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Rhodamines 110 and 123, and rhodamine 110 linked via peptide bonds to Arg, Cbz-Arg and Cbz-Ile-Pr-Arg interact with free base porphyrins or cytochrome C. Rhodamines 110 and 123 essentially form 1:1 complexes while the other derivatives form 2:1 complexes. The possible biological implications of these results are discussed.
A microplate screening method has been developed to evaluate the effects of test agents on the accumulation of the fluorescent P-glycoprotein (Pgp) substrates Hoechst 33342, rhodamine 123, and rhodamine 6G in multidrug-resistant (MDR) breast cancer cells that overexpress Pgp. All three substrates exhibit substantially higher accumulation in MCF7 non-MDR cells versus NCI/ADR-RES MDR cells, while incubation with 50 microM reserpine significantly reduces or eliminates these differences. Rhodamine 123 shows the lowest substrate accumulation efficiency in non-MDR cells relative to the substrate incubation level. The effects of several chemosensitizing agents and a series of paclitaxel analogs on the accumulation of each fluorescent substrate suggest that there are distinct differences in the substrate interaction profiles exhibited by these different agents. The described methods may be useful in Pgp-related research in the areas of cancer MDR, oral drug absorption, the blood-brain barrier, renal/hepatic transport processes, and drug-drug interactions.
Texas Red sulfonyl chloride (TR-SC) and Lissamine rhodamine B sulfonyl chloride (LRB-SC) are popular dyes often used to prepare red fluorescent conjugates that are useful second labels in combination with fluorescein. Unfortunately, being sulfonyl chloride derivatives, both are unstable to moisture during storage and prone to hydrolysis in the conjugation reaction. Their instability causes the percentage of reactive dye to vary from lot to lot and requires use of low temperatures and a relatively high pH to optimize conjugation efficiency. Succinimidyl esters of the aminohexanoic acid sulfonamides of both dyes have been prepared, which are designated Texas Red-X succinimidyl ester (TR-X-SE) and Rhodamine Red-X succinimidyl ester, respectively. Their spectral properties are similar to those of their sulfonyl chloride analogs; moreover, incorporation of the succinimidyl ester at the end of the aliphatic chain spacer facilitates conjugation, decreases precipitation of proteins during conjugation and storage, and usually increases the fluorescence yield of the conjugate. Comparison of the rate of hydrolysis of TR-SC with that of TR-X-SE shows that, while the former was completely hydrolyzed within 5 min by exposure to water, TR-X-SE retains most of its reactivity for more than an hour. The reactivity of both new derivatives is high between pH 7.5 and 8.5, allowing conjugation of proteins that do not tolerate the high pH required for reaction with sulfonyl chlorides. In addition, Texas Red maleimides and haloacetamides containing spacer groups were prepared for labeling sulfhydryl groups. A Texas Red-X derivative of phalloidin has also been prepared, and its use for labeling F-actin has been characterized.
Platinum rhodamine 123 [Pt(Rh-123)2] was synthesized in an effort to produce a new drug which would have the selective uptake into carcinoma cells of Rh-123 and the alkylating and radiosensitizing properties of the chloroplatinum moiety. Because both Rh-123 and cis-diamminedichloroplatinum(II) (CDDP) have been shown to become more cytotoxic at elevated temperatures, we tested the interactions between Pt(Rh-123)2 and hyperthermia both in EMT6 cells in vitro and in the Lewis lung carcinoma in vivo. In the EMT6 cells, CDDP was far more cytotoxic than Pt(Rh-123)2 at 37 degrees C, but its cytotoxicity was less enhanced by exposure of cells to the drug at 42 degrees C than was true for Pt(Rh-123)2 [about 2 logs of increased killing at 42 degrees C after exposure to 10 microM CDDP versus over 3 logs of increased killing at 42 degrees C after exposure to 500 microM Pt(Rh-123)2]. Both Rh-123 and K2PtCl4 also are more cytotoxic to EMT6 cells at 42 degrees C than at 37 degrees C, but the hyperthermic enhancement was far less striking. In the Lewis lung carcinoma, the growth delay produced by CDDP (8 mg/kg) increased by a factor of approximately 2.5 when the drug was given i.p. just prior to local heating of the s.c. thigh tumor to 43 degrees C for 30 min, but the growth delay produced by Pt(Rh-123)2 (100 mg/kg) given i.p. 1 h before local hyperthermia increased by a factor of 5. In contrast, K2PtCl4 and Rh-123 given i.p. produced very short growth delays at normal temperatures and these growth delays were not enhanced by hyperthermia. The effect of these drugs at 37 degrees C and 42 degrees C on the conformation of superhelical pBR322 DNA was also examined. Exposure to CDDP caused progressive alteration from the supercoiled to the linear form of the DNA over time. In contrast, Pt(Rh-123)2 apparently produced progressive degradation of the DNA. Hyperthermia did not alter the qualitative damage produced by the drugs but increased the rate at which the changes occurred. These results suggest both that Pt(Rh-123)2 probably has a different mechanism of action at the DNA than does CDDP and that Pt(Rh-123)2 may be a good drug to use with local hyperthermia and radiation.
