IGF-I and EGF receptors in the pigmented rabbit bulbar conjunctiva.

The purpose of this study was to investigate whether receptors for insulin-like growth factors I and II (IGF-I and IGF-II), insulin, epidermal growth factor (EGF), and transforming growth factor alpha (TGF alpha) are present on the apical surface of the pigmented rabbit bulbar conjunctiva. Binding of 125I-labelled ligands to the apical surface of the pigmented rabbit bulbar conjunctiva was conducted at 4 degrees C in the absence and presence of excess unlabeled ligands. There was no evidence for the existence of IGF-II, insulin or TGF alpha receptors in the isolated pigmented bulbar conjunctiva. Only IGF-I and EGF receptors appeared to be present. The apparent dissociation constant (Kd) of IGF-I receptors was 206 +/- 13 pM and that for EGF was 51 +/- 5 pM. The number of receptors per 95 mm2 of bulbar conjunctiva was (6.0 +/- 0.2)X10(9) for IGF-I and (2.4 +/- 0.1)X10(9) for EGF. There was no crossover binding of either IGF-I or EGF to one another's receptors. The IC50 value for competitive displacement of bound 125I-IGF-I was: 44 +/- 2 nM by IGF-I, 156 +/- 13 nM by IGF-II and 812 +/- 78 nM by insulin. The IC50 value for displacement of bound 125I-EGF was 0.37 +/- 0.03 nM by EGF and 0.42 +/- 0.04 nM by TGF alpha. In conclusion, only IGF-I and EGF receptors appear to be present on the apical surface of the pigmented rabbit bulbar conjunctiva. The IGF-I receptor is also capable of binding IGF-II and insulin, whereas the EGF receptor is also capable of binding TGF alpha.

Ocular absorption of topically applied FK506 from liposomal and oil formulations in the rabbit eye.

PURPOSE: To investigate the use of topically applied FK506, a new immunosuppressive compound, systemic and ocular absorption was determined in serum and various ocular tissues. METHODS: Two drops of 20 microliters FK506 were applied using oil dissolved (OD-FK506) or liposome-bound (LIP-FK506) drug. FK506 concentrations were measured at intervals of 30, 60, and 120 minutes by immunoassay. RESULTS: After application of OD-FK506, the highest concentrations of FK506 were found in the cornea and the conjunctiva (200-1200 ng/g) with substantial drug also present in anterior and posterior sclera. Relatively low concentrations were measured in the aqueous and vitreous humors (0.2-1.0 ng/g) of these animals. Using the same treatment regimen, LIP-FK506 was effective in delivering significantly higher drug concentrations (P < 0.05) to all ocular tissues and particularly aqueous humor (5-28 ng/g) and vitreous humor (12-22 ng/g) at all time points. During the observation period drug concentrations produced by LIP-FK506 remained well above the therapeutic range. FK506 levels were not detectable in serum (< 0.2 ng/ml) with either drug formulation. CONCLUSION: These findings indicate that liposomes may be a promising formulation for topical use of FK506 in ocular immune-mediated diseases.

Segmental differences in drug permeability, esterase activity and ketone reductase activity in the albino rabbit intestine.

Possible segmental differences in drug permeability as well as esterase and ketone reductase activities in the albino rabbit intestine were investigated. Beta adrenergic antagonists and timolol prodrugs spanning four orders of magnitude in distribution coefficient were used as model drugs. Drug penetration was evaluated in Ussing chambers using isolated segments of the duodenum, jejunum, ileum, ascending colon, descending colon, and rectum. Esterase and ketone reductase activities were determined in homogenates of the above segments using timolol ester prodrugs and levobunolol as substrates, respectively. The results indicate that the hydrophilic beta adrenergic antagonists atenolol and sotalol and moderately lipophilic metoprolol penetrated all intestinal segments equally well, whereas moderately lipophilic timolol and lipophilic propranolol, levobunolol and betaxolol were better absorbed from the large than from the small intestinal segments. Changes in lipophilicity exerted a more pronounced effect on the penetration of beta adrenergic antagonists in the large than the small intestinal segments. A similar pattern existed for timolol prodrugs. In addition to segmental differences in drug permeability, segmental differences in esterase and ketone reductase activities also existed. The level of esterase and ketone reductase activities in the small intestinal segments was, on average, 12 times and 5 times higher, respectively, than in the large intestinal segments. The implication of the above findings is that segmental differences in drug permeability and metabolism must be considered in the design of oral drug delivery systems.