RESUMO
The eye is a complex organ with a series of anatomic barriers that provide protection from physical and chemical injury while maintaining homeostasis and function. The physiology of the eye is multifaceted, with dynamic flows and clearance mechanisms. This review highlights that in vitro ocular transport and metabolism models are confined by the availability of clinically relevant absorption, distribution, metabolism, and excretion (ADME) data. In vitro ocular transport models used for pharmacology and toxicity poorly predict ocular exposure. Although ocular cell lines cannot replicate in vivo conditions, these models can help rank-order new chemical entities in discovery. Historic ocular metabolism of small molecules was assumed to be inconsequential or assessed using authentic standards. While various in vitro models have been cited, no single system is perfect, and many must be used in combination. Several studies document the use of laboratory animals for the prediction of ocular pharmacokinetics in humans. This review focuses on the use of human-relevant and human-derived models which can be utilized in discovery and development to understand ocular disposition of new chemical entities. The benefits and caveats of each model are discussed. Furthermore, ADME case studies are summarized retrospectively and capture the ADME data collected for health authorities in the absence of definitive guidelines. Finally, we discuss the novel technologies and a hypothesis-driven ocular drug classification system to provide a holistic perspective on the ADME properties of drugs administered by the ocular route.
Assuntos
Olho/efeitos dos fármacos , Olho/metabolismo , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/metabolismo , Administração Oftálmica , Animais , Descoberta de Drogas/métodos , Humanos , Bibliotecas de Moléculas Pequenas/efeitos adversosAssuntos
Ensaios Clínicos como Assunto/métodos , Avaliação Pré-Clínica de Medicamentos/efeitos adversos , Guias como Assunto , Animais , Ensaios Clínicos como Assunto/normas , Estudos de Coortes , Aprovação de Drogas/legislação & jurisprudência , Aprovação de Drogas/organização & administração , Indústria Farmacêutica/legislação & jurisprudência , Indústria Farmacêutica/organização & administração , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Europa (Continente) , Órgãos Governamentais/legislação & jurisprudência , Órgãos Governamentais/organização & administração , Humanos , Farmacocinética , Farmacologia/métodos , Estados Unidos , United States Food and Drug AdministrationRESUMO
Drug transporters, including efflux transporters (the ATP binding cassette (ABC) proteins) and uptake transporters (the solute carrier proteins (SLC)), have an important impact on drug disposition, efficacy, drug-drug interactions and toxicity. Identification of the interactions of chemical scaffolds with transporters at the early stages of drug development can assist in the optimization and selection of new drug candidates. In this review, we discuss current in vitro and in vivo models used to investigate the interactions between drugs and transporters such as P-gp, MRP, BCRP, BSEP, OAT, OATP, OCT, NTCP, PEPT1/2 and NT. In vitro models including cell-based, cell-free, and yeast systems as well as in vivo models such as genetic knockout, gene deficient and chemical knockout animals are discussed and compared. The applications, throughput, advantages and limitations of each model are also addressed in this review.