ABSTRACT
CJ-12,918, a 5-lipoxygenase (5-LO) inhibitor, caused cataracts during a 1-month safety assessment studies in rats whereas the structurally similar ZD-2138 was without effect. For CJ-12,918 analogs, blocking different sites of metabolic liability reduced (CJ-13,454) and eliminated (CJ-13,610) cataract formation in both rats and dogs. Using this chemical series as a test set, models and mechanisms of toxicity were first explored by testing the utility of ex vivo rat lens explant cultures as a safety screen. This model overpredicted the cataractogenic potential of ZD-2138 due to appreciably high lens drug levels and was abandoned in favor of a mechanism-based screen. Perturbations in lens sterol content, from a decline in lathosterol content, preceded cataract formation suggesting CJ-12,918 inhibited lens cholesterol biosynthesis (LCB). A 2-day bioassay in rats using ex vivo LCB assessments showed that the level of LCB inhibition was correlated with incidence of cataract formation in animal studies by these 5-LO inhibitors. Thereafter, this 2-day bioassay was applied to other pharmaceutical programs (neuronal nitric oxide synthase, sorbitol dehydrogenase inhibitor, squalene synthetase inhibitor and stearoyl-CoA desaturase-1 inhibitors/D4 antagonists) that demonstrated cataract formation in either rats or dogs. LCB inhibition >40% was associated with a high incidence of cataract formation in both rats and dogs that was species specific. Bioassay sensitivity/specificity were further explored with positive (RGH-6201/ciglitazone/U18666A) and negative (tamoxifen/naphthalene/galactose) mechanistic controls. This body of work over two decades shows that LCB inhibition was a common mechanism of cataract formation by pharmaceutical agents and defined a level of inhibition >40% that was typically associated with causing cataracts in safety assessment studies typically ≥1 month.
Subject(s)
Cataract/chemically induced , Cholesterol/biosynthesis , Cholesterol/toxicity , Enzyme Inhibitors/toxicity , Lens, Crystalline/drug effects , Lens, Crystalline/metabolism , Thiazolidinediones/toxicity , Animals , Animals, Laboratory , Cataract/metabolism , Dogs , Female , Male , Pharmaceutical Preparations , Rats , Rats, Sprague-DawleyABSTRACT
The ability to predict ocular side effects of systemically delivered drugs is an important issue for pharmaceutical companies. Although animal models involving standard clinical ophthalmic examinations and postmortem microscopic examinations of eyes are still used to identify ocular issues, these methods are being supplemented with additional in silico, in vitro, and in vivo techniques to identify potential safety issues and assess risk. The addition of these tests to a development plan for a potential new drug provides the opportunity to save time and money by detecting ocular issues earlier in the program. This review summarizes a current practice for minimizing the potential for systemically administered, new medicines to cause adverse effects in the eye.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , Eye/drug effects , Toxicity Tests , Animals , Biological Assay , Cholesterol/biosynthesis , Diagnostic Techniques, Ophthalmological , Humans , Lens, Crystalline/metabolism , Structure-Activity RelationshipABSTRACT
PURPOSE: This study was conducted to develop and validate a dog colon model that predicts colon permeability in humans. METHODS: The following compounds were studied: Class 1 highly soluble (HS)/highly permeable (HP): aminophylline, propranolol, CP-409092; Class 2 LS/HP: nifedipine; trovafloxacin, sertraline; Class 3 HS/LP: azithromycin, atenolol, CP-331684, CP-424391; Class 4 LS/LP: CJ-13610. Administration to dogs was made 30 cm cranial to the anal sphincter with a lubricated Schott Model VFS-5 flexible endoscope. The bioavailability of the compound following the colon administration in dogs, relative to the same formulation administered orally (relative bioavailability), was determined. RESULTS: Except for atenolol, a small hydrophillic molecule, the relative bioavailability from administration to the colon of the dog correlated well with the following compound properties: high solubility and high, passive permeability > high solubility, low permeability > low solubility, high, passive permeability approximately low solubility, low permeability. CONCLUSION: The dog colon model is proposed as a surrogate for human intubation studies when the controlled release candidate falls in BCS Classes 2 (LS/HP), 3 (HS/LP), and 4 (LS/LP). However, no human intubation or dog colon studies are required for Class 1 (HS/HP), as these compounds are likely to be well absorbed from the colon.
