Advertisement

Archives of Toxicology

, Volume 92, Issue 6, pp 1953–1967 | Cite as

The pharmacokinetics and metabolism of diclofenac in chimeric humanized and murinized FRG mice

  • C. E. Wilson
  • A. P. Dickie
  • K. Schreiter
  • R. Wehr
  • E. M. Wilson
  • J. Bial
  • N. Scheer
  • I. D. Wilson
  • R. J. Riley
Toxicokinetics and Metabolism
  • 205 Downloads

Abstract

The pharmacokinetics of diclofenac were investigated following single oral doses of 10 mg/kg to chimeric liver humanized and murinized FRG and C57BL/6 mice. In addition, the metabolism and excretion were investigated in chimeric liver humanized and murinized FRG mice. Diclofenac reached maximum blood concentrations of 2.43 ± 0.9 µg/mL (n = 3) at 0.25 h post-dose with an AUCinf of 3.67 µg h/mL and an effective half-life of 0.86 h (n = 2). In the murinized animals, maximum blood concentrations were determined as 3.86 ± 2.31 µg/mL at 0.25 h post-dose with an AUCinf of 4.94 ± 2.93 µg h/mL and a half-life of 0.52 ± 0.03 h (n = 3). In C57BL/6J mice, mean peak blood concentrations of 2.31 ± 0.53 µg/mL were seen 0.25 h post-dose with a mean AUCinf of 2.10 ± 0.49 µg h/mL and a half-life of 0.51 ± 0.49 h (n = 3). Analysis of blood indicated only trace quantities of drug-related material in chimeric humanized and murinized FRG mice. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles in humanized mice were different to those of both murinized and wild-type animals, e.g., a higher proportion of the dose was detected in the form of acyl glucuronide metabolites and much reduced amounts as taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57BL/6J mice and humans revealed a greater, though not complete, match between chimeric humanized mice and humans, such that the liver humanized FRG model may represent a model for assessing the biotransformation of such compounds in humans.

Keywords

Liver Humanized mice Metabolism Pharmacokinetics Reactive metabolites 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

204_2018_2212_MOESM1_ESM.docx (1.4 mb)
Supplementary material 1 (DOCX 1441 KB)

