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      Potent human uric acid transporter 1 inhibitors: in vitro and in vivo metabolism and pharmacokinetic studies

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          Abstract

          Human uric acid transporter 1 (hURAT1; SLC22A12) is a very important urate anion exchanger. Elevated urate levels are known to play a pivotal role in cardiovascular diseases, chronic renal disease, diabetes, and hypertension. Therefore, the development of potent uric acid transport inhibitors may lead to novel therapeutic agents to combat these human diseases. The current study investigates small molecular weight compounds and their ability to inhibit 14C-urate uptake in oocytes expressing hURAT1. Using the most promising drug candidates generated from our structure–activity relationship findings, we subsequently conducted in vitro hepatic metabolism and pharmacokinetic (PK) studies in male Sprague-Dawley rats. Compounds were incubated with rat liver microsomes containing cofactors nicotinamide adenine dinucleotide phosphate and uridine 5′-diphosphoglucuronic acid. In vitro metabolism and PK samples were analyzed using liquid chromatography/mass spectrometry-mass spectrometry methods. Independently, six different inhibitors were orally (capsule dosing) or intravenously (orbital sinus) administered to fasting male Sprague-Dawley rats. Blood samples were collected and analyzed; these data were used to compare in vitro and in vivo metabolism and to compute noncompartmental model PK values. Mono-oxidation (Phase I) and glucuronidation (Phase II) pathways were observed in vitro and in vivo. The in vitro data were used to compute hepatic intrinsic clearance, and the in vivo data were used to compute peak blood concentration, time after administration to achieve peak blood concentration, area under the curve, and orally absorbed fraction. The experimental data provide additional insight into the hURAT1 inhibitor structure–activity relationship and in vitro–in vivo correlation. Furthermore, the results illustrate that one may successfully prepare potent inhibitors that exhibit moderate to good oral bioavailability.

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          Author and article information

          Journal
          Drug Des Devel Ther
          Drug Des Devel Ther
          Drug Design, Development and Therapy
          Dove Medical Press
          1177-8881
          2012
          08 November 2012
          : 6
          : 323-339
          Affiliations
          [1 ]Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
          [2 ]Department of Pharmacology, East Tennessee State University, Johnson City, TN, USA
          [3 ]Department of Toxicology, Azabu University School of Veterinary Medicine, Chuo Sagamihara, Kanagawa, Japan
          [4 ]Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Mibu, Shimotsuga, Tochigi, Japan
          [5 ]Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan
          Author notes
          Correspondence: Michael F Wempe, Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Anschutz Medical Campus, C238; 12850 E Montview Blvd, Aurora, CO 80045, USA, Tel +1 303 724 8982, Fax +1 303 724 7266, Email michael.wempe@ 123456ucdenver.edu
          Article
          dddt-6-323
          10.2147/DDDT.S35805
          3496402
          23152669
          © 2012 Wempe et al, publisher and licensee Dove Medical Press Ltd.

          This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

          Categories
          Original Research

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