title: Potent human uric acid transporter 1 inhibitors: in vitro and in vivo metabolism and pharmacokinetic studies.
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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA. michael.wempe@ucdenver.edu
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wempe
authors.forename: Janet W
authors.initials: JW
authors.lastname: Lightner
authors.forename: Bettina
authors.initials: B
authors.lastname: Miller
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Iwen
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Rice
authors.forename: Shin
authors.initials: S
authors.lastname: Wakui
authors.forename: Naohiko
authors.initials: N
authors.lastname: Anzai
authors.forename: Promsuk
authors.initials: P
authors.lastname: Jutabha
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endou
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001553:Benzbromarone / Q000031:analogs & derivatives* / Q000378:metabolism*; D001682:Biological Availability; D006801:Humans; D008297:Male; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors*; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; D001553:Benzbromarone