The systemic absorption of ocularly applied tritiated [D‐Ala2]metenkephalinamide (YAGFM) and inulin was studied in the albino rabbit with respect to rate, extent, pathways, and vehicle effects and compared with epinephrine. Peak concentration was achieved within 20 min except for inulin, for which absorption was still ongoing at 120 min. For YAGFM, the apparent absorption rate was slower than the elimination rate, thus obeying “flip‐flop” pharmacokinetics. Based on the area under the plasma concentration curve from zero to 120 min, the percent of dose systemically absorbed was 36.1 ± 4.4% for YAGFM, at least 3.3 ± 0.2% for inulin, and 58.5 ± 4.4% for epinephrine. This suggests that loss of drug to the systemic circulation is a more important factor in reducing the ocular absorption of YAGFM than for inulin. The conjunctival mucosa played as important a role as the nasal mucosa in the systemic absorption of YAGFM, while playing a secondary role in the case of inulin. Unlike nonpeptide drugs, the systemic absorption of ocularly administered YAGFM and inulin was not adversely affected by incorporation in 5% polyvinyl alcohol. Overall, the contact time of the instilled dose with the conjunctival and the nasal mucosae, their intrinsic permeability, and the extent of dilution of the instilled dose are key factors determining the vehicle effects on the extent of systemic absorption of ocularly applied peptides.
ASJC Scopus subject areas
- Pharmaceutical Science