RT Journal Article
SR Electronic
T1 Formation of the Accumulative Human Metabolite and Human-Specific Glutathione Conjugate of Diclofenac in TK-NOG Chimeric Mice with Humanized Livers
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 309
OP 316
DO 10.1124/dmd.114.061689
VO 43
IS 3
A1 Kamimura, Hidetaka
A1 Ito, Satoshi
A1 Nozawa, Kohei
A1 Nakamura, Shota
A1 Chijiwa, Hiroyuki
A1 Nagatsuka, Shin-ichiro
A1 Kuronuma, Miyuki
A1 Ohnishi, Yasuyuki
A1 Suemizu, Hiroshi
A1 Ninomiya, Shin-ichi
YR 2015
UL http://dmd.aspetjournals.org/content/43/3/309.abstract
AB 3′-Hydroxy-4′-methoxydiclofenac (VI) is a human-specific metabolite known to accumulate in the plasma of patients after repeated administration of diclofenac sodium. Diclofenac also produces glutathione-conjugated metabolites, some of which are human-specific. In the present study, we investigated whether these metabolites could be generated in humanized chimeric mice produced from TK-NOG mice. After a single oral administration of diclofenac to humanized mice, the unchanged drug in plasma peaked at 0.25 hour and then declined with a half-life (t1/2) of 2.4 hours. 4′-Hydroxydiclofenac (II) and 3′-hydroxydiclofenac also peaked at 0.25 hour and were undetectable within 24 hours. However, VI peaked at 8 hours and declined with a t1/2 of 13 hours. When diclofenac was given once per day, peak and trough levels of VI reached plateau within 3 days. Studies with administration of II suggested VI was generated via II as an intermediate. Among six reported glutathione-conjugated metabolites of diclofenac, M1 (5-hydroxy-4-(glutathion-S-yl)diclofenac) to M6 (2′-(glutathion-S-yl)monoclofenac), we found three dichlorinated conjugates [M1, M2 (4′-hydroxy-3′-(glutathion-S-yl)diclofenac), and M3 (5-hydroxy-6-(glutathion-S-yl)diclofenac)], and a single monochlorinated conjugate [M4 (2′-hydroxy-3′-(glutathion-S-yl)monoclofenac) or M5 (4′-hydroxy-2′-(glutathion-S-yl)monoclofenac)], in the bile of humanized chimeric mice. M4 and M5 are positional isomers and have been previously reported as human-specific in vitro metabolites likely generated via arene oxide and quinone imine–type intermediates, respectively. The biliary monochlorinated metabolite exhibited the same mass spectrum as those of M4 and M5, and we discuss whether this conjugate corresponded to M4 or M5. Overall, humanized TK-NOG chimeric mice were considered to be a functional tool for the study of drug metabolism of diclofenac in humans.