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Biomedical subjects

V H Lee

Publications and source records attributed to V H Lee.

At least 73 records · Page 4Linked to original sources
PubMed1995

Possible existence of Na(+)-coupled amino acid transport in the pigmented rabbit conjunctiva.

The objective of the present study was to determine whether Na(+)-amino acid cotransport contributed to the short-circuit current (ISC) in the isolated pigmented rabbit conjunctiva. Glycine, L-arginine, D-arginine, and L-glutamic acid were the amino acids tested, and bioelectric measurements were made in the Using chamber. The ISC was increased from 4% (L-glutamic acid) to 44% (L-arginine). The EC50 was 0.35 mM for glycine, 0.06 mM for L-arginine, 0.16 mM for D-arginine, and 1 mM for L-glutamic acid. No elevation in ISC was seen in the absence of Na+ in the mucosal bathing fluid. The above findings are consistent with the possible existence of a Na(+)-amino acid cotransport process on the apical side of the pigmented rabbit conjunctiva.

Amino Acids↗
PubMed1995

Development and characterization of rabbit tracheal epithelial cell monolayer models for drug transport studies.

PURPOSE: The objective of this study was to investigate how culture conditions would affect the morphological, functional, and permeability characteristics of rabbit tracheal epithelial cell layers being considered for drug transport studies. METHODS: Rabbit tracheocytes were isolated by protease treatment and plated onto collagen-treated permeable supports at 1.3 x 10(6) cells/cm2. After 24 hr, cell layers were cultured either air-interfaced (AIC) on their apical surface or under conventional liquid covered conditions (LCC). RESULTS: Scanning electron microscopy revealed mature cilia in AIC cell layers and ciliated cells denuded of cilia in LCC cell layers. Compared with LCC, AIC cell layers (n = 20) achieved a significantly higher peak equivalent short-circuit current (74.1 +/- 6.5 vs. 51.6 +/- 3.4 microA/cm2), a higher potential difference (70.9 +/- 2.8 vs. 60.5 +/- 3.0 mV), and a lower peak transepithelial electrical resistance (1.1 +/- 0.03 vs, 1.5 +/- 0.02 kohms.cm2). About 70% of the short-circuit current in AIC was amiloride-sensitive whereas < 10% was furosemide-sensitive, similar to that found in native tissue. The corresponding values in LCC were 50% and 46%. The permeability of both AIC and LCC to lipophilic solutes (dexamethasone and propranolol) was similar, whereas the permeability of hydrophilic solutes (mannitol, sucrose, and albuterol) in AIC was only half that in LCC. CONCLUSIONS: Given the striking similarity in morphological and functional characteristics of the AIC to those in the in vivo situation, the AIC is favored as an in vitro model for future drug transport studies.

Animals↗
PubMed1995

In vitro transformation of rabbit cytotrophoblast cells into syncytiotrophoblast: stimulation of hormone secretion by progesterone and dibutyryl cyclic 3',5'-adenosine monophosphate.

Rabbit placenta syncytiotrophoblast cells exhibit immunostaining for the hormone relaxin. The objectives of this study were to evaluate the ability of cultured rabbit trophoblast cells to secrete immunoreactive (IR) relaxin and then to study the effects of progesterone, which is essential for maintenance of the placenta and of pregnancy in the rabbit, on that secretion. On Day 1, both treated and untreated trophoblast cell cultures consisted of 90% relaxin-negative mononuclear cells (cytotrophoblast and fibroblast) and 10% relaxin-positive multinuclear cells (syncytiotrophoblast). Media from untreated cultures, collected throughout 9 days of culture, contained low but constant levels of relaxin. Electron microscopy studies indicated that relaxin was localized in dense granules of the multinuclear cells and that these cells formed by fusion of mononuclear cytotrophoblast. Progesterone treatment (40 and 80 ng/ml) increased (p < 0.0001) media concentrations of relaxin, increased the number of desmosomes between cytotrophoblast cells (12 vs. 4 for controls on Day 5), and increased the percentage of multinuclear cells (73% of the cell population vs. 20% for controls on Day 7). Specificity of the progesterone effect was evaluated by treatment of cultures with dibutyryl cAMP (dbcAMP), insulin, hCG, estradiol-17 beta, prostaglandin E2, and prostaglandin F2 alpha. Only dbcAMP (2 mM and 4 mM) produced an increase (p < 0.0001) in media concentrations of relaxin. These results indicate that, like the intact placenta, cultured cytotrophoblast cells fuse to form syncytiotrophoblast and that the latter contain IR relaxin.