A new chemosensor based on rhodamine B thiohydrazide is described. Chemosensor B was found to show a reversible dual chromo- and fluorogenic response toward Hg2+ in aqueous solution in a highly selective and sensitive manner. This was suggested to result from the coordination of Hg2+ at the N, S binding sites in B to open its spiro ring.
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NTP Toxicology and Carcinogenesis studies of rhodamine 6G were conducted because of potential human exposure related to its use as a dye for natural and synthetic fibers and as a research chemical. These studies were conducted by administering rhodamine 6G (greater than 95% pure) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies (0, 310, 620, 1,250, 2,500, or 5,000 ppm), all five male and five female rats that received 5,000 ppm and 1/5 male rats that received 2,500 ppm died before the end of the studies; all mice lived to the end of the study. The final mean body weights of rats that received 2,500 ppm were lower than the initial weights. The final mean body weights of mice that received 2,500 or 5,000 ppm were 8% or 18% lower than that of controls for males and 2% or 8% lower for females. In the 13-week studies, all rats lived to the end of the studies (dietary concentrations of 0 or 120-2,000 ppm). The final mean body weights of rats that received 500, 1,000 or 2,000 ppm were 12%, 13%, or 32% lower than that of controls for males and 4%, 8%, or 20% lower for females. Feed consumption by rats that received 2,000 ppm was somewhat lower than that by controls. Bone marrow atrophy was observed at increased incidences and severity in dosed rats. In the 13-week study (0 or 500-8,000 ppm), 1/10 male mice that received the highest concentration died before the end of the studies. The final mean body weights of mice that received 8,000 ppm were lower than the initial mean body weights. The final mean body weights of male mice that received 4,000 ppm and of female mice that received 2,000 or 4,000 ppm were 13%-19% lower than those of controls. Feed consumption was not related to dose. Minimal-to-moderate cytoplasmic vacuolization of hepatocytes was seen in 8/10 male mice that received 8,000 ppm. Based on these results, dietary concentrations selected for the 2-year studies were 0, 120, or 250 ppm rhodamine 6G for rats, 0, 1,000, or 2,000 ppm for male mice, and 0, 500, 1,000 ppm for female mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were similar to those of controls throughout the studies. The average daily feed consumption by dosed rats was within 5% that by controls for all dosed groups. The average amount of rhodamine 6G consumed per day was approximately 5 mg/kg for low dose rats and 10 or 12 mg/kg for high dose male or female rats. Mean body weights of high dose male and dosed female mice were generally 5%-14% lower than those of controls. The average daily feed consumption by dosed mice was within 5% that by controls for all dosed groups. The average amount of rhodamine 6G consumed per day was approximately 210 or 440 mg/kg for low dose or high dose male mice and 125 or 250 mg/kg for low dose or high dose female mice. No significant differences in survival were observed between any groups of rats or mice (male rats: control, 22/50; low dose, 21/50; high dose, 27/50; female rats: 29/50; 30/50; 30/50; male mice: 36/50; 32/50; 38/50; female mice: 39/50; 35/50; 36/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: No chemically related nonneoplastic lesions in male or female rats and no chemically related neoplastic or nonneoplastic lesions in male or female mice were observed in these studies. The incidences of keratoacanthomas of the skin was increased in high dose male rats (control, 1/50; low dose, 2/50; high dose, 8/50). The historical incidence of keratoacanthomas in untreated control male F344/N rats is 31/1,936 (1.6%; range, 0/50-7/49). Both fur and skin of rats in the dosed