Relevance of Drug-Melanin Interactions to Ocular Pharmacology and Toxicology

Salazar-Bookaman, Maria Margarita; Wainer, Irving W.; Patil, Popat N.

doi:10.1089/jop.1994.10.217

Cited by 77 publications

(45 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In contrast, the s-receptor ligand DTG did not inhibit B16 cell growth (33). Moreover, chloroquine (34) and phenothiazine derivatives have been reported to have a high affinity for melanin and to accumulate in pigmented cells of eyes (35,36). Some in vitro studies were not conclusive in their ability to show the haloperidol inhibition of 125 I-BZA binding to B16 pigmented cells (26).…”

Section: Discussionmentioning

confidence: 99%

Preparation and Biologic Evaluation of a Novel Radioiodinated Benzylpiperazine, 123I-MEL037, for Malignant Melanoma

Pham¹,

Berghofer²,

Liu³

et al. 2007

Journal of Nuclear Medicine

View full text Add to dashboard Cite

Radiopharmaceuticals that can target the random metastatic dissemination of melanoma tumors may present opportunities for imaging and staging the disease as well as potential radiotherapeutic applications. A novel molecule, 2-(2-(4-(4-123 Iiodobenzyl)piperazin-1-yl)-2-oxoethyl)isoindoline-1,3-dione (MEL037), was synthesized, labeled with 123 I, and evaluated for application in melanoma tumor scintigraphy and radiotherapy. Methods: The tumor imaging potential of 123 I-MEL037 was studied in vivo in C57BL/6J female mice bearing the B16F0 murine melanoma tumor and in BALB/c nude mice bearing the A375 human amelanotic melanoma tumor by biodistribution, competition studies, and SPECT. Results: 123 I-MEL037 exhibited high and rapid uptake in the B16F0 melanoma tumor at 1 h (13 %ID/g [percentage injected dose per gram]), increasing with time to reach 25 %ID/g at 6 h. A significant uptake was also observed in the eyes (2 %ID, at 3-6 h after injection) of black mice. No uptake was observed in the tumor or in the eyes of nude mice bearing the A375 tumor. Because of high uptake and long retention in the tumor and rapid body clearance, the mean contrast ratios (MCR) of 123 I-MEL037 were 30 and 60, at 24 and 48 h after injection, respectively. At 24 h after injection of mice bearing the B16 melanoma, SPECT indicated that the radioactivity was located predominately in the tumor followed by the eyes, whereas no specific localization of the radioactivity was noted in mice bearing the A375 human amelanotic tumor. In competition experiments, uptake of 123 I-MEL037 in brain, lung, heart, and kidney-organs known to contain s-receptors-was not significantly different in haloperidol-treated animals compared with control animals. Therefore, reduction of uptake in tumor and eyes of the pigmented mice bearing the B16F0 tumor suggested that the mechanism of tumor uptake was likely due to an interaction with melanin. Conclusion: These findings suggested that 123 I-MEL037, which displays a rapid and very high tumor uptake, appeared to be a promising imaging agent for detection of most melanoma tumors with the potential for development as a therapeutic agent in melanoma tumor proliferation.

show abstract

Section: Discussionmentioning

confidence: 99%

Preparation and Biologic Evaluation of a Novel Radioiodinated Benzylpiperazine, 123I-MEL037, for Malignant Melanoma

Pham¹,

Berghofer²,

Liu³

et al. 2007

Journal of Nuclear Medicine

View full text Add to dashboard Cite

show abstract

“…18,19 Some drug ocular toxicity have been related to its binding to the ocular pigment, 20 while other drugs, such as atropine, have been used to its advantage to bind to the ocular pigment. 21 The binding of a drug to the ocular pigment affects the drug ocular pharmacokinetics and pharmacodynamics. 22 Therefore, ocular drug delivery calls for the study of qualitative and quantitative aspects of the drug-melanin interaction, which is particularly relevant to trans-scleral drug delivery because of abundant pigments in the choroid and RPE.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Ocular Pigmentation on Transscleral Delivery of Triamcinolone Acetonide

Sun

et al. 2013

Journal of Ocular Pharmacology and Therapeutics

View full text Add to dashboard Cite

Purpose: To determine the capacity and kinetics of the binding between triamcinolone acetonide (TA) and the ocular pigment for a better understanding of the transscleral delivery. Methods: In the in vitro study, natural melanin (sepia officinalis, Sigma-Aldrich) was incubated at 37°C with different concentrations of TA and the binding capacity/binding affinity was measured. The TA releasing profile from the melanin was also studied through repeated incubation of TA-melanin in fresh phosphate-buffed saline. In the ex vivo study, the effect of the choroidal pigment on the trans sclera/choroid permeability of TA was investigated through Franz-type vertical diffusion cells using both a TA suspension and a saturated TA solution.Results: The amount of TA bound to melanin increases with the increase of the TA concentration and with an increase in the incubation time. A Scatchard analysis revealed that the maximum number of moles of TA bound to melanin is predicted to be 22.43 nmol/mg, with a binding affinity of K = 2.4 · 10 -5 nM -1 . TA released from a pigment showed a fast phase within the first 24 h and a slow phase thereafter. About 40% of the bound TA released in the first day and 73.94% of accumulative release was observed after 5 days. The TA suspension showed more TA penetration through the scleral-choroid complex than the saturated solution (P = 0.0104). The apparent permeability coefficients for the suspension across the sclera-choroid of pigmented and albino rabbits are 7.48 -1.53 · 10 -6 cm/s and 10.78 -2.49 · 10 -6 cm/s, respectively. Conclusions: TA can bind to and release from the ocular pigment, which may extend the TA ocular half-life and therapeutic duration when TA is delivered through a subtenon injection. A further in vivo study is warranted to validate the findings and to quantitate the magnitude of the difference between pigmented and albino animals.

show abstract

“…Melanins are polyanions containing a relatively high amount of negatively charged carboxyl groups and o-semiquinones (Larsson, 1993;Salazar-Bookaman et al, 1994). Electrostatic forces have been reported to play an important role in the binding of cationic drugs to melanin, whereas nonelectrostatic contributions, including hydrophobic interactions, van der Waals' forces, and charge-transfer reactions, also contribute to binding for drugs such as chlorpromazine and chloroquine (Ings, 1984;Tanaka et al, 2004a).…”

Section: Discussionmentioning

confidence: 99%

Investigation of Long-Term Retention of Unchanged (−)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide, A Novel “Funny” If Current Channel Inhibitor, and Its Metabolites in the Eyeball and Thoracic Aorta of Rats

Umehara

Nakada²,

Noguchi³

et al. 2009

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

Relevance of Drug-Melanin Interactions to Ocular Pharmacology and Toxicology

Cited by 77 publications

References 13 publications

Preparation and Biologic Evaluation of a Novel Radioiodinated Benzylpiperazine, 123I-MEL037, for Malignant Melanoma

Preparation and Biologic Evaluation of a Novel Radioiodinated Benzylpiperazine, 123I-MEL037, for Malignant Melanoma

The Effect of Ocular Pigmentation on Transscleral Delivery of Triamcinolone Acetonide

Investigation of Long-Term Retention of Unchanged (−)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide, A Novel “Funny” If Current Channel Inhibitor, and Its Metabolites in the Eyeball and Thoracic Aorta of Rats

Contact Info

Product

Resources

About