Lipophilicity influence on conjunctival drug penetration in the pigmented rabbit: A comparison with corneal penetration

Abstract

The influence of lipophilicity on the conjunctival penetration of beta blockers in the pigmented rabbit was investigated and compared with that on corneal penetration. The beta blockers were hydrophilic sotalol, atenolol, nadolol, pindolol, and acebutolol; lipophilic metoprolol, timolol, oxprenolol, levobunolol, labetalol, and alprenolol; and the very lipophilic propranolol and betaxolol. Drug penetration was evaluated by using the isolated pigmented rabbit conjunctiva and cornea in the modified Ussing chamber and was monitored by reversed phase HPLC. The conjunctiva was more permeable to all the beta blockers than was the cornea. A sigmoidal relationship, rather than the familiar parabolic relationship, best described the influence of lipophilicity on both conjunctival and corneal drug penetration. The ratio of corneal to conjunctival permeability coefficients was most sensitive to changes in log PC within the region of 1.5 and 2.5. Outside of this region, the ratio was relatively independent of changes in lipophilicity. For several beta blockers, their intrinsic sympathomimetic activity may play a minor role in influencing their conjunctival and corneal penetration.

Transport of Acebutolol through Rabbit Corneal Epithelium

“…In fact, the P transcell value of acebutolol (1.88ϫ10 Ϫ6 cm/s) was almost agreed with its permeability coefficients (1.10ϫ10 Ϫ6 cm/s) through an excised cornea reported previously. 6) This agreement indicates that acebutolol predominantly permeate via transcellular route across excised tight cornea.…”

“…6,11) Among them, however, permeability of acebutolol was much lower than that expected by its lipophilicity. This results indicated the possibility that acebutolol was secreted by specific transporter in corneal epithelium.…”

“…10) There was a relationship between the permeability of beta-blockers, which are often used in ophthalmic therapy, through an excised rabbit cornea and their lipophilicities. 6,11) Among them, however, permeability of acebutolol was much lower than that expected by its lipophilicity. This results indicated the possibility that acebutolol was secreted by specific transporter in corneal epithelium.…”

“…Many drugs had an almost parabolic relationship between the corneal permeability and the drug lipophilicity. 5,6) On the other hand, several transporters are expressed in ocular tissue. Jain-Vakkalagadda et al identified an active transport system for L-arginine on rabbit corneal epithelium and human cornea and showed that amino acid ester prodrugs of acyclovir appeared to be substrates for this transporter.…”

Transport of Timolol and Tilisolol in Rabbit Corneal Epithelium

“…14) The permeability of 14 C-mannitol, 6-CF, and FD-4 of the RCEC layer was much higher than for the whole cornea 15) because of a lower TEER in this culture system. On the other hand, the transcellular permeability of timolol and tilisolol (P transcell values) almost agreed with their permeability coefficients through an excised cornea, as reported previously 16,17) (corneal permeability coefficient: 1.23ϫ10 Ϫ5 cm/s for timolol and 0.272ϫ10 Ϫ5 cm/s for tilisolol). This agreement indicates that beta-blockers predominantly permeate via the transcellular route across the tight cornea.…”