Animals↗
PubMed1995

Immunogenicity enhancement of recombinant rabbit 55-kilodalton zona pellucida protein expressed using the baculovirus expression system.

In the present study we have used a molecular approach to evaluate the immunogenicity and antigenicity of glycosylated and non-glycosylated recombinant rabbit 55-kDa zona pellucida (ZP) protein. The 55-kDa cDNA was expressed in insect (Sf9) cells through use of a baculovirus expression system to obtain nonfusion glycosylated recombinant ZP protein (BV-55). SDS-PAGE and immunoblot analysis demonstrated that the recombinant protein is expressed as two forms having relative molecular masses of 70 kDa and 80 kDa. Because cells treated with tunicamycin produce predominantly the 70-kDa form, this heterogeneity is presumed to be due to differential glycosylation. Further studies using lectin blot and immunoblot analyses showed that the BV-55 protein has both N-linked and O-linked oligosaccharides. However, this glycosylation is distinct from that of the native 55-kDa ZP protein, since it was not recognized by a monoclonal antibody associated with lactosaminoglycan-type carbohydrate epitopes in native ZP proteins. Immunogenicity studies demonstrated that antibodies against the BV-55 protein are developed by female rabbits and guinea pigs and that these antibodies recognize epitopes associated with native, enzyme-deglycosylated as well as nonglycosylated recombinant forms of the rabbit 55-kDa ZP protein. In contrast, recombinant protein expressed in bacteria did not elicit antibodies in either rabbits or guinea pigs. These results demonstrate that expression of the 55-kDa recombinant protein in the baculovirus expression system enhances its immunogenicity.

Animals↗
PubMed1995

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.

Animals↗
PubMed1995

Role of Na+ in the asymmetric paracellular transport of 4-phenylazobenzyloxycarbonyl-L-Pro-L-Leu-Gly-L-Pro-D-Arg across rabbit colonic segments and Caco-2 cell monolayers.

This study was conducted to demonstrate that Na+ played a role in the paracellular transport of 4-phenylazobenzyloxycarbonyl-L-Pro-L-Leu-Gly-L-Pro-D-Arg (Pz-peptide), a hydrophilic proline-containing pentapeptide, across the rabbit colonic mucosa and Caco-2 cell monolayers. Over the 1 to 5 mM concentration range, Pz-peptide transport was 25 to 180 times greater from the mucosal-to-serosal than from the opposite direction. This asymmetry in transport was consistent with the ability of Pz-peptide to lower the transepithelial electrical resistance of Caco-2 cell monolayers only from the mucosal side. Blockade of Na+ access to the apically located amiloride-sensitive Na+ channel in the lower intestinal segments by mucosal 10 microM amiloride, serosal 100 microM ouabain or removal of Na+ ions in the mucosal fluid dramatically reduced Pz-peptide transport to 5% of the control. Moreover, Pz-peptide transport across Caco-2 cell monolayers could be titrated against mucosal Na+ concentration. There was a small mucosal-to-serosal solvent drag effect induced by transepithelial Na+ flux stimulated by Pz-peptide in the colon, contributing in part to enhanced paracellular solute transport. Overall, the above findings are consistent with a scenario whereby Pz-peptide stimulates transepithelial Na+ flux across the colonic segments at the level of the amiloride-sensitive Na+ channel, thereby triggering yet to be identified intracellular biochemical changes that ultimately result in tight junctional opening and enhanced paracellular solute transport.

Amiloride↗
PubMed1994

Transport of thyrotropin-releasing hormone across rat alveolar epithelial cell monolayers.

