@article {Zhang320, author = {Yueping Zhang and Yong-Hae Han and Siva Prasad Putluru and Murali Krishna Matta and Prashant Kole and Sandhya Mandlekar and Michael T. Furlong and Tongtong Liu and Ramaswamy A. Iyer and Punit Marathe and Zheng Yang and Yurong Lai and A. David Rodrigues}, title = {Diclofenac and Its Acyl Glucuronide: Determination of In Vivo Exposure in Human Subjects and Characterization as Human Drug Transporter Substrates In Vitro}, volume = {44}, number = {3}, pages = {320--328}, year = {2016}, doi = {10.1124/dmd.115.066944}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Although the metabolism and disposition of diclofenac (DF) has been studied extensively, information regarding the plasma levels of its acyl-β-d-glucuronide (DF-AG), a major metabolite, in human subjects is limited. Therefore, DF-AG concentrations were determined in plasma (acidified blood derived) of six healthy volunteers following a single oral DF dose (50 mg). Levels of DF-AG in plasma were high, as reflected by a DF-AG/DF ratio of 0.62 {\textpm} 0.21 (Cmax mean {\textpm} S.D.) and 0.84 {\textpm} 0.21 (area under the concentration-time curve mean {\textpm} S.D.). Both DF and DF-AG were also studied as substrates of different human drug transporters in vitro. DF was identified as a substrate of organic anion transporter (OAT) 2 only (Km = 46.8 {\textmu}M). In contrast, DF-AG was identified as a substrate of numerous OATs (Km = 8.6, 60.2, 103.9, and 112 {\textmu}M for OAT2, OAT1, OAT4, and OAT3, respectively), two organic anion{\textendash}transporting polypeptides (OATP1B1, Km = 34 {\textmu}M; OATP2B1, Km = 105 {\textmu}M), breast cancer resistance protein (Km = 152 {\textmu}M), and two multidrug resistance proteins (MRP2, Km = 145 {\textmu}M; MRP3, Km = 196 {\textmu}M). It is concluded that the disposition of DF-AG, once formed, can be mediated by various candidate transporters known to be expressed in the kidney (basolateral, OAT1, OAT2, and OAT3; apical, MRP2, BCRP, and OAT4) and liver (canalicular, MRP2 and BCRP; basolateral, OATP1B1, OATP2B1, OAT2, and MRP3). DF-AG is unstable in plasma and undergoes conversion to parent DF. Therefore, caution is warranted when assessing renal and hepatic transporter-mediated drug-drug interactions with DF and DF-AG.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/44/3/320}, eprint = {https://dmd.aspetjournals.org/content/44/3/320.full.pdf}, journal = {Drug Metabolism and Disposition} }