groups apparently were exposed to feed dust containing rhodamine 6G; the intensity of staining was proportional to the concentration of rhodamine 6G in feed. Because of the variable background incidence of keratoacanthomas in F344/N rats, the incideentration of rhodamine 6G in feed. Because of the variable background incidence of keratoacanthomas in F344/N rats, the incidence of keratoacanthomas cannot be conclusively related to exposure to rhodamine 6G. The incidences of pheochromocytomas (3/50; 3/50; 8/50) or malignant pheochromocytomas (combined: 3/50; 3/50; 10/50) of the adrenal gland were increased in high dose female rats. The historical incidence of adrenal medullary neoplasms in untreated control F344/N female rats is 99/1,968 (5%; range, 0/50-8/50). This marginal increase may be related to the administration of rhodamine 6G. Genetic Toxicology: Rhodamine 6G was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested with and without exogenous metabolic activation (S9). Rhodamine 6G gave a positive response in the absence of S9 in the mouse lymphoma assay for induction of trifluorothymidine (Tft) resistance in L5178Y cells; in the presence of S9, rhodamine 6G was negative. Rhodamine 6G induced sister chromatid exchanges (SCEs) and chromosomal aberrations in cultured CHO cells in the presence, but not the absence, of S9. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity for male F344/N rats administered rhodamine 6G, as indicated by a marginally increased incidence of integumentary keratoacanthomas. There was equivocal evidence of carcinogenic activity for female F344/N rats administered rhodamine 6G, as indicated by a marginal increase in pheochromocytomas or malignant pheochromocytomas (combined) of the adrenal gland. There was no evidence of carcinogenic activity for male B6C3F1 mice administered 1,000 or 2,000 ppm rhodamine 6G in the diet. There was no evidence of carcinogenic activity for female B6C3F1 mice administered 500 or 1,000 ppm rhodamine 6G in the diet. There were no significant nonneoplastic lesions attributed to rhodamine 6G administration to male or female rats or male or female mice. Male and female rats might have been able to tolerate a higher concentration of rhodamine 6G in the feed. Synonym: 2-[6-(ethylamino)-3-(ethylimino)2,7-dimethyl-3H-xanthen-9-yl] benzoic acid ethyl ester, monohydrochloride Common Names: Basic Red 1; Basic Rhodamine Yellow; Basic Rhodaminic Yellow; Calcozine Red 6G; Calcozine Rhodamine 6GX; C.I. Basic Red 1, Monohydrochloride; Elcozine Rhodamine 6GDN; Eljon Pink Toner; Fanal Pink GFK; Fanal Red 25532; Flexo Red 482; Heliostable Brilliant Pink B extra; Mitsui Rhodamine 6GCP; Nyco Liquid Red GF; Rhodamine 69DN Extra; Rhodamine F4G; Rhodamine F5G; Rhodamine F5G chloride; Rhodamine 6GB; Rhodamine 6GBN; Rhodamine 6GCP; Rhodamine 6GD; Rhodamine 4GD; Rhodamine GDN; Rhodamine 5GDN; Rhodamine 6 GDN; Rhodamine GDN Extra; Rhodamine 6GEx ethyl ester; Rhodamine 6G Extra; Rhodamine 6G Extra Base; Rhodamine 4GH; Rhodamine 6GH; Rhodamine 5GL; Rhodamine 6G lake; Rhodamine 6GX; Rhodamine J; Rhodamine 6JH; Rhodamine 7JH; Rhodamine Lake Red 6G; Rhodamine Y 20-7425; Rhodamine Zh; Rhodamine 6ZH-DN; Silosuper Pink B; Valley Fast Red 1308
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The bidirectional permeation characteristics of rhodamine 123 and Hoechst 33342, fluorescence probes of the binding sites on P-glycoprotein (P-gp), across monolayers of MDCK cells transfected with the human MDR1 gene (MDCK-MDR1) were investigated. The ratios of the apparent permeability coefficients (P(app)) of rhodamine 123 and Hoechst 33342 flux measured in the basolateral (BL) to apical (AP) direction versus the flux in the AP-to-BL direction (P(app BL-to-AP)/P(app AP-to-BL)) were 115 and 177, respectively. The P-gp inhibitor GF-120918 could significantly reduce the polarized efflux of both rhodamine 123 and Hoechst 33342. Rhodamine 123 appeared to "stimulate" the polarized efflux of Hoechst 33342 across MDCK-MDR1 cell monolayers. In contrast, Hoechst 33342 partially inhibited the polarized efflux of rhodamine 123 across these cell monolayers whereas daunorubicin partially inhibited the polarized efflux of both rhodamine 123 and Hoechst 33342. The uptake characteristics of rhodamine 123 and Hoechst 33342 in MDCK-MDR1 cells were measured in the absence and presence of GF-120918 and known P-gp substrates (Hoechst 33342, rhodamine 123, and daunorubicin). The uptake of rhodamine 123 and Hoechst 33342 in MDCK-MDR1 cells was enhanced more than twofold by inclusion of GF-120918 (2 microM) in the incubation medium. Daunorubicin (160 microM) increased the relative fluorescence unit (RFU) values of cytoplasm-associated rhodamine 123 by up to 30%. However, daunorubicin (40 microM) and rhodamine 123 (5 microM) decreased the RFU values of cell membrane-associated Hoechst 33342 by 70% and 40%, respectively. To further explore what appears to be a "stimulatory" effect of daunorubicin and rhodamine 123 on the uptake of Hoechst 33342 and a stimulatory effect of daunorubicin on Hoechst 33342 transport across cell monolayer, uptake of Hoechst 33342 into liposomes in the presence and absence of GF-120918, daunorubicin, and rhodamine 123 was determined. GF-120918 exhibited no effect on the RFU values of liposome-associated Hoechst 33342. In contrast, rhodamine 123 and daunorubicin decreased the fluorescence of liposome-associated Hoechst 33342 suggesting these molecules were either quenching the fluorescence of this chemical probe or displacing it from the lipid bilayer. In conclusion, these bidirectional transport data indicate that rhodamine 123 and Hoechst 33342 are excellent substrates of P-gp in MDCK-MDR1 cells. The ability of Hoechst 33342 to partially inhibit the polarized efflux of rhodamine 123 is consistent with these substrates binding to the same site on P-gp. In contrast, the ability of rhodamine 123 to apparently "stimulate" the efflux of Hoechst 33342 in both the transport and uptake experiments suggests the substrates might bind to different sites on P-gp. However, experimental results using liposomes suggested that this "stimulation" phenomenon by rhodamine 123 on Hoechst 33342 uptake and efflux might simply be an artifact. Thus, the use of Hoechst 33342 to probe the binding sites on a membrane-bound protein such as P-gp might be problematic.
The effect of the cosmetic dye rhodamine B on the proliferation of human lip fibroblasts (KD cells) was investigated in a culture system. Rhodamine B at 25 micrograms/ml and above significantly decreased the number of the cells after a 72 h culture. A time course study revealed that 50 micrograms/ml of rhodamine B-induced decrease in the cell number occurred after 48 h and longer, suggesting that the dye inhibited cell proliferation without a decrease in cell attachment. The detachment of [3H]thymidine-labeled cells from the monolayer was unaffected by rhodamine B at 100 micrograms/ml and below. The incorporation of [3H]thymidine and [14C]leucine into the acid-insoluble fraction of the cell layer was significantly inhibited by 50 micrograms/ml rhodamine B treatment. Histologically, the damage of KD cells was not marked, however, a degenerative change of nuclei and an irregular shape of the cells as well as a decrease in the cell number were caused by 50 micrograms/ml rhodamine B. Rhodamine 6G caused a severe damage of the cells, and rhodamine B significantly decreased the cell number; rhodamine 123 had no significant effect; rhodamine 116 significantly increased the cell number. Furthermore, rhodamine B decreased the number of both vascular endothelial cells from bovine aorta and vascular smooth muscle cells from murine aorta after a 72 h culture. It is concluded that rhodamine B inhibits the proliferation of human lip fibroblasts. This rhodamine B effect may be a warning sign for the dye toxicity.
