06/01/2021 - Role of transporters in drug toxicity
Md Masud Parvez, Abdul Basit, Parth B. Jariwala, Zsuzsanna Gáborik, Emese Kis, Scott Heyward, Matthew R. Redinbo and Bhagwat Prasad
Drug Metabolism and Disposition June 1, 2021, DMD-AR-2021-000476; DOI: https://doi.org/10.1124/dmd.121.000476
Anticancer drug, irinotecan shows serious dose-limiting gastrointestinal toxicity regardless of intravenous dosing. Although enzymes and transporters involved in irinotecan disposition are known, quantitative contributions of these mechanisms in complex in vivo disposition of irinotecan are poorly understood. We explained intestinal disposition and toxicity of irinotecan by integrating i) in vitro metabolism and transport data of rinotecan and its metabolites, ii) ex vivo gut microbial activation of the toxic metabolite, SN-38, and iii) the tissue protein abundance data of enzymes and transporters relevant to irinotecan and its metabolites. Integration of in vitro kinetics data with the tissue enzyme and transporter abundance predicted that carboxylesterase (CES) mediated hydrolysis of irinotecan is the rate-limiting process in the liver, where the toxic metabolite formed is rapidly deactivated by glucuronidation. In contrast, the poor SN-38 glucuronidation rate as compared to its efficient formation by CES2 in the enterocytes is the key mechanism of the intestinal accumulation of the toxic metabolite. The biliary efflux and OATP2B1 mediated enterocyte uptake can also synergize buildup of SN-38 in the enterocytes, whereas intestinal P-glycoprotein (P-gp) likely facilitates SN38 detoxification in the enterocytes. The higher SN-38 concentration in the intestine can be further nourished by β-d-glucuronidases. Understanding the quantitative significance of the key metabolism and transport processes of irinotecan and its metabolites can be leveraged to alleviate its intestinal side effects. Further, the proteomics-informed quantitative approach to determine intracellular disposition can be extended to determine susceptibility of cancer cells over normal cells for precision irinotecan therapy.
Significance Statement This work provides a deeper insight into the quantitative relevance of irinotecan hydrolysis (activation), conjugation (deactivation), and deconjugation (reactivation) by human or gut microbial enzymes or transporters. The results of this study explain the characteristic intestinal exposure and toxicity of irinotecan. Quantitative tissue-specific in vitro to in vivo extrapolation approach presented in this study can be extended to cancer cells.open_in_new Read the Source