Diclofenac and Its Acyl Glucuronide: Determination of in Vivo Exposure in Human Subjects and Characterization as Human Drug Transporter Substrates in Vitro

Drug Metabolism and Disposition

Volumn 44, Issue 3, 2016, Pages 320-328

  Zhang, Yueping ^a   Han, Yong Hae ^a,b   Putluru, Siva Prasad ^a   Matta, Murali Krishna ^a   Kole, Prashant ^a   Mandlekar, Sandhya ^a   Furlong, Michael T ^a,c   Liu, Tongtong ^a   Iyer, Ramaswamy A ^a   Marathe, Punit ^a   Yang, Zheng ^a   Lai, Yurong ^a   Rodrigues, A David ^a,d  

^a BRISTOL MYERS SQUIBB   (United States)

^b Enzychem Lifesciences Corp   (South Korea)

^c FORUM Pharmaceuticals   (United States)

^d PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACYL BETA GLUCURONIDE; BREAST CANCER RESISTANCE PROTEIN; DICLOFENAC; DRUG METABOLITE; GLUCURONIDE; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 2; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 3; ORGANIC ANION TRANSPORTER 1; ORGANIC ANION TRANSPORTER 2; ORGANIC ANION TRANSPORTER 3; ORGANIC ANION TRANSPORTER 4; ORGANIC ANION TRANSPORTER B; SOLUTE CARRIER ORGANIC ANION TRANSPORTER 1B1; UNCLASSIFIED DRUG; ABC TRANSPORTER; ABCG2 PROTEIN, HUMAN; MULTIDRUG RESISTANCE PROTEIN; ORGANIC ANION TRANSPORTER; TUMOR PROTEIN;

ADULT; ARTICLE; DRUG BLOOD LEVEL; DRUG EXPOSURE; DRUG METABOLISM; HUMAN; HUMAN CELL; HUMAN EXPERIMENT; IN VITRO STUDY; KIDNEY; LIVER; MALE; MAXIMUM PLASMA CONCENTRATION; NORMAL HUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; SINGLE DRUG DOSE; DRUG INTERACTION; METABOLISM; PHYSIOLOGY; TRANSPORT AT THE CELLULAR LEVEL; YOUNG ADULT;

ADULT; ATP BINDING CASSETTE TRANSPORTER, SUB-FAMILY G, MEMBER 2; ATP-BINDING CASSETTE TRANSPORTERS; BIOLOGICAL TRANSPORT; DICLOFENAC; DRUG INTERACTIONS; GLUCURONIDES; HUMANS; KIDNEY; LIVER; MALE; NEOPLASM PROTEINS; ORGANIC ANION TRANSPORTERS; ORGANIC ANION TRANSPORTERS, SODIUM-INDEPENDENT; P-GLYCOPROTEINS; YOUNG ADULT;

EID: 84958967937     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.115.066944     Document Type: Article

References (33)