Rhodamine 123 is a lipophilic cationic compound that is selectively taken up by cancer cell mitochondria. This compound is toxic to epithelial cancer cells in vitro and displays significant anticancer activity in vivo. However, the mechanism of action of rhodamine 123 in intact, actively metabolizing cell preparations is unknown. We have used 31P- and 13C-nuclear magnetic resonance spectroscopy to quantitatively characterize how rhodamine 123 affects the energetics of human colon cancer cells (HCT-116) and spontaneously immortalized normal epithelial cells (CV-1). Rhodamine 123 differentially altered the phosphorus and glucose metabolism of HCT-116 and CV-1 cells. 31P-nuclear magnetic resonance detected mitochondrial poisoning in the HCT-116 human colon cancer cell line in its early stages after selective uptake of rhodamine 123. When we compared administration of rhodamine 123 and [1-C13]glucose to administration of [1-C13]glucose alone in the HCT-116 cells, we noted a marked decrease in intracellular pH to 6.7 +/- 0.06 (mean +/- SD) units, a 2.2-fold increase in lactate production, and a 1.8-fold increase in glucose consumption after 10 h. In addition, we found a 2-fold rise in intracellular free magnesium 12 h after rhodamine 123 administration. These results suggest that when rhodamine 123 inhibits mitochondrial ATP production, it initially stimulates cytoplasmic glycolysis in an attempt to maintain cellular energy demands. The marked fall in intracellular pH and rise in intracellular free magnesium after administration of rhodamine 123 may inhibit activity of several glycolytic enzymes: this effect would inhibit cytoplasmic ATP generation and interfere with multiple cell enzymatic processes, leading to cell death. The CV-1 cells showed no change in intracellular pH, intracellular free magnesium, or magnesium-bound ATP levels over the 24-h period following rhodamine 123 administration. Rhodamine 123 also failed to alter glucose utilization and lactate production levels significantly in the CV-1 cells. These results prove the usefulness of 31P- and 13C-nuclear magnetic resonance spectroscopy for quantifying differing effects of rhodamine 123 on the high energy phosphate metabolism and glucose metabolism of HCT-116 and CV-1 cells.
The human multidrug resistance P-glycoprotein (P-gp, ABCB1) actively extrudes a broad range of potentially cytotoxic compounds out of the cell. Key steps in understanding the transport process are binding of drug substrates in the transmembrane domains, initiation of ATPase activity, and subsequent drug efflux. We used cysteine-scanning mutagenesis of the transmembrane segment residues and reaction with the thiol-reactive drug substrate analog of rhodamine, methane-thiosulfonate-rhodamine (MTS-rhodamine), to test whether P-gp could be trapped in an activated state with high levels of ATPase activity. The presence of such an activated P-gp could be used to further investigate P-gp-drug substrate interactions. Single cysteine mutants (149) were treated with MTS-rhodamine, and ATPase activities were determined after removal of unreacted MTS-rhodamine. One mutant, F343C(TM6), showed a 5.8-fold increase in activity after reaction with MTS-rhodamine. Pre-treatment of mutant F343C with rhodamine B protected it from activation by MTS-rhodamine, indicating that residue Cys-343 contributes to the rhodamine-binding site. The ATPase activity of MTS-rhodamine-treated mutant F343C, however, was not stimulated further by colchicine or calcein-AM. By contrast, verapamil and Hoechst 33342 stimulated and inhibited, respectively, the ATPase activity of the MTS-rhodamine-treated mutant F343C. These results indicate that the MTS-rhodamine binding site overlaps that of colchicine and calcein-AM but not that of verapamil and Hoechst 33342 within the common drug-binding pocket.
