH volume of thevitreous humor; V_Serum= volume of the serum compartment. Reproduced with permission from Ref.