It has been recently shown that epithelial cell monolayers of rat type II pneumocytes cultivated on tissue culture-treated polycarbonate Transwell filters are tight (> 2,000 ohm-cm2) and exhibit morphological and phenotypic characteristics of in vivo type I pneumocytes. We studied, utilizing these tight monolayers, the transepithelial transport of thyrotropin-releasing hormone (TRH). Either [125I]TRH or [3H]TRH was used to measure the transalveolar epithelial radiolabel fluxes across the monolayer. Radiochromatography was performed, utilizing reverse-phase HPLC techniques, to determine the presence of TRH and its subspecies in dosing, donor and receiver fluids. The apparent permeability coefficient (Papp) estimated from 125I-radiolabel fluxes was approximately 1.7 x 10(-7) cm/sec in both the apical-to-basolateral (AB) and basolateral-to-apical (BA) directions. In contrast, the Papp for 3H-radiolabels was approximately 4.2 x 10(-7) cm/sec in both directions. Radiochromatography results indicated that neither apical nor basolateral receiver fluid collected at the end of 4 h flux studies contained metabolites of [125I]TRH or [3H]TRH. In the presence of 1,000-fold excess of unlabeled TRH in the donor fluid, the Papp of neither [125I]- or [3H]-TRH in either direction was altered. These data taken together provide evidence for restricted diffusional transport of intact TRH across the rat alveolar epithelial cell monolayer, most likely via paracellular pathways. Thus, it appears that TRH delivery via pulmonary alveolar epithelium in the distal airspaces of the mammalian lung may be feasible without significant interference from peptidase activities.

Animals↗
PubMed1994

Effects of protease inhibitors on vasopressin transport across rat alveolar epithelial cell monolayers.

The transepithelial transport of arginine vasopressin (AVP) across cultured rat alveolar epithelial cell monolayers was studied. At 0.1 nM donor [125I]AVP, the radiolabel flux measured in the apical-to-basolateral (AB) direction was about 10 times greater than that in the reverse (BA) direction. HPLC analyses of the basolateral receiver fluid collected at the end of these flux measurements showed that about 97% of the total [125I]label represented subspecies of AVP, whereas the apical receiver fluid contained largely intact AVP (approximately 85% of total [125I]label). Both donor fluids contained virtually no degradation products of AVP (> 99%). In the presence of an excess 0.1 mM unlabeled AVP in the apical donor fluid, the Papp for radiolabeled AVP in the AB direction was decreased by approximately 68%, while the fraction of intact AVP in the basolateral receiver fluid was increased six-fold as compared to that observed at 0.1 nM [125I]AVP alone. Under this condition, the flux of intact AVP was approximately the same in both directions. When the concentration of apical camostat mesylate, an aminopeptidase inhibitor, was varied from 0 to 2 mM, the radiolabeled flux in the AB direction (with 0.1 nM [125I]AVP in the donor fluid) was significantly decreased in a dose-dependent manner, yielding commensurably elevated concentrations of intact AVP in the basolateral receiver fluid. In contrast, leupeptin (0.5 mM), a serine protease inhibitor, was without effect. These data, taken together, suggest that apically-presented AVP undergoes proteolysis (most likely by peptidases localized at apical cell membranes of alveolar epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Influence of drug release rate on systemic timolol absorption from polymeric ocular inserts in the pigmented rabbit.

