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1. PLoS One. 2012;7(2):e30456. Epub 2012 Feb 10.

Extra-Renal Elimination of Uric Acid via Intestinal Efflux Transporter
BCRP/ABCG2.

Hosomi A, Nakanishi T, Fujita T, Tamai I.

Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmacy,
Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University,
Kanazawa, Japan.

Urinary excretion accounts for two-thirds of total elimination of uric acid and
the remainder is excreted in feces. However, the mechanism of extra-renal
elimination is poorly understood. In the present study, we aimed to clarify the
mechanism and the extent of elimination of uric acid through liver and intestine
using oxonate-treated rats and Caco-2 cells as a model of human intestinal
epithelium. In oxonate-treated rats, significant amounts of externally
administered and endogenous uric acid were recovered in the intestinal lumen,
while biliary excretion was minimal. Accordingly, direct intestinal secretion was
thought to be a substantial contributor to extra-renal elimination of uric acid.
Since human efflux transporter BCRP/ABCG2 accepts uric acid as a substrate and
genetic polymorphism causing a decrease of BCRP activity is known to be
associated with hyperuricemia and gout, the contribution of rBcrp to intestinal
secretion was examined. rBcrp was confirmed to transport uric acid in a membrane
vesicle study, and intestinal regional differences of expression of rBcrp mRNA
were well correlated with uric acid secretory activity into the intestinal lumen.
Bcrp1 knockout mice exhibited significantly decreased intestinal secretion and an
increased plasma concentration of uric acid. Furthermore, a Bcrp inhibitor,
elacridar, caused a decrease of intestinal secretion of uric acid. In Caco-2
cells, uric acid showed a polarized flux from the basolateral to apical side, and
this flux was almost abolished in the presence of elacridar. These results
demonstrate that BCRP contributes at least in part to the intestinal excretion of
uric acid as extra-renal elimination pathway in humans and rats.

PMID: 22348008 [PubMed - in process]