Biomedical subjects

V H Lee

Publications and source records attributed to V H Lee.

At least 91 records · Page 5Linked to original sources

PubMed1993

Active chloride transport in the pigmented rabbit conjunctiva.

The present study demonstrates, for the first time, that the excised pigmented rabbit conjunctiva is a tight barrier capable of active Cl- transport. The transepithelial potential difference was 17.7 +/- 0.8 mV (tear-side negative), the short-circuit current was 14.5 +/- 0.7 microA/cm2, and the transconjunctival resistance was 1.3 +/- 0.1 k omega.cm2 for n = 45 tissues. Various inhibitors including ouabain (a Na+/K(+)-ATPase inhibitor), amiloride (a Na+ transport blocker), N-phenylanthranilic acid (a chloride transport inhibitor), bumetanide (an inhibitor of Na(+)-(K+)-Cl- cotransport process), and BaCl2 (a K+ channel blocker) were used on the mucosal and serosal sides of the tissue mounted in Ussing chambers to determine the involvement of the respective ion transport processes in the observed short-circuit current across the conjunctiva. The results suggest that a Cl- conductive pathway is present on the mucosal side of the conjunctiva, whereas Na+/K(+)-ATPase, Na(+)-(K+)-Cl- cotransport process, and K+ conductive pathways are present on its serosal side. Amiloride-sensitive Na(+)-conductive pathways do not appear to be present on either side of the pigmented rabbit conjunctiva.

Animals↗

PubMed1993

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.

Adrenergic beta-Antagonists↗

PubMed1993

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.

Absorption↗

PubMed1993

A model to predict aqueous humor and plasma pharmacokinetics of ocularly applied drugs.

PURPOSE: To develop methods for constructing a pharmacokinetic model to predict the time course of aqueous humor and plasma drug concentrations after topical dosage in rabbits using the simulation program iThink (formerly STELLA; High Performance Systems, Lyme, NH). METHOD: The model was constructed in experimentally verifiable segments using previously published data on intravenous, nasal, and ocular dosage, and was used to describe the influence of prolonging precorneal retention and varying drug release rate on the ratio of drug absorbed locally to drug absorbed systemically in rabbits. RESULTS: The model developed is comprehensive; it includes precorneal kinetics, nasal absorption kinetics, and plasma kinetics. CONCLUSIONS: Such a model may be useful in designing drug delivery strategies to improve the safety of topical eye medications through minimization of systemic absorption and maximization of drug delivery to ocular tissues.

Absorption↗

PubMed1992

Improving the safety of topically applied timolol in the pigmented rabbit through manipulation of formulation composition.

The objective of this study was to compare the efficiency of various formulations in maximizing the ratio of ocular to systemic absorption of topically applied timolol in the pigmented rabbit. Formulations of various pHs, tonicities, and concentrations of benzalkonium chloride, EDTA, poly(vinyl alcohol), poly(vinylpyrrolidone), hydroxypropylcellulose, and Na hyaluronate were tested. Ocular absorption was determined by monitoring the timolol concentration in various anterior segment tissues 30 min after instillation of timolol solution, while systemic absorption was determined by monitoring the time course of timolol concentration over 120 min. Timolol was assayed by reversed-phase HPLC. Lowering the solution tonicity to 80 mosmol kg-1 and incorporating polymers into the formulation were the only approaches that promised to improve the safety of topically applied timolol, since they afforded the desired increase in ocular absorption and reduction in systemic absorption. Lowering the solution pH to 6.4 and increasing the tonicity of the solution to 600 mosmol kg-1 reduced systemic absorption but caused either no change or a decrease in ocular absorption. Raising the solution pH to 8.4 and incorporating 0.025% benzalkonium chloride and 0.5% EDTA into the formulation led to an undesirable increase in systemic absorption although ocular absorption was also increased. In the final analysis, the net effect of formulation changes on the ratio of ocular to systemic absorption depended on the interplay of changes in solution drainage; permeability of the cornea, conjunctiva, and nasal mucosa; and fraction of drug in the preferentially absorbed form.

Administration, Topical↗

PubMed1992

Light-dark variations in ocular timolol concentrations following topical solution instillation in the pigmented rabbit.