1. Amundsen R, Christensen H, Zabihyan B, and Asberg A (2010) Cyclosporine A, but not tacrolimus, shows relevant inhibition of organic anion-transporting protein 1B1-mediated transport of atorvastatin. Drug Metab Dispos 38:1499-1504.
2. Asberg A, Hartmann A, Fjeldså E, and Holdaas H (2001) Atorvastatin improves endothelial function in renal-transplant recipients. Nephrol Dial Transplant 16:1920-1924.
3. Chang JH, Plise E, Cheong J, Ho Q, and Lin M (2013) Evaluating the in vitro inhibition of UGT1A1, OATP1B1, OATP1B3, MRP2, and BSEP in predicting drug-induced hyperbilirubinemia. Mol Pharm 10:3067-3075.
4. Davies NM and Anderson KE (1997) Clinical pharmacokinetics of diclofenac. Therapeutic insights and pitfalls. Clin Pharmacokinet 33:184-213.
5. Ebner T, Heinzel G, Prox A, Beschke K, and Wachsmuth H (1999) Disposition and chemical stability of telmisartan 1-O-acylglucuronide. Drug Metab Dispos 27:1143-1149.
6. Hammond TG, Meng X, Jenkins RE, Maggs JL, Castelazo AS, Regan SL, Bennett SN, Earnshaw CJ, Aithal GP, and Pande I, et al. (2014) Mass spectrometric characterization of circulating covalent protein adducts derived from a drug acyl glucuronide metabolite: Multiple albumin adductions in diclofenac patients. J Pharmacol Exp Ther 350:387-402.
7. Han YH, Busler D, Hong Y, Tian Y, Chen C, and Rodrigues AD (2010) Transporter studies with the 3-O-sulfate conjugate of 17alpha-ethinylestradiol: Assessment of human kidney drug transporters. Drug Metab Dispos 38:1064-1071.
8. Ho RH, Tirona RG, Leake BF, Glaeser H, Lee W, Lemke CJ, Wang Y, and Kim RB (2006) Drug and bile acid transporters in rosuvastatin hepatic uptake: Function, expression, and pharmacogenetics. Gastroenterology 130:1793-1806.
9. John VA (1979) The pharmacokinetics and metabolism of diclofenac sodium (Voltarol) in animals and man. Rheumatol Rehabil (Suppl 2):22-37.
10. Juvale K and Wiese M (2012) 4-Substituted-2-phenylquinazolines as inhibitors of BCRP. Bioorg Med Chem Lett 22:6766-6769.
11. Kendall MJ, Thornhill DP, and Willis JV (1979) Factors affecting the pharmacokinetics of diclofenac sodium (Voltarol). Rheumatol Rehabil (Suppl 2):38-46.
12. Kindla J, Müller F, Mieth M, Fromm MF, and König J (2011) Influence of non-steroidal antiinflammatory drugs on organic anion transporting polypeptide (OATP) 1B1-and OATP1B3-mediated drug transport. Drug Metab Dispos 39:1047-1053.
13. Kobayashi Y, Ohshiro N, Sakai R, Ohbayashi M, Kohyama N, and Yamamoto T (2005) Transport mechanism and substrate specificity of human organic anion transporter 2 (hOat2 [SLC22A7]). J Pharm Pharmacol 57:573-578.
14. Köck K, Ferslew BC, Netterberg I, Yang K, Urban TJ, Swaan PW, Stewart PW, and Brouwer KL (2014) Risk factors for development of cholestatic drug-induced liver injury: Inhibition of hepatic basolateral bile acid transporters multidrug resistance-associated proteins 3 and 4. Drug Metab Dispos 42:665-674.
15. Kovarik JM, Kurki P, Mueller E, Guerret M, Markert E, Alten R, Zeidler H, and Genth-Stolzenburg S (1996) Diclofenac combined with cyclosporine in treatment refractory rheumatoid arthritis: Longitudinal safety assessment and evidence of a pharmacokinetic/dynamic interaction. J Rheumatol 23:2033-2038.
16. Kumar S, Samuel K, Subramanian R, Braun MP, Stearns RA, Chiu SH, Evans DC, and Baillie TA (2002) Extrapolation of diclofenac clearance from in vitro microsomal metabolism data: Role of acyl glucuronidation and sequential oxidative metabolism of the acyl glucuronide. J Pharmacol Exp Ther 303:969-978.
17. Lagas JS, Sparidans RW, Wagenaar E, Beijnen JH, and Schinkel AH (2010) Hepatic clearance of reactive glucuronide metabolites of diclofenac in the mouse is dependent on multiple ATPbinding cassette efflux transporters. Mol Pharmacol 77:687-694.
