Although the metabolism and disposition of diclofenac (DF) has been studied extensively, information regarding the plasma levels of its acyl-b-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 6 0.21 (C max mean 6 S.D.) and 0.84 6 0.21 (area under the concentration-time curve mean 6 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 (K m = 46.8 mM). In contrast, DF-AG was identified as a substrate of numerous OATs (K m = 8.6, 60.2, 103.9, and 112 mM for OAT2, OAT1, OAT4, and OAT3, respectively), two organic aniontransporting polypeptides (OATP1B1, K m = 34 mM; OATP2B1, K m = 105 mM), breast cancer resistance protein (K m = 152 mM), and two multidrug resistance proteins (MRP2, K m = 145 mM; MRP3, K m = 196 mM). 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.