There is an expectation that ocular inserts, regardless of the nature of the polymer, will faithfully reduce systemic drug absorption. This may not necessarily be so, however, since not all polymers would release drug at the same rate and to the same extent. The objective of the present study was to determine how drug release rate from various polymeric ocular inserts may influence systemic timolol absorption in the pigmented rabbit. The inserts tested were made of polyvinyl alcohol (PVA), hydroxypropylcellulose (HPC), or partial ethyl ester of poly(vinyl methyl ether/maleic anhydride) (PVMMA), approximately 89.4% w/w in all cases. Some polyvinyl alcohol inserts contained timolol in salt form with Carbopol 940 (PVA-C940), 8.6% w/w. The time course of timolol in plasma over 6 hr was monitored using reversed phase HPLC. While all inserts reduced the peak timolol concentration in plasma (Cmax), only the PVA and HPC inserts, which released timolol rapidly in vitro, reduced the extent of systemic timolol absorption (AUC). On the other hand, both PVA-C940 and PVMMA inserts, which released timolol relatively slowly in vitro, increased the extent of systemic timolol absorption. Moreover, the time at which peak timolol concentration was achieved in the plasma was much delayed, raising the possibility of delayed timolol absorption until discharge of the presumably viscous and/or mucoadhesive solutions of PVA-C940 and PVMMA inserts into the nasal cavity. It may be concluded that not all polymeric ocular inserts reduce systemic timolol absorption. Whether an insert would do so depends on the interplay of residence time in the conjunctival sac and rate of drug release from the insert.

Absorption↗
PubMed1994

Improved ocular penetration of gentamicin by mucoadhesive polymer polycarbophil in the pigmented rabbit.

PURPOSE: To investigate whether polycarbophil, a mucoadhesive polymer of the poly(acrylic acid) type, would improve the ocular delivery of topically applied gentamicin. METHODS: Two gentamicin formulations of this polymer (neutralized versus non-neutralized) and an aqueous control formulation in saline were administered to the pigmented rabbit eye. Drug concentrations in plasma, as well as in cornea, bulbar conjunctiva, anterior sclera, iris-ciliary body, aqueous humor, and vitreous humor, were measured by fluorescence polarization immunoassay. RESULTS: Both polymeric formulations increased the uptake of gentamicin by the bulbar conjunctiva two times. Drug penetration into the aqueous humor was observed with only the non-neutralized polymer, probably occurring via the conjunctival-scleral pathway facilitated by intensified contact between the mucoadhesive polymer and the underlying bulbar conjunctiva. CONCLUSION: Polymers of the poly(acrylic acid) type are potentially useful for improving topical antibiotic drug delivery, particularly when irritancy potential due to low pH can be overcome.

Absorption↗
PubMed1993

Identification and structural characterization of the 75-kDa rabbit zona pellucida protein.

A cDNA (rc75) encoding a 75-kDa rabbit zona pellucida (ZP) glycoprotein (R75) has been cloned and sequenced. The predicted amino acid sequence consists of 676 amino acids including seven potential N-glycosylation sites. The cDNA hybridizes to a 2.4-kilobase mRNA in ovary that is not detectable in other rabbit tissues. The R75 mRNA was also found to be expressed during the early stages of rabbit ovarian development (2-6 weeks of age) when the ovary contains primordial, primary, and early secondary follicles. The deduced amino acid sequence of rc75 has 77% similarity to the mouse ZP2 protein but no similarity to mouse ZP3. R75 also contains regions with 35-55% similarity to a previously cloned rabbit 55-kDa ZP protein. Monte Carlo simulation comparison confirmed that R75 has a significant probability of homology with mouse ZP2 and the rabbit 55-kDa ZP protein. Antibodies were developed against a fragment of R75 (rc75a cDNA) expressed in the pEX expression vector. These antibodies were used to confirm that the expressed protein contained epitopes found in the native rabbit ZP glycoprotein. These data suggest that some, but not all, ZP proteins may be conserved among different species and that within a species ZP proteins may share similar regions.

Aging↗
PubMed1993

Developmental expression of the rabbit 55-kDa zona pellucida protein and messenger RNA in ovarian follicles.