The objective of this study was to determine whether ocular absorption of topically applied timolol in the pigmented rabbit varied with the time of drop instillation. Twenty-five microliters of a 0.65% timolol maleate solution were instilled in the pigmented rabbit eye at 0600, 0900, 1200, 1500, 1800, 2100, 2400, or 0300 hr. Timolol concentrations in the conjunctiva, sclera, corneal epithelium, corneal stroma, aqueous humor, and iris-ciliary body at 15 and 30 min post-dosing were monitored using reversed phase HPLC. Ocular timolol concentrations were higher when the drug was administered during the light period (0900-1800 hr) than when it was administered during the dark period (1800-0600 hr). There exist, therefore, light-dark variations in the ocular absorption of topically applied timolol.

Absorption↗

PubMed1992

A sensitive fluorometric assay for reducing sugars.

A simple and rapid fluorometric assay for reducing sugars that is sensitive to the nanomolar range has been developed. The assay involves the derivatization of a given sugar with hydrazine at pH 3 to form a hydrazone, which is reacted with fluorescamine following adjustment of pH to first 9.4 and then 7.4. The amount of sugar in a sample is quantitated by measuring the fluorescence intensity at an excitation wavelength of 400 nm and an emission wavelength of 490 nm. The assay is precise and reproducible, as indicated by intra- and inter-run variations of at most 3% and 4%, respectively. In addition to reducing sugars, the assay can also be used to measure aliphatic and aromatic aldehydes, but not acetone. Compared with an existing fluorometric sugar assay, the assay reported here does not require chromatographic separation of the fluorescent derivative from unreacted fluorescamine. The assay can, however, be potentially adapted for postcolumn detection of aldehydes, reducing sugars, and hydrazones in HPLC.

Aldehydes↗

PubMed1992

Aminopeptidase activity in the jejunal and ileal Peyer's patches of the albino rabbit.

The objectives of this study were (a) to compare the aminopeptidase activity in the Peyer's patches of the jejunum and ileum of the albino rabbit against that in the adjacent patch-free segments and (b) to determine the relative sensitivities of the aminopeptidase activity in the Peyer's and non-Peyer's patches to aminopeptidase inhibitors and penetration enhancers. The results indicated that the Peyer's patches were about equal in aminopeptidase activity in the jejunum and in the ileum but were only 20-30% as rich in aminopeptidase activity as their neighboring patch-free areas. Compared to non-Peyer's patches, the aminopeptidase activity in the Peyer's patches was not as sensitive to the inhibitory effect of amastatin. It was, however, much more sensitive to the inhibitory effect of puromycin and p-chloromercuribenzoate and was somewhat more sensitive to the inhibitory effect of Na deoxycholate, Na glycocholate, and polyoxyethylene-9-lauryl ether. Therefore, based on substrate preferences and on the relative sensitivity of aminopeptidase activity to inhibition by aminopeptidase inhibitors and penetration enhancers, the relative proportions of various aminopeptidases in the Peyer's patches and in the non-Peyer's patches are likely different.

Amino Acids↗

PubMed1992

Conjunctival penetration of insulin and peptide drugs in the albino rabbit.

An in vitro model was used to evaluate the conjunctival penetration of three peptides, [D-ala2]metenkephalinamide (YAGFM, MW 647), substance P (MW 1348), and insulin (MW 5778), in comparison with two nonpeptides, atenolol (MW 266) and timolol (MW 433). All three peptides were hydrolyzed to varying extents during penetration across the conjunctiva. The permeability coefficient for intact YAGFM and insulin was 4.5 +/- 0.3 and 4.6 +/- 0.7 microns sec-1, respectively. These values were about two to five times lower than those for atenolol and timolol. No permeability coefficient could be calculated for substance P, since its transconjunctival flux never reached steady state. The conjunctival penetration of YAGFM and insulin was improved by about two and three times, respectively, with the addition of 1% Na glycocholate. Increasing the Na glycocholate concentration was more effective than changing the type of bile salt in improving the conjunctival penetration of insulin. The maximum factor of improvement was 12, as the Na glycocholate concentration was raised to 4%. The way in which Na deoxycholate, glycocholate, and taurocholate affected the conjunctival penetration of atenolol, timolol, and insulin suggests that these three bile salts improved mainly the transcellular penetration of the compounds studied.

Administration, Topical↗

PubMed1992

Molecular analysis of the antigenicity and immunogenicity of recombinant zona pellucida antigens in a primate model.

