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 DO - 10.1124/dmd.115.066944 SP - dmd.115.066944 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 - David A Rodrigues Y1 - 2015/01/01 UR - http://dmd.aspetjournals.org/content/early/2015/12/29/dmd.115.066944.abstract N2 - Although the metabolism and disposition of diclofenac (DF) has been studied extensively, information regarding the plasma levels of diclofenac 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 ± SD) and 0.84 ± 0.21 (area under the concentration-time curve mean ± SD). 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 2 only (OAT2, Km = 46.8 μM). In contrast, DF-AG was identified as a substrate of numerous OATs (Km = 8.6, 112, 207, 244 μM; OAT2, OAT3, OAT4, and OAT1, 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, 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 -