title: Cellular pharmacokinetic and pharmacodynamic analyses of ethacrynic acid: Implications in topical drug delivery in the eye.
abstract: OBJECTIVE
  Ethacrynic acid (ECA) is a potential trabecular meshwork (TM) drug that has shown promising results in preclinical studies for treatment of primary open-angle glaucoma. However, topical application of ECA is currently limited by adverse effects in corneal tissues. To this end, we developed a new theoretical model to evaluate time-dependent toxicity induced by ECA in corneal epithelial cells.
  
  
  METHODS
  The model consisted of a cellular pharmacokinetic (PK) module to determine intracellular concentration of ECA, and a pharmacodynamic (PD) module to determine the cytotoxicity of ECA. It was assumed that ECA-induced cytotoxicity depended on drug exposure time and peak concentration of bound ECA in cells. In addition to the model development, we experimentally determined the intracellular concentration of ECA as a function of drug dose and treatment time.
  
  
  RESULTS
  The intracellular concentration increased linearly (i.e., no saturation) with increasing the dose of ECA. It also increased initially with time and then reached a steady-state at ~40 min. The percent of cells survived after treatment decreased with increasing the dose of drug or the time of treatment. The experimental data were fit by the new PK and PD models to obtain values of model constants. One of the unique applications of these models was to predict cell survival relative to control when extracellular concentration of ECA varied with time. The prediction showed that the toxicity of ECA might be significantly overestimated by using the traditional LC(50) determined in vitro.
  
  
  CONCLUSIONS
  The new PK and PD models developed in this study were capable to fit experimental data and predict time-dependent toxicity of ECA in corneal epithelial cells. The models may be useful for optimizing the dose and schedule in topical application of ECA for glaucoma treatment.
authors: Department of Biomedical Engineering, Duke University, Durham, NC, USA.
authors: Cheng-Wen
authors: CW
authors: Lin
authors: Pedro
authors: P
authors: Gonzalez
authors: Fan
authors: F
authors: Yuan
mesh_terms: D000287:Administration, Topical; D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D003315:Cornea / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004976:Ethacrynic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005902:Glaucoma, Open-Angle / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007700:Kinetics; D008962:Models, Theoretical; D009883:Ophthalmic Solutions / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D061251:Primary Cell Culture; D013552:Swine
chemical_list: D009883:Ophthalmic Solutions; D004976:Ethacrynic Acid