AbstractThe ocular bioavailability of phenylephrine oxazolidine (PO), a prodrug intended for rapid corneal penetration, was micronized and suspended in sesame oil (1 and 10 per cent) and compared in bioavailability to phenylephrine HCl (PE) dissolved (10 per cent) in a buffered (pH 5.75), viscous (30 centipoise) vehicle. Cornea and aqueous humor of New Zealand rabbits were measured over time following 10 μl instillation to the eye. Based upon AUC measurements, corneal and aqueous humor levels were approximately 6 and 8 times greater for 10 per cent PO versus 10 per cent PE, respectively. In addition, the ocular pharmacokinetic values were determined for PE applied in a constant concentration (1 per cent) to the cornea over 180 min to anesthetized rabbits. Cornea and aqueous humor were measured for drug content over time. Using moment analysis and an initial slope method, the absorption rate constant, Ka, the steady state volume of distribution in the eye, Vss and ocular clearance, Qe, were calculated. Values obtained for PE were 4–15 × 10−5 min−1, 0.423ml and 14.6 μl min−1, respectively. The half‐life for drug elimination ranged from 63‐83 min depending on the tissue or route of administration.