title: Diclofenac and Its Acyl Glucuronide: Determination of In Vivo Exposure in Human Subjects and Characterization as Human Drug Transporter Substrates In Vitro.
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 ± 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.
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Yueping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Yong-Hae
authors.initials: YH
authors.lastname: Han
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Siva Prasad
authors.initials: SP
authors.lastname: Putluru
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Murali Krishna
authors.initials: MK
authors.lastname: Matta
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Prashant
authors.initials: P
authors.lastname: Kole
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Mandlekar
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Furlong
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Tongtong
authors.initials: T
authors.lastname: Liu
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Ramaswamy A
authors.initials: RA
authors.lastname: Iyer
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey yurong.lai@bms.com.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: A David
authors.initials: AD
authors.lastname: Rodrigues
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000328:Adult; D001692:Biological Transport / Q000502:physiology*; D004008:Diclofenac / Q000378:metabolism*; D004347:Drug Interactions / Q000502:physiology; D020719:Glucuronides / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D055815:Young Adult
chemical_list: C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D020719:Glucuronides; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D004008:Diclofenac