The events associated with the early stages of oocyte activation and granulosa cell (GC) differentiation during ovarian follicular development have been investigated using immunological and cDNA probes. Because zona pellucida (ZP) proteins provide excellent markers for oocyte activation during early stages of ovarian development, a cDNA encoding a full-length ZP protein with calculated molecular weight of 57,185 (rc55) and a specific antibody to the corresponding native rabbit ZP protein (R55) were developed. Immunohistochemical analysis of ovaries demonstrated that R55 was localized in follicles of animals 2 weeks and older. R55 was localized in the oocytes of primordial follicles and the oocytes and GCs of primary follicles but was undetectable in the GCs of large antral follicles. GCs were isolated from 6-week-old rabbit ovaries and cultured in defined media to demonstrate expression of rabbit ZP proteins by GCs in vitro. Rabbit ZP proteins were localized in the cytoplasm of cultured GCs if these cells were treated with monensin, a compound that blocks glycoprotein secretion. Northern blot analysis with the cDNA probe rc55 revealed that cultured GCs contained a mRNA for R55 and that there is stage-specific expression of the R55 mRNA in developing rabbit ovaries. Immunoblot analysis demonstrated that R55 is detectable at 4 weeks and accumulates in 6-, 8-, and 12-week ovaries which contain developing primary and secondary follicles. Collectively, these data illustrate developmental expression of R55 in oocytes and GCs of rabbit ovarian follicles.

Animals↗
PubMed1993

Systemic absorption pathways of topically applied beta adrenergic antagonists in the pigmented rabbit.

The objective of this study was to determine the influence of drug lipophilicity on extent of systemic absorption and relative contributions of the nasal and conjunctival mucosae to systemic absorption following topical solution instillation in the pigmented rabbit. Relatively hydrophilic atenolol, moderately lipophilic timolol and levobunolol, and lipophilic betaxolol were chosen as model drugs. Twenty-five microliters of a 15 mM drug solution in isotonic pH 7.4 buffer was instilled in each eye, with or without nasolacrimal occlusion, and plasma drug concentration was monitored using reversed phase HPLC. An equivalent amount of all four beta adrenergic antagonists was instilled directly into the nasolacrimal duct to assess the nasal contribution to systemic drug absorption following topical solution instillation. The systemic bioavailability ranged from 61% for atenolol to 100% for timolol. At least 50% of the systemically absorbed drug reached the bloodstream from the nasal mucosa; the nasal contribution was 83% for atenolol and 55-74% for the other three drugs. Occluding the nasolacrimal duct for 5 min reduced the extent of systemic absorption of timolol and levobunolol but did not do so for atenolol and betaxolol. Additional prolongation of solution retention in the conjunctival sac brought about further reduction for only atenolol (480-min prolongation) and timolol (120-min prolongation). Taken together, the above findings suggest that the systemic bioavailability of topically applied ophthalmic drugs would be modest for drugs at the extremes of lipophilicity and that the contribution of the nasal pathway to systemically absorbed drug diminishes with increasing drug lipophilicity.

Administration, Topical↗
PubMed1993

Use of the gamma-ray perturbed angular correlation (PAC) technique for monitoring liposomal phospholipid bilayer integrity.

A membrane labeling method based on the principle of gamma-ray perturbed angular correction (PAC) was developed to monitor the structural integrity of liposomal membranes. The reporter group was 111In(III) complexed with the lipophilic diethylenetriaminepentaacetic acid (DTPA) derivative of dipalmitoylphosphatidylethanolamine (DPPE) embedded in the phospholipid bilayers of small unilamellar liposomes. Using this method, complete chemical digestion of the constituent phospholipids in these DTPA-conjugated liposomes by phospholipase A2 or phospholipase C in the presence of Ca2+ was found not to be followed by an immediate disruption of the liposomal membrane. Compared with other methods, the method developed permits the continuous noninvasive monitoring of the microenvironment of the lipid bilayer at the molecular level. It may potentially be applicable to evaluate liposomal fusion, screen for penetration enhancers under development for enhancement in mucosal drug penetration, and monitor liposomal degradation within the living animal.

Gamma Rays↗
PubMed1993

A fluorescence quenching method for estimating chelating groups in chelate-conjugated macromolecules.

