TY - JOUR T1 - Diclofenac and Its Acyl Glucuronide: Determination of In Vivo Exposure in Human Subjects and Characterization as Human Drug Transporter Substrates In Vitro JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 320 LP - 328 DO - 10.1124/dmd.115.066944 VL - 44 IS - 3 AU - Yueping Zhang AU - Yong-Hae Han AU - Siva Prasad Putluru AU - Murali Krishna Matta AU - Prashant Kole AU - Sandhya Mandlekar AU - Michael T. Furlong AU - Tongtong Liu AU - Ramaswamy A. Iyer AU - Punit Marathe AU - Zheng Yang AU - Yurong Lai AU - A. David Rodrigues Y1 - 2016/03/01 UR - http://dmd.aspetjournals.org/content/44/3/320.abstract N2 - 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 ± 0.21 (Cmax mean ± S.D.) and 0.84 ± 0.21 (area under the concentration-time curve mean ± 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 µM). In contrast, DF-AG was identified as a substrate of numerous OATs (Km = 8.6, 60.2, 103.9, and 112 µM for OAT2, OAT1, OAT4, and OAT3, respectively), two organic anion–transporting polypeptides (OATP1B1, Km = 34 µM; OATP2B1, Km = 105 µM), breast cancer resistance protein (Km = 152 µM), and two multidrug resistance proteins (MRP2, Km = 145 µM; MRP3, Km = 196 µM). 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. ER -