RT Journal Article
SR Electronic
T1 CHARACTERIZATION OF STEREOSELECTIVE METABOLISM, INHIBITORY EFFECT ON URIC ACID UPTAKE TRANSPORTERS, AND PHARMACOKINETICS OFLESINURAD ATROPISOMERS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.118.080549
DO 10.1124/dmd.118.080549
A1 Chun Yang
A1 Dongmei Zhou
A1 Zancong Shen
A1 David M Wilson
A1 Matthew Renner
A1 Jeffrey N Miner
A1 Jean-Luc Girardet
A1 Caroline A Lee
YR 2018
UL http://dmd.aspetjournals.org/content/early/2018/11/13/dmd.118.080549.abstract
AB Lesinurad (Zurampic), a selective inhibitor of uric acid reabsorption transporters used clinically for the treatment of gout, is a racemate of two atropisomers. The objectives were to evaluate the stereoselectivity of the metabolism, the inhibitory potency on (URAT1 and OAT4), and the clinical pharmacokinetics of the two atropisomers. In vitro incubations with human liver microsomes (HLM) or recombinant CYP2C9 and CYP3A4 and hydrolases were carried out to characterize metabolic stereoselectivity for the formation of two major metabolites in human, M3 (hydroxylation) and M4 (a dihydrodiol metabolite). Formation of M3 and M4 were catalyzed predominately by CYP2C9. M4 was formed via an epoxide intermediate, M3c, which was subsequently hydrolyzed by microsomal epoxide hydrolase to M4. The formation of M3 with atropisomer 1 in HLM was approximately twice that formed with atropisomer 2, whereas M4 formation with atropisomer 1 was 8- to 12-fold greater than that with atropisomer 2. There were no significant differences in the plasma protein binding among lesinurad and the two atropisomers. Following oral administration of 400 mg lesinurad once daily for 14 days to healthy humans, the systemic exposure (steady state Cmax,SS and AUCtau) of atropisomer 1 was approximately 30% lower than that of atropisomer 2, whereas renal clearance was similar. In vitro cell-based assays using HEK293 cells stably expressing URAT1 and OAT4 demonstrated that atropisomer 2 was approximately 4-fold more potent against URAT1 than atropisomer 1 and equally active against OAT4. In conclusion, lesinurad atropisomers showed stereoselectivity in clinical pharmacokinetics, metabolism, and inhibitory potency against URAT1.