Exploration of the Plausible Mechanism of Ethambutol Induced Ocular Toxicity by Using Proteomics Informed Physiologically Based Pharmacokinetic (PBPK) Modeling

Ethambutol (EMB) is a first-line anti-tubercular drug that is known to cause optic neuropathy. The exact mechanism of its eye toxicity is unknown; however, proposition is metal chelating effect of both EMB and its metabolite 2,2'-(ethylenediamino)-dibutyric acid (EDBA). The latter is formed by sequential metabolism of EMB by alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs). The purpose of this study was to predict the levels of drug and EDBA in the eye using physiologically based pharmacokinetic (PBPK) modeling.The PBPK model of EMB was developed using GastroPlus. The intrinsic hepatic clearance of ALDH, calculated by the model, was scaled down using proteomics data to estimate the rate of formation of EDBA in the eye. Additionally, the comparative permeability of EMB and EDBA was assessed by employing in silico and in vitro approaches. The rate of formation of EDBA in the eye and permeability data were then incorporated in a compartmental model to predict the ocular levels of EMB and EDBA.The simulation results of compartmental model highlighted that there was an on-site formation of EDBA upon metabolism of EMB. Furthermore, in silico and in vitro studies revealed that EDBA possessed much lower permeability than EMB. These observations meant that once EDBA was formed in the eye, it was not permeated out and hence achieved higher ocular concentration.The on-site formation of EDBA in the eye, its higher local concentration due to lower ocular clearance and its pre-known characteristic to chelate metal species better explains the ocular toxicity shown by EMB.