References

  1. Aithal GP, Ramsay L, Daly AK, Sonchit N, Leathart JB, Alexander G, Kenna JG, Caldwell J, Day CP (2004) Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity. Hepatology 39:1430–1440CrossRefPubMedGoogle Scholar
  2. Boelsterli UA (2003) Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity. Toxicol Appl Pharmacol 192:307322CrossRefGoogle Scholar
  3. Boelsterli UA, Lim PL (2007) Mitochondrial abnormalities—a link to idiosyncratic drug hepatotoxicity? Toxicol Appl Pharmacol 220:92107CrossRefGoogle Scholar
  4. Bort R, Ponsoda X, Jover R, Gómez-Lechón MJ, Castell JV (1999) Diclofenac toxicity to hepatocytes: a role for drug metabolism in cell toxicity. J Pharmacol Exp Ther 288(1):65–72PubMedGoogle Scholar
  5. Daly AK, Aithal GP, Leathart JB, Swainsbury RA, Dang TS, Day CP (2007) Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 132:272281CrossRefGoogle Scholar
  6. de Abajo FJ, Montero D, Madurga M, GarcÃa RodrÃguez LA (2004) Acute and clinically relevant drug-induced liver injury: a population based case–control study. Br J Clin Pharmacol 58:71–80CrossRefPubMedPubMedCentralGoogle Scholar
  7. Degen PH, Dieterle W, Schneider W, Theobald W, Sinterhauf U (1988) Pharmacokinetics of diclofenac and five metabolites after single doses in healthy volunteers and after repeated doses in patients. Xenobiotica 18:144955CrossRefGoogle Scholar
  8. Dickie AP, Wilson CE, Schreiter K, Wehr R, Wilson EM, Bial J, Scheer D, Wilson ID, Riley RJ (2017) The pharmacokinetics and metabolism of lumiracoxib in chimeric humanized and murinized FRG mice. Biochem Pharmacol 135:139–150CrossRefPubMedGoogle Scholar
  9. Faigle JW, Böttcher I, Godbillon J, Kriemler HP, Schlumpf E, Schneider W, Schweizer A, Stierlin H, Winkler T (1988) A new metabolite of diclofenac sodium in human plasma. Xenobiotica 18:1191–1197CrossRefPubMedGoogle Scholar
  10. Gomez-Lechon MJ, Ponsoda X, O’Connor E, Donato T, Castell JV (2003a) Diclofenac induces apoptosis in hepatocytes. Toxicol In Vitro 17:675680CrossRefGoogle Scholar
  11. Gomez-Lechon MJ, Ponsoda X, O’Connor E, Donato T, Castell JV, Jover R (2003b) Diclofenac induces apoptosis in hepatocytes by alteration of mitochondrial function and generation of ROS. Biochem Pharmacol 66:21552167CrossRefGoogle Scholar
  12. Hammond TG, Meng X, Jenkins RE, Maggs JL, Castelazo AS, Regan SL, Bennett SNL, Earnshaw CJ, Aithal GP, Pande I, Kenna JG, Stachulski AV, Park BK, Williams DP (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 350:387402CrossRefGoogle Scholar
  13. Hargus SJ, Amouzedeh HR, Pumford NR, Myers TG, McCoy SC, Pohl LR (1994) Metabolic activation and immunochemical localization of liver protein adducts of the nonsteroidal anti-inflammatory drug diclofenac. Chem Res Toxicol 7:575582CrossRefGoogle Scholar
  14. Kamimura H, Nakada N, Suzuki K, Mera A, Souda K, Murakami Y, Tanaka K, Iwatsubo T, Kawamura A, Usui T (2010) Assessment of chimeric mice with humanized liver as a tool for predicting circulating human metabolites. Drug Metab Pharmacokinet 25:223235CrossRefGoogle Scholar
  15. Kola I, Lanhis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discovery 3:711716CrossRefGoogle Scholar
  16. Kretz-Rommel A, Boelsterli U (1993) Diclofenac covalent protein binding is dependent on acyl glucuronide formation and is inversely related to acute cell injury in cultured rat hepatocytes. Toxicol Appl Pharmacol 120:155161Google Scholar
  17. Kretz-Rommel A, Boelsterli UA (1994) Selective protein adducts to membrane proteins in cultured rat hepatocytes exposed to diclofenac. Radiochemical and immunochemical analysis. Mol Pharmacol 45:237244Google Scholar
  18. Kumar S, Samuel K, Subramanian R, Braun MP, Stearns RA, Chiu SH, Evans DC, 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 303:96978CrossRefGoogle Scholar
  19. Le HT, Franklin MR (1997) Selective induction of phase II drug metabolizing enzyme activities by quinolines and isoquinolines. Chem Biol Interact 103:167178CrossRefGoogle Scholar
  20. Lichtenstein D, Sygal S, Wolfe M (1995) Nonsteroidal antiinflammatory drugs and the gastrointestinal tract: the double-edged sword. Arthritis Rheum 38:518CrossRefGoogle Scholar
  21. Lim MS, Lim PLK, Gupta R, Boelsterli UA (2006) Critical role of free cytosolic calcium, but not uncoupling, in mitochondrial permeability transition and cell death induced by diclofenac oxidative metabolites in immortalized human hepatocytes. Toxicol Appl Pharmacol 217:322331CrossRefGoogle Scholar
  22. LoGuidice A, Wallace BA, Bendel L, Redinbo MR, Boelsteri UA (2012) Pharmacologic targeting of bacterial B-glucuronidase alleviates nonsteroidal anti-inflammatory drug-induce enteropathy in mice. J Pharmacol Exp Therapeutics 341:447–454CrossRefGoogle Scholar
  23. Martinez C, Garcia-Martin E, Ladero JM, Herraez O, Ortega L, Taxonera C, Suárez A, DíazRubio M, Agúndez JA (2007) GSTT1 and GSTM1 null genotypes may facilitate hepatitis C virus infection becoming chronic. J Infect Dis 195:13201323CrossRefGoogle Scholar
