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

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

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Acknowledgements

Authors would like to sincerely thank Simulation Plus (Lancaster, USA) for providing the academic license of Gastroplus and ADMET predictorTM to our institute, NIPER, SAS Nagar.

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Author notes

  1. Mayur K. Ladumor

    Present address: Department of Pharmaceutics, University of Washington, Seattle, WA, 99202, USA

Authors and Affiliations

  1. Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S Nagar, 160062, Punjab, India

    Ankit Balhara, Mayur K. Ladumor & Saranjit Singh

  2. Aurigene Discovery Technologies Ltd., Electronics City Phase II, Bengaluru, 560100, Karnataka, India

    Rakesh P. Nankar, Samiulla Dodheri Syed & Sanjeev Giri

  3. Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA

    Bhagwat Prasad

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Balhara, A., Ladumor, M.K., Nankar, R.P. et al. Exploration of the Plausible Mechanism of Ethambutol Induced Ocular Toxicity by Using Proteomics Informed Physiologically Based Pharmacokinetic (PBPK) Modeling. Pharm Res 39, 677–689 (2022). https://doi.org/10.1007/s11095-022-03227-9

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