PT  - JOURNAL ARTICLE
AU  - Jennifer L. Dumouchel
AU  - Nagendra Chemuturi
AU  - Mark N. Milton
AU  - Gian Camenisch
AU  - James Chastain
AU  - Markus Walles
AU  - Vito Sasseville
AU  - Mithat Gunduz
AU  - Ganesh R. Iyer
AU  - Upendra A. Argikar
TI  - Models and Approaches Describing the Metabolism, Transport, and Toxicity of Drugs Administered by the Ocular Route
AID  - 10.1124/dmd.118.082974
DP  - 2018 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 1670--1683
VI  - 46
IP  - 11
4099  - http://dmd.aspetjournals.org/content/46/11/1670.short
4100  - http://dmd.aspetjournals.org/content/46/11/1670.full
SO  - Drug Metab Dispos2018 Nov 01; 46
AB  - 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.