RT Journal Article
SR Electronic
T1 Impact on Creatinine Renal Clearance by the Interplay of Multiple Renal Transporters: A Case Study with INCB039110
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 485
OP 489
DO 10.1124/dmd.114.060673
VO 43
IS 4
A1 Zhang, Yan
A1 Warren, Mark S.
A1 Zhang, Xuexiang
A1 Diamond, Sharon
A1 Williams, Bill
A1 Punwani, Naresh
A1 Huang, Jane
A1 Huang, Yong
A1 Yeleswaram, Swamy
YR 2015
UL http://dmd.aspetjournals.org/content/43/4/485.abstract
AB Serum creatinine is commonly used as a marker of renal function, but increases in serum creatinine might not represent changes in glomerular filtration rate (GFR). INCB039110 (2-(3-(4-(7H-pyrrolo[2,3-day]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile) is an inhibitor of the Janus kinases (JAKs) with selectivity for JAK1. In a phase 1 study, a modest and reversible increase in serum creatinine was observed after treatment with INCB039110. However, a dedicated renal function study with INCB039110, assessed by iohexol plasma clearance, conducted in healthy volunteers indicated no change in GFR. In vitro studies were therefore conducted to investigate the interaction of INCB039110 with five transporters that are likely involved in the renal clearance of creatinine. Cell systems expressing individual or multiple transporters were used, including a novel quintuple-transporter model OAT2/OCT2/OCT3/MATE1/MATE2-K. INCB039110 potently inhibited OCT2-mediated uptake of creatinine as well as MATE1-/MATE2-K-mediated efflux of creatinine. Given the interactions of INCB039110 with multiple transporters affecting creatinine uptake and efflux, an integrated system expressing all five transporters was sought; in that system, INCB039110 caused a dose-dependent decrease in transcellular transport of creatinine with weaker net inhibition compared with the effects on individual transporters. In summary, a molecular mechanism for the increase in serum creatinine by INCB039110 has been established. These studies also underline the limitations of using serum creatinine as a marker of renal function.