  24. Masubuchi Y, Nakayama S, Horie T (2002) Role of mitochondrial permeability transition in diclofenac-induced hepatocyte injury in rats. Hepatology 35:544551CrossRefGoogle Scholar
  25. Park BK, Coleman JW, Kitteringham NR (1987) Drug disposition and drug hypersensitivity. Biochem Pharmacol 36:58190CrossRefGoogle Scholar
  26. Petrescu I, Tarba C (1997) Uncoupling effects of diclofenac and aspirin in the perfused liver and isolated hepatic mitochondria of rat. Biochim Biophys Acta 1318:38594Google Scholar
  27. Pickup K, Gavin A, Jones HB, Karlsson E, Page C, Ratcliffe K, Sarda S, SchulzUtermoehl T, Wilson I (2012) The hepatic reductase null mouse as a model for exploring hepatic conjugation of xenobiotics: application to the metabolism of diclofenac. Xenobiotica 42:195–205CrossRefPubMedGoogle Scholar
  28. Poon GK, Chen Q, Teffera Y, Ngui JS, Griffin PR, Braun MP, Doss GA, Freeden C, Stearns RA, Evans DC, Baillie TA, Tang W (2001) Bioactivation of diclofenac via benzoquinone imine intermediates-identification of urinary mercapturic acid derivatives in rats and humans. Drug Metab Dispos 29:1608–1613PubMedGoogle Scholar
  29. Reid G, Wielinga P, Zelcer N, De Haas M, Van Deemter L, Wijnholds J, Balzarini J, Borst P (2003) Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Mol Pharmacol 63:1094103CrossRefGoogle Scholar
  30. Riess W, Stierlin H, Degen P, Faigle JW, Gérardin A, Moppert J, Sallmann A, Schmid K, Schweizer A, Sulc M, Theobald W, Wagner J (1978) Pharmacokinetics and metabolism of the antiinflammatory agent Voltaren. Scand J Rheumatol Suppl 22:17–29CrossRefGoogle Scholar
  31. Sarda S, Page C, Pickup K, Schulz-Utermoehl T, Wilson I (2012) Diclofenac metabolism in the mouse: novel in vivo metabolites identified by high performance liquid chromatography coupled to linear ion trap mass spectrometry. Xenobiotica 42:179194CrossRefGoogle Scholar
  32. Sarda S, Partridge EA, Pickup K, McCarthy A, Wilson ID (2014) HPLCMS profiling and structural identification of [14C]-diclofenac metabolites in mouse bile. Chromatographia 77:233239CrossRefGoogle Scholar
  33. Scheer N, Wilson ID (2016) A comparison between genetically humanized and chimeric liver humanized mouse models for studies in drug metabolism and toxicity. Drug Discov Today 21:250263CrossRefGoogle Scholar
  34. Schmeltzer PA, Kosinski AS, Kleiner DE, Hoofnagle JH, Stolz A, Fontana RJ, Russo MW (2016) Liver injury from nonsteroidal anti-inflammatory drugs in the United States. Liver Int 36:603609CrossRefGoogle Scholar
  35. Schneider HT, Nuernberg B, Dietzel K, Brune K (1990) Biliary elimination of non-steroidal antiinflammatory drugs in patients. Br J Clin Pharmacol 29:127 – 31CrossRefPubMedPubMedCentralGoogle Scholar
  36. Scialis RJ, Manautou JE (2016) Elucidation of the mechanisms through which the reactive metabolite diclofenac acyl glucuronide can mediate toxicity. J Pharmacol Exp Ther 57:167 – 76CrossRefGoogle Scholar
  37. Shaw PJ, Ganey PE, Roth RA (2010) Idiosyncratic drug-induced liver injury and the role of inflammatory stress with an emphasis on an animal model of trovafloxacin hepatotoxicity. Toxicol Sci 118:718CrossRefGoogle Scholar
  38. Stierlin H, 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 – 21CrossRefPubMedGoogle Scholar
  39. Stierlin H, Faigle JW, Sallmann A, Küng W, Richter WJ, Kriemler HP, Alt KO, Winkler T (1979) Biotransformation of diclofenac sodium (Voltaren) in animals and in man. I. Isolation and identification of principal metabolites. Xenobiotica 9:601 – 10CrossRefPubMedGoogle Scholar
  40. Strom SC, Davila J, Grompe M (2010) Chimeric mice with humanized liver: tools for the study of drug metabolism, excretion, and toxicity. Methods Mol Biol 640:491509Google Scholar
  41. Tang W, Stearns RA, Bandiera SM, Zhang Y, Raab C, Braun MP, Dean DC, Pang J, Leung KH, Doss GA, Strauss JR, Kwei GY, Rushmore TH, Chiu SH, Baillie TA (1999) Studies on cytochrome P-450-mediated bioactivation of diclofenac in rats and in human hepatocytes: identification of glutathione conjugated metabolites. Drug Metab Dispos 27:365372Google Scholar
  42. Uetrecht J (2003) Screening for the potential of a drug candidate to cause idiosyncratic drug reactions. Drug Discov Today 8:832–837CrossRefPubMedGoogle Scholar
  43. Waring MJ, Arrowsmith J, Leach AR, Leeson PD, Mandrell S, Owen RM, Pairaudeau G, Pennie WD, Pickett SD, Wang J, Wallace O, Weir A (2015) An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nat Rev Drug Discov 14:475486CrossRefGoogle Scholar
  44. Willis JV, Kendall MJ, Flinn RM, Thornhill DP, Welling PG (1976) The pharmacokinetics of diclofenac sodium following intravenous and oral administration. Eur J Clin Pharmacol 16:405410Google Scholar
  45. Zhang Y, Han YH, Putluru SP, Matta MK, Kole P, Mandlekar S, Furlong MT, Liu T, Iyer RA, Marathe P, Yang Z, Lai Y, Rodrigues AD (2016) Diclofenac and its acyl glucuronide: determination of in vivo exposure in human subjects and characterization as human drug transporter substrates in vitro. Drug Metab Dispos 44:320328Google Scholar
  46. Zhou SF, Zhou ZW, Yang LP, Cai JP (2009) Substrates