RT Journal Article
SR Electronic
T1 Models and Approaches Describing the Metabolism, Transport, and Toxicity of Drugs Administered by the Ocular Route
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1670
OP 1683
DO 10.1124/dmd.118.082974
VO 46
IS 11
A1 Jennifer L. Dumouchel
A1 Nagendra Chemuturi
A1 Mark N. Milton
A1 Gian Camenisch
A1 James Chastain
A1 Markus Walles
A1 Vito Sasseville
A1 Mithat Gunduz
A1 Ganesh R. Iyer
A1 Upendra A. Argikar
YR 2018
UL http://dmd.aspetjournals.org/content/46/11/1670.abstract
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.