A terbium-dipicolinic acid (Tb-DPA) fluorescence quenching method for estimating free chelating groups conjugated to protein molecules was developed. This method was based on competitive displacement of DPA from binding to terbium by stronger chelating groups such as diethylenetriaminepentaacetic acid (DTPA), EDTA, nitrilotriacetic acid (NTA), DTPA-conjugated bovine serum albumin (BSA-DTPA), or DTPA-conjugated immunoglobulin G (IgG-DTPA), resulting in a significant reduction in terbium fluorescence. The chelating ability of the tested reagent, from high to low, was in the following order: BSA-DTPA > DTPA > IgG-DTPA > EDTA, NTA. At low terbium concentrations, the reduction was linear for DTPA. This fluorescence quenching method was not only rapid, simple, and as accurate as conventional radiosotopic or chromatographic methods, but also sensitive and reproductible. The detection limit was 10 nM for DTPA. The interrun coefficient of variation was at most 8%. The advantage of this method over other indirect methods is that it reveals the actual chelating ability of the tested macromolecule, unencumbered by complicating factors such as trace metal contamination and dimer/polymer formation during conjugation.

Chelating Agents↗
PubMed1993

Dipeptide transport across rat alveolar epithelial cell monolayers.

The transepithelial transport and metabolism of two model peptides, glycyl-D-phenylalanine (Gly-D-Phe) and glycyl-L-phenylalanine (Gly-L-Phe), across primary cultured monolayers of rat alveolar epithelial cells were studied. These tight monolayers (> 2000 omega-cm2) exhibited type I pneumocyte morphological and phenotypic characteristics. A reverse-phase HPLC was used to monitor the appearance of parent dipeptides and their metabolites (D- or L-Phe) in the receiver fluid. The apparent permeability coefficient (Papp) for Gly-D-Phe was about 1.6 x 10(-7) cm/sec at both 1 and 10 mM and in both the apical-to-basolateral (AB) and the basolateral-to-apical (BA) directions. In contrast, the Papp of Gly-L-Phe at 1 mM was about two times higher than that at 10 mM in the AB direction. The Papp of Gly-L-Phe in the BA direction at either concentration was about the same (about 1.4 x 10(-7) cm/sec). Whereas no metabolite was detected during Gly-D-Phe transport, the proportions of a metabolite, L-Phe, observed at 4 hr in the basolateral receiver fluid for 1 and 10 mM apical donor Gly-L-Phe accounted for 83 and 77% of the estimated total Gly-L-Phe (i.e., L-Phe+Gly-L-Phe), respectively. The corresponding values in the BA direction were 40 and 19% of the estimated total Gly-L-Phe in the apical receiver reservoir. Metabolism of Gly-L-Phe was significantly reduced in the presence of 3 microM actinonin (an inhibitor relatively specific for aminopeptides M) in the apical but not the basolateral fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Formulation influence on ocular and systemic absorption of topically applied atenolol in the pigmented rabbit.

The objective of this study was to determine the relative efficacy of various formulations in maximizing the ratio of ocular to systemic absorption of topically applied atenolol following solution instillation in the pigmented rabbit. Formulations of various pH's and tonicities and containing various preservatives and polymers were tested. Ocular absorption was determined by monitoring atenolol concentrations in various anterior segment tissues at 30 min following solution instillation, while systemic absorption was determined by monitoring the time course of atenolol concentration over 480 min. Reversed phase HPLC was the analytical methodology. All formulations except those containing 0.025% benzalkonium chloride or 0.5% EDTA showed similar drug concentration vs. time profiles in plasma, attaining a peak concentration of 30-50 ng/ml at about 100 min. For benzalkonium chloride and EDTA, there was an undesirable increase in systemic absorption, although ocular absorption was also increased. By contrast, lowering the solution tonicity to 80 mOsm/kg increased the ratio of aqueous humor to plasma peak concentrations 2 times and the ratio of iris-ciliary body to plasma peak concentrations 3 times. Incorporation of 3.75% poly(vinyl alcohol) into the formulation afforded yet a larger increase in the iris-ciliary body to plasma drug concentration ratio (52 times.) It may therefore be concluded that, for a hydrophilic drug like atenolol, formulation changes that increase membrane permeability and/or enhance noncorneal drug access may be more promising than those that increase drug residence in the conjunctival sac with respect to maximizing the ratio of ocular to systemic drug absorption.

Absorption↗