The studies reported here are the first to demonstrate that recombinant zona pellucida (ZP) proteins will elicit a humoral immune response that recognizes native ZP proteins. Three cDNAs encoding rabbit ZP protein antigens expressed in bacteria were used to immunize cynomolgus monkeys. Four groups of six monkeys each were immunized with bacterially expressed cro-beta-galactosidase recombinant proteins encoded by a full-length cDNA (rc55) encoding the 55-kDa rabbit ZP recombinant protein (rec55), two partial cDNAs (rc75a and rc75b) encoding two recombinant peptides (rec75a and rec75b) of the 75-kDa rabbit ZP protein, and the plasmid-encoded cro-beta-galactosidase control protein. Initial immunizations with these fusion proteins using the muramyl dipeptide adjuvant did not elicit significant levels of antibodies to native or recombinant ZP proteins. Further immunizations were therefore carried out using recombinant ZP proteins conjugated to either protein A or keyhole limpet hemocyanin. Antibodies were detected in the groups immunized with the rec55 and rec75a; however, no antibodies were generated against the rec75b protein. These antibodies have been characterized by two-dimensional PAGE immunoblotting and shown to recognize antigenic domains associated with two of the native rabbit ZP proteins. Reprobes of these immunoblots with sheep anti-total native rabbit ZP proteins, affinity-purified on pig ZP, further demonstrate that a fourth distinct rabbit ZP antigen may be present. The characterization of species-conserved antigenic domains of mammalian ZP proteins is important for studies of the functional regions of ZP proteins and is critical for the design of safe and effective contraceptive vaccines.

Animals↗

PubMed1992

Characterization of equine zona pellucida glycoproteins by polyacrylamide gel electrophoresis and immunological techniques.

This study was designed to explore the composition of the equine zona pellucida (EZP) by one- and two-dimensional polyacrylamide gel electrophoresis (1D- and 2D-PAGE), silver staining and immunoblotting techniques. Antral follicles palpable on frozen-thawed equine ovaries were aspirated with a needle and syringe, and the resultant follicular fluid, cellular material and oocytes were pooled. Oocytes were placed in Petri dishes, moved by narrow-bore pipette to droplets of phosphate-buffered saline (PBS) and mechanically cleaned of cumulus cells. The EZP from these collected oocytes was solubilized, and then analysed by 1D- and 2D-PAGE. Silver stained 2D-PAGE of the EZP revealed the presence of three EZP glycoprotein families of apparent molecular mass ranges of 93-120 kDa, 73-90 kDa and 45-80 kDa. Immunoblot analysis of EZP glycoproteins resolved by 2D-PAGE using rabbit antisera against pig zonae pellucidae (R alpha HSPZ) confirmed the presence of three EZP glycoprotein families and established the existence of common epitopes between equine and porcine ZP glycoproteins. Further immunodetection using 2D-PAGE-separated glycoproteins illustrated that the 45-80 kDa family is recognized by the monoclonal antibody R5, developed against the porcine ZP glycoprotein of molecular mass 55-120 kDa. Guinea-pig antiserum against endo-beta-galactosidase-treated rabbit ZP 55 kDa glycoprotein (R55K), which specifically recognizes the rabbit ZP glycoprotein with the lowest molecular mass, also recognized the EZP 45-80 kDa glycoprotein family. Guinea-pig polyclonal antisera developed against total heat-solubilized rabbit ZP (GP alpha HSRZ) recognized the 73-90 kDa EZP glycoprotein family exclusively. After heat solubilization and treatment of EZP with endo-beta-galactosidase to remove polylactosaminoglycans, silver stained 1D-PAGE again demonstrated the presence of three glycoproteins with apparent molecular masses of 60, 75 and 90 kDa. The partially deglycosylated 60 kDa equine glycoprotein is recognized on immunoblot by the monoclonal antibody R5; the 75 kDa EZP glycoprotein is recognized by GP alpha HSRZ; and all three EZP glycoproteins separated by 1D-PAGE are recognized by R alpha HSPZ. These data add further support to the concept of cross-species zona pellucida glycoprotein antigenicity.

Animals↗

PubMed1992

A mechanistic study on the enhancement of corneal penetration of phenylephrine by flurbiprofen in the rabbit.

