1. Academic Validation
  2. 6-Hydroxyindole is an endogenous long-lasting OATP1B1 inhibitor elevated in renal failure patients

6-Hydroxyindole is an endogenous long-lasting OATP1B1 inhibitor elevated in renal failure patients

  • Drug Metab Pharmacokinet. 2020 Dec;35(6):555-562. doi: 10.1016/j.dmpk.2020.09.001.
Yusuke Masuo 1 Ken-Ichi Fujita 2 Kenji Mishiro 1 Natsumi Seba 1 Tatsuya Kogi 1 Hidenori Okumura 1 Natsumi Matsumoto 2 Munetaka Kunishima 1 Yukio Kato 3
Affiliations

Affiliations

  • 1 Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
  • 2 Division of Cancer Genome and Pharmacotherapy, Department of Clinical Pharmacy, Showa University School of Pharmacy, Tokyo, Japan.
  • 3 Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan. Electronic address: ykato@p.kanazawa-u.ac.jp.
Abstract

The hepatic uptake transporter organic anion transporting polypeptide (OATP) 1B1 is inhibited by some uremic toxins; however, direct inhibition can only partially explain the delayed systemic elimination of substrate drugs in renal failure patients. This study aimed to examine the long-lasting inhibition of OATP1B1 by uremic toxins and their metabolites. Preincubation of HEK293/OATP1B1 cells with 21 uremic toxins resulted in almost no change in the uptake of a typical substrate [3H]estrone-3-sulfate (E1S), although some directly inhibited [3H]E1S uptake. In contrast, preincubation with an indole metabolite, 6-hydroxyindole, reduced [3H]E1S uptake, even after the inhibitor was washed out before [3H]E1S incubation. Such long-lasting inhibition by 6-hydroxyindole was time-dependent and recovered after a 3-h incubation without 6-hydroxyindole. Preincubation with 6-hydroxyindole increased the Km for [3H]E1S uptake with minimal change in Vmax. This was compatible with no change in the cell-surface expression of OATP1B1, as assessed by a biotinylation assay. Preincubation with 6-hydroxyindole reduced [3H]E1S uptake in human hepatocytes without changes in OATP1B1 mRNA. Plasma concentration of 6-hydroxyindole in renal failure patients increased as renal function decreased, but might be insufficient to exhibit potent OATP1B1 inhibition. In conclusion, 6-hydroxyindole is an endogenous long-lasting OATP1B1 inhibitor with elevated plasma concentrations in renal failure patients.

Keywords

Hydroxyindole; Long-lasting inhibition; Organic anion transporting polypeptide; Transporters; Uremic toxins.

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