5.2  Drug Distribution

5.2.1  Drug Distribution from the Anterior Ocular Surface to the Posterior Segment

In comparison to studies of the oral bioavailability of drugs and their absorption across intestinal tissue, the penetration of drugs into the eye from drops applied to anterior ocular surface appears to be driven by a drug concentration gradient established at the corneal and/or scleral surfaces and is less dependent on the number of potential hydrogen bonds, molecular weight, or lipophilicity of the drug (Ahmed et al. 1987; Lipinski et al. 2001). At the corneal epithelial surface, drug can cross the epithelium either by going between (para-cellular) or through (trans-cellular) the epithelial cells. Drug penetration by either of these routes is linearly related to drug concentration in tear and favors drugs formulated at high concentrations and with long residence times on the ocular surface (Table 5.1) (Huang et al. 1983; Chung et al. 1998; Pade and Stavchansky 1997). In general, hydrophilic drugs cross the corneal epithelial barrier by the para-cellular route (e.g., Inulin or Atenolol); they are restricted to the aqueous extracellular environment and must move through the limited space in the tight junctions between epithelial cells. In contrast, lipophilic or hydrophobic drugs cross the corneal epithelial barrier by the trans-cellular route (e.g., Timolol or Propanolol), have the advantage of a much larger surface area or window of absorption, and generally have a higher permeability across the epithelium.

In marketed drugs, excipients can be added to the formulation to enhance the drugs’ penetration into ocular tissues. For example, the addition of EDTA to the Atenolol formulation loosens the tight junctions between epithelial cells by chelating the calcium needed to maintain their integrity (Rojanasakul and Robinson 1991), and increases the para-cellular space and penetration of Atenolol through the corneal epithelium by the para-cellular route (Chung et al. 1998). No effect is seen on the trans-cellular uptake of Propanolol with the addition of EDTA to the formulation.

Once in the corneal stroma, there is typically little resistance at the corneal endothelium to diffusion further into the anterior chamber (Huang et al. 1983). In studies of Inulin vs. Timolol (Ahmed and Patton 1985) and Propranolol vs. Atenolol (Chung et al. 1998) in rabbits after application of an ophthalmic drop, drug levels were highest in the cornea with sequentially declining levels in the sclera, aqueous humor, and vitreous humor. Interestingly, levels in the posterior sclera are within a fewfold of those in the cornea for Inulin and Timolol in as little as 20 min after a drop is applied to the cornea surface. Consequently, it appears that once on the surface of the eye, there can be rapid distribution of drug driven by a concentration gradient across the compartments of the eye.

To distinguish transit via the periocular trans-scleral route from the trans-vitreous and uvea-scleral trans-corneal routes, Patton devised a chamber which could be placed with a tight seal to the ocular surface around the cornea (Ahmed and Patton 1985). Drug introduced into the chamber is restricted to contacting the corneal surface only.

Table 5.1  The concentration of inulin, timolol, propanolol, and atenolol 20 min after administration of a drop to a rabbit eye

Retina

 Equator-1.67

 Posterior-0.14

Periocular tissue

 Equator-1.78

 Posterior-0.21

(+Cornea) indicates access of the drop to the cornea, (−Cornea) indicates drop excluded from cornea for Inulin and Timolol, (+EDTA) indicates the addition of EDTA as a corneal epithelial penetration enhancer for propranolol and atenolol. Data taken from Ahmed and Patton (1985); Ahmed et al. (1987); Chung et al. (1998); and Mizuno et al. (2009)

%F % oral bioavailability; AH aqueous humor; VH vitreous humor; BLQ below limit of quantitation; ND not done

aPost hepatic bioavailability

Drug administered in this manner was also denied lateral diffusion across the anterior ocular surface and access to the conjunctiva. Thus, any drug access to ocular tissues is by way of corneal penetration into the aqueous humor of the anterior chamber. It is surprising to note that when Inulin and Timolol are delivered to the cornea using this chamber, drug levels in the aqueous humor are similar despite their differences in trans-cellular vs. para-cellular uptake, and a greater than 15-fold difference in molecular weight (Table 5.1). Drug introduced onto the ocular surface outside the chamber was capable of diffusion across the conjunctiva, where it gained