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Conversion of Olmesartan to Olmesartan Medoxomil, A Prodrug that Improves Intestinal Absorption, Confers Substrate Recognition by OATP2B1

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Abstract

Purpose

Olmesartan medoxomil (olmesartan-MX), an ester-type prodrug of the angiotensin II receptor blocker (ARB) olmesartan, is predominantly anionic at intestinal pH. Human organic anion transporting polypeptide 2B1 (OATP2B1) is expressed in the small intestine and is involved in the absorption of various acidic drugs. This study was designed to test the hypothesis that OATP2B1-mediated uptake contributes to the enhanced intestinal absorption of olmesartan-MX, even though olmesartan itself is not a substrate of OATP2B1.

Methods

Tetracycline-inducible human OATP2B1- and rat Oatp2b1-overexpressing HEK 293 cell lines (hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293, respectively) were established to characterize OATP2B1-mediated uptake. Rat jejunal permeability was measured using Ussing chambers. ARBs were quantified by liquid chromatography-tandem mass spectrometry.

Results

Significant olmesartan-MX uptake was observed in hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293 cells, whereas olmesartan uptake was undetectable or much lower than olmesartan-MX uptake, respectively. Furthermore, olmesartan-MX exhibited several-fold higher uptake in Caco-2 cells and greater permeability in rat jejunum compared to olmesartan. Olmesartan-MX uptake in hOATP2B1/T-REx-293 cells and in Caco-2 cells was significantly decreased by OATP2B1 substrates/inhibitors such as 1 mM estrone-3-sulfate, 100 µM rifamycin SV, and 100 µM fluvastatin. Rat Oatp2b1-mediated uptake and rat jejunal permeability of olmesartan-MX were significantly decreased by 50 µM naringin, an OATP2B1 inhibitor. Oral administration of olmesartan-MX with 50 µM naringin to rats significantly reduced the area under the plasma concentration–time curve of olmesartan to 76.9%.

Conclusion

Olmesartan-MX is a substrate for OATP2B1, and the naringin-sensitive transport system contributes to the improved intestinal absorption of olmesartan-MX compared with its parent drug, olmesartan.

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Abbreviations

candesartan-CX:

Candesartan cilexetil

OATP/Oatp:

Organic anion transporting polypeptide

olmesartan-MX:

Olmesartan medoxomil

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Funding

This work was supported in part by JSPS KAKENHI grant numbers 18K06900, 21H02651, and 22K06750, as well as by JST SPRING, Grant Number JPMJSP2123 and AMED CREST, Grant Number JP20gm1310009. It was also funded in part by the Keio Gijuku Academic Development Fund, the Fukuzawa Memorial Fund, the Hoansha Foundation, and the Mochida Memorial Foundation for Medical and Pharmaceutical Research.

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  1. Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku 105-8512, Tokyo, Japan

    Naomi Fukazawa, Tomohiro Nishimura, Keisuke Orii, Saki Noguchi & Masatoshi Tomi

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  1. Naomi Fukazawa
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Fukazawa, N., Nishimura, T., Orii, K. et al. Conversion of Olmesartan to Olmesartan Medoxomil, A Prodrug that Improves Intestinal Absorption, Confers Substrate Recognition by OATP2B1. Pharm Res (2024). https://doi.org/10.1007/s11095-024-03687-1

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