The effect of flurbiprofen on the corneal penetration of phenylephrine was investigated using isolated albino rabbit corneas mounted in the Ussing diffusion chamber. The corneal penetration of phenylephrine was increased 5-11 times by 4-16 mM flurbiprofen. Such an increase in the corneal penetration of phenylephrine by flurbiprofen appeared to correlate with the increase in the lipophilicity of phenylephrine by flurbiprofen due to ion pair formation. The magnitude of increase at 16 mM flurbiprofen was 2.4 times less than that afforded by 0.5% EDTA and 16.3 times less than that afforded by deepithelizing the cornea. Since flurbiprofen also increased the corneal penetration of benzoic acid and sorbitol with which it cannot form ion pairs, increased lipophilicity of phenylephrine due to ion pair formation with flurbiprofen was unlikely to be the only mechanism that enhanced corneal penetration. An additional mechanism under our experimental conditions of prolonged exposure of the cornea to the phenylephrine-flurbiprofen combination was lowering of the barrier function of the corneal epithelium by concentrations of flurbiprofen greater than that used therapeutically.

Animals↗

PubMed1992

A mechanistic study on enhancement of rectal permeability to insulin in the albino rabbit.

This study was conducted mainly to investigate the relative contributions of various mechanisms by which bile salts and EDTA may improve the in vitro rectal penetration of insulin in the albino rabbit. Insulin could not cross the rectal mucosa unless Na glycocholate or other penetration enhancers were present. Penetration enhancement was attributed primarily to Na glycocholate's ability to reduce the barrier function of the rectal membrane and to increase the fraction of insulin in its monomeric form, and secondarily to Na glycocholate's ability to protect insulin from proteolysis. Na glycocholate was more effective than Na taurocholate, but less effective than Na deoxycholate and polyoxyethylene-9-lauryl ether in enhancing rectal insulin penetration. Although EDTA at 0.01 and 0.1% did not affect rectal insulin penetration, it augmented the penetration enhancement effect of 1% Na glycocholate without causing additional damage to the rectal membrane, as judged by protein release. Such an action was attributed to the synergistic effect associated with: 1) an increase in the permeability of the paracellular pathway by EDTA and 2) an increase in the proportion of insulin in the monomeric form by Na glycocholate. Results from parallel in vivo experiments have indicated that it may be possible to achieve significant penetration enhancement by using a combination of otherwise membrane-damaging penetration enhancers which act by complementary mechanisms at concentrations that are both effective and well tolerated by mucosal epithelial cells.

Animals↗

PubMed1991

Formulation influence on conjunctival penetration of four beta blockers in the pigmented rabbit: a comparison with corneal penetration.

The objective of this study was to compare the influence of pH, tonicity, benzalkonium chloride, and EDTA on the conjunctival and corneal penetration of four beta blockers--atenolol, timolol, levobunolol, and betaxolol. Drug penetration was evaluated using the isolated pigmented rabbit conjunctiva and cornea in the modified Ussing chamber. The conjunctiva was more permeable than the cornea to all four beta blockers. Formulation changes caused larger changes in corneal than in conjunctival drug penetration, especially for the hydrophilic beta blockers, atenolol and timolol. Raising the solution pH to 8.4 caused the largest increase in corneal penetration for all drugs except atenolol. This increase was greater than that obtained by removing the corneal epithelium. The same formulation also increased conjunctival drug penetration, although to a lesser extent. In the case of timolol, the formulation changes evaluated brought about similar changes in its ocular and systemic absorption with good in vitro-in vivo correlations. The above findings indicate that in making formulation changes to maximize corneal drug penetration, it is necessary to evaluate possible changes in conjunctival drug penetration, hence systemic absorption. Moreover, because the conjunctiva plays an active role in the noncorneal route of ocular drug absorption, the relative contribution of the noncorneal to the corneal routes to ocular drug absorption may also be altered by formulation changes.

Animals↗

PubMed1991

Role of enzymatic lability in the corneal and conjunctival penetration of timolol ester prodrugs in the pigmented rabbit.

The main objective of this study was to investigate how enzymatic lability would affect the extent of corneal and conjunctival penetration of a series of alkyl, cycloalkyl, and aryl ester prodrugs of timolol in the pigmented rabbit. Enzymatic lability of the prodrugs was studied in corneal epithelial and conjunctival homogenates, while their corneal and conjunctival penetration was determined using the isolated tissues in the modified Ussing chamber. The straight-chain alkyl and the unsubstituted cycloalkyl esters were hydrolyzed more rapidly than their corresponding branched-chain and substituted analogues as well as the aryl esters. The corneal and conjunctival penetration of all prodrugs, regardless of enzymatic lability, varied parabolically with lipophilicity. Moreover, the enzymatically more labile straight-chain alkyl esters penetrated the cornea and the conjunctiva more readily than the more stable branched-chain esters of comparable lipophilicity. Enzymatic lability is, therefore, an additional factor that should be considered in designing alkyl ester prodrugs with improved ocular drug delivery characteristics. Enzymatic lability does not, however, play as important a role as lipophilicity in the corneal and conjunctival penetration of cycloalkyl and aryl ester prodrugs.