The effects of eight permeant fluorescent dyes on the in vitro growth of Plasmodium falciparum was investigated. First, P. falciparum-infected human erythrocytes were synchronized with D-sorbitol and treated with the cationic fluorescent dye rhodamine 123 at 37 degrees C for 30 minutes, and the growth of the treated parasites monitored by examining daily parasitaemias. Rhodamine 123 inhibited the parasite growth at more than 5 microM, the 50% effective concentration being 6 microM. Ring forms and trophozoites were more susceptible to the dye than schizonts. The development of dye-treated ring forms and trophozoites to schizonts was greatly inhibited, and so few new ring forms were produced. In contrast, the dye-treated schizonts produced a large number of new ring forms, though to a slightly lesser extent than untreated schizonts. The rhodamine 123-induced growth inhibition was partially reversed by treating the dye-pre-exposed infected erythrocytes with the proton ionophore carbonyl-cyanide m-chlorophenylhydrazone, which dissipates transmembrane proton gradients. A survey of seven other fluorescent dyes demonstrated that the cationic dyes, including rhodamine 123, rhodamine 6G, rhodamine 6G perchlorate and rhodamine 3B perchlorate, exerted the growth inhibitory effect, whereas the neutral dyes rhodamine B, rhodamine 110, and rhodamine 19 perchlorate, and the anionic dye fluorescein, did not. Fluorescent microscopy revealed that P. falciparum accumulated the cationic dyes but not the neutral and anionic dyes. These results indicate that the cationic rhodamine dyes, which accumulated in the parasite, inhibit the growth of P. falciparum.
The spectral and metabolic properties of Rhodamine 123, a fluorescent cationic dye used to label mitochondria in living cells, were investigated in suspensions of isolated rat-liver mitochondria. A red shift of Rhodamine 123 absorbance and fluorescence occurred following mitochondrial energization. Fluorescence quenching of as much as 75% also occurred. The red shift and quenching varied linearly with the potassium diffusion potential, but did not respond to delta pH. These energy-linked changes were accompanied by dye uptake into the matrix space. Concentration ratios, in-to-out, approached 4000:1. A large fraction of internalized dye was bound. At concentrations higher than those needed to record these spectral changes, Rhodamine 123 inhibited ADP-stimulated (State 3) respiration of mitochondria (Ki = 12 microM) and ATPase activity of inverted inner membrane vesicles (Ki = 126 microM) and partially purified F1-ATPase (Ki = 177 microM). The smaller Ki for coupled mitochondria was accounted for by energy-dependent Rhodamine 123 uptake into the matrix. Above about 20 nmol/mg protein (10 microM), Rhodamine 123 caused rapid swelling of energized mitochondria. Effects on electron-transfer reactions and coupling were small or negligible even at the highest Rhodamine 123 concentrations employed. delta psi-dependent Rhodamine 123 uptake together with Rhodamine 123 binding account for the intense fluorescent staining of mitochondria in living cells. Inhibition of mitochondria ATPase likely accounts for the cytotoxicity of Rhodamine 123. At concentrations which do not inhibit mitochondrial function, Rhodamine 123 is a sensitive and specific probe of delta psi in isolated mitochondria.
PURPOSE: To determine the in vitro human scleral permeability of several dyes and drugdye combinations with varying molecular weights (MW) and lipid solubilities (fluorescein, dexamethasone-fluorescein, methotrexate-fluorescein, and rhodamine). Coils coated with rhodamine were also evaluated for scleral permeability and sustained release. METHODS: Scleral sections excised from moist chamber stored human globes were mounted in a 2-compartment perfusion chamber. A small depot of drug/dye (100 microl of 10(-4) M fluorescein, dexamethasone-fluorescein, methotrexate-fluorescein or rhodamine) or a coated coil in 100 microl of BSS was added to the episcleral surface while perfusing BSS to the choroidal side. The perfusate was collected and measured for fluorescence. Permeability was calculated as Ktrans from the flux measurements. RESULTS: Ktrans values (cm/sec, mean +/- SE) for the studied dyes and drug-dye combinations were 5.21 +/- 0.71 x 10(-6) for fluorescein, 1.64 +/- 0.17 x 10(-6) for dexamethasone-fluorescein, 3.36 +/- 0.62 x 10(-6) for methotrexate-fluorescein, 1.86 +/- 0.39 x 10(-6) for rhodamine and 2.18 +/- 0.23 x 10(-6) for the rhodamine from the coils. We found a significant difference between the permeability of the sclera to fluorescein and dexamethasone-fluorescein (P < 0.001), methotrexate-fluorescein (P < 0.05) and rhodamine (P < 0.001). Steady state flux was observed from the rhodamine coil. CONCLUSION: The rank order of scleral permeability to the studied dyes is as follows: fluorescein > methotrexate-fluorescein > rhodamine coil > rhodamine 6G > dexamethasone-fluorescein. Differences in scleral permeability are related to MW and lipid solubility. Prolonged transscleral diffusion of rhodamine delivered by solution and by coil are similar.