18. Lagas JS, Van Der Kruijssen CM, Van De Wetering K, Beijnen JH, and Schinkel AH (2009) Transport of diclofenac by breast cancer resistance protein (ABCG2) and stimulation of multidrug resistance protein 2 (ABCC2)-mediated drug transport by diclofenac and benzbromarone. Drug Metab Dispos 37:129-136.
19. Lechner C, Reichel V, Moenning U, Reichel A, and Fricker G (2010) Development of a fluorescence-based assay for drug interactions with human Multidrug Resistance Related Protein (MRP2; ABCC2) in MDCKII-MRP2 membrane vesicles. Eur J Pharm Biopharm 75:284-290.
20. Mueller EA, Kovarik JM, Koelle EU, Merdjan H, Johnston A, and Hitzenberger G (1993) Pharmacokinetics of cyclosporine and multiple-dose diclofenac during coadministration. J Clin Pharmacol 33:936-943.
21. Peris-Ribera JE, Torres-Molina F, Garcia-Carbonell MC, Aristorena JC, and Pla-Delfina JM (1991) Pharmacokinetics and bioavailability of diclofenac in the rat. J Pharmacokinet Biopharm 19:647-665.
22. Riess W, Stierlin H, Degen P, Faigle JW, Gérardin A, Moppert J, Sallmann A, Schmid K, Schweizer A, and Sulc M, et al. (1978) Pharmacokinetics and metabolism of the antiinflammatory agent Voltaren. Scand J Rheumatol Suppl 22:17-29.
23. Rodrigues AD (2005) Impact of CYP2C9 genotype on pharmacokinetics: Are all cyclooxygenase inhibitors the same? Drug Metab Dispos 33:1567-1575.
24. Scialis RJ, Csanaky IL, Goedken MJ, and Manautou JE (2015) Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac. Drug Metab Dispos 43:944-950.
25. Seitz S and Boelsterli UA (1998) Diclofenac acyl glucuronide, a major biliary metabolite, is directly involved in small intestinal injury in rats. Gastroenterology 115:1476-1482.
26. Seitz S, Kretz-Rommel A, Oude Elferink RP, and Boelsterli UA (1998) Selective protein adduct formation of diclofenac glucuronide is critically dependent on the rat canalicular conjugate export pump (Mrp2). Chem Res Toxicol 11:513-519.
27. Shen H, Liu T, Morse BL, Zhao Y, Zhang Y, Qiu X, Chen C, Lewin AC, Wang XT, and Liu G, et al. (2015) Characterization of Organic Anion Transporter 2 (SLC22A7): A Highly Efficient Transporter for Creatinine and Species-Dependent Renal Tubular Expression. Drug Metab Dispos 43:984-993.
28. Stierlin H and Faigle JW (1979) Biotransformation of diclofenac sodium (Voltaren) in animals and in man. II. Quantitative determination of the unchanged drug and principal phenolic metabolites, in urine and bile. Xenobiotica 9:611-621.
29. Stierlin H, Faigle JW, Sallmann A, Küng W, Richter WJ, Kriemler HP, Alt KO, and Winkler T (1979) Biotransformation of diclofenac sodium (Voltaren) in animals and in man. I. Isolation and identification of principal metabolites. Xenobiotica 9:601-610.
30. Uwai Y, Motohashi H, Tsuji Y, Ueo H, Katsura T, and Inui K (2007) Interaction and transport characteristics of mycophenolic acid and its glucuronide via human organic anion transporters hOAT1 and hOAT3. Biochem Pharmacol 74:161-168.
31. Willis JV, Kendall MJ, Flinn RM, Thornhill DP, and Welling PG (1979) The pharmacokinetics of diclofenac sodium following intravenous and oral administration. Eur J Clin Pharmacol 16:405-410.
32. Xia CQ, Liu N, Miwa GT, and Gan LS (2007) Interactions of cyclosporin a with breast cancer resistance protein. Drug Metab Dispos 35:576-582.
33. Zhang D, Raghavan N, Wang L, Xue Y, Obermeier M, Chen S, Tao S, Zhang H, Cheng PT, and Li W, et al. (2011) Plasma stability-dependent circulation of acyl glucuronide metabolites in humans: How circulating metabolite profiles of muraglitazar and peliglitazar can lead to misleading risk assessment. Drug Metab Dispos 39:123-131.