Animals↗

PubMed1991

Conceptus-mediated integrity of endometrial epithelial cells and maintenance of relaxin synthesis in pregnant rabbits: effects of unilateral oviduct ligation.

A previous study indicated rabbit endometrial relaxin synthesis is stimulated by blastocyst (Lee VH, Fields PA, Biol Reprod 1990; 40:737-745). To evaluate this hypothesis, unilateral oviduct ligations were placed (A) at the oviduct isthmus on Day 1 post-copulation and (B), in a separate group of rabbits, at the infundibulum before copulation. Blastocysts migrate into and implant in the uterine horn contralateral to the ligated oviduct only (conceptus-bearing uterus). The uterine horn ipsilateral to the ligated oviduct will be referred to as the non-conceptus-bearing uterus. Uteri and ovaries were removed on Days 4-28 of pregnancy and were evaluated for relaxin using guinea pig anti-porcine relaxin serum and avidin-biotin light microscopy immunohistochemistry. Results were identical for both models. Blastocysts first attach to the antimesometrial uterine surface by Day 7 post-copulation. Implantation on the mesometrial surface occurs on Days 8-11. Relaxin was observed in antimesometrial endometrial glands of both conceptus and non-conceptus-bearing uteri on Days 4-7 of pregnancy. Beyond Day 7, relaxin was observed in antimesometrial and mesometrial endometrial glandular and luminal epithelial cells at implantation sites of the conceptus-bearing uterus only. Relaxin was not found between implantation sites. Endometrial epithelial cells of the non-conceptus-bearing uterus were regressing by Day 9. These data indicate a conceptus-mediated maintenance of endometrial epithelial cells. Furthermore, the data suggest a paracrine maintenance of epithelial cell integrity and relaxin synthesis since these parameters are preserved only in the conceptus-bearing uterus. Cell-cell communication between conceptus and endometrium appears to be specific since endometrium between implantation sites does not contain relaxin. Uterine tissue from pseudopregnant rabbits (Days 1-16) was evaluated. Relaxin was observed in the antimesometrial glands on Day 7 only. Like the endometrium in the ligation model, endometrial epithelial cells of the pseudopregnant rabbit uterus were regressing by Day 9. These results indicate that pregnancy is not required for, but may enhance, relaxin synthesis. In addition, endometrial epithelial cells regress in the absence of pregnancy. Regression of endometrial epithelial cells on Day 9 suggests that maternal recognition of pregnancy occurs during the preimplantation period (Days 4-8).

Animals↗

PubMed1991

Rabbit relaxin: the influence of pregnancy and ovariectomy during pregnancy on the plasma profile.

A porcine relaxin radioimmunoassay was developed to evaluate the profile of immunoreactive relaxin in rabbit plasma. Relaxin was nondetectable in pseudopregnant (Days 1, 4, 5-8, 12, and 16), nonpregnant, and male rabbits. However, in pregnant rabbits, relaxin was detected during the peri-implantation period (Days 4-9). Peak concentrations were reached on Day 15 and were maintained until parturition (Day 32). Relaxin concentrations abruptly decreased on Day 1 postpartum to low but detectable concentrations that were unchanged during the first week postpartum. In contrast, progesterone concentrations peaked earlier (Day 13), decreased after Day 25, and were not detectable on Day 1 postpartum. The effect of ovariectomy on the profile of plasma relaxin was evaluated. Four pregnant rabbits were ovariectomized (Day 13) and treated with medroxyprogesterone acetate to maintain pregnancy. As in normal pregnant rabbits, relaxin was observed initially during the peri-implantation period (Days 4-9) and increased to peak concentrations by Day 16. These concentrations were maintained until parturition and abruptly decreased on Day 1 postpartum to low yet detectable concentrations during the first week postpartum. The concentrations of relaxin in the plasma of ovariectomized medroxyprogesterone-treated rabbits were not different from those in three sham controls. These results indicate that the ovary is not a significant source of relaxin in pregnant rabbits. The unique observation of the presence of relaxin during the peri-implantation period suggests that this hormone has a role in preparing the rabbit uterus for implantation. The continued presence of relaxin during the first week postpartum may represent residual hormone, or it may suggest a physiological role during the early postpartum period.

Animals↗

PubMed1991

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

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.

Adrenergic beta-Antagonists↗