Mechanisms of cellular retention of melanin bound drugs: Experiments and computational modeling.

Autor: Bahrpeyma S; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70210 Kuopio, Finland; Faculty of Pharmacy, University of Helsinki, 00014, University of Helsinki, Finland. Electronic address: sina.bahrpeyma@uef.fi., Reinisalo M; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70210 Kuopio, Finland., Hellinen L; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70210 Kuopio, Finland., Auriola S; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70210 Kuopio, Finland., Del Amo EM; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70210 Kuopio, Finland., Urtti A; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70210 Kuopio, Finland; Faculty of Pharmacy, University of Helsinki, 00014, University of Helsinki, Finland; Institute of Chemistry, St. Petersburg State University, Petergoff, Russian Federation. Electronic address: arto.urtti@uef.fi.
Jazyk: angličtina
Zdroj: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2022 Aug; Vol. 348, pp. 760-770. Date of Electronic Publication: 2022 Jun 25.
DOI: 10.1016/j.jconrel.2022.05.059
Abstrakt: Melanin binding of drugs is known to increase drug concentrations and retention in pigmented eye tissues. Even though the correlation between melanin binding in vitro and exposure to pigmented eye in vivo has been shown, there is a discrepancy between rapid drug release from melanin particles in vitro and the long in vivo retention in the pigmented tissues. We investigated mechanisms and kinetics of pigment-related drug retention experimentally using isolated melanin particles from porcine retinal pigment epithelium and choroid, isolated porcine eye melanosomes, and re-pigmented ARPE-19 cells in a dynamic flow system. The experimental studies were supplemented with kinetic simulations. Affinity and capacity of levofloxacin, terazosin, papaverine, and timolol binding to melanin revealed K d values of ≈ 50-150 μM and B max  ≈ 40-112 nmol.mg -1 . The drugs were released from melanin in <1 h (timolol) or in 6-12 h (other drugs). The drugs were released slower from the melanosomes than from melanin; the experimental differences ranged from 1.2-fold (papaverine) to 7.4-fold (timolol). Kinetic simulations supported the role of the melanosomal membrane in slowing down the release of melanin binders. In release studies from the pigmented ARPE-19 cells, drugs were released from the cellular melanin to the extracellular space in ≈ 1 day (timolol) and ≈ 11 days (levofloxacin), i.e., much slower than the release from melanin or melanosomes. Simulations of drug release from pigmented cells in the flow system matched the experimental data and enabled further sensitivity analyses. The simulations demonstrated a significant prolongation of drug retention in the cells as a function of decreasing drug permeability in the melanosomal membranes and increasing melanin content in the cells. Overall, we report the impact of cellular factors in prolonging drug retention and release from melanin-containing cells. These data and simulations will facilitate the design of melanin binding drugs with prolonged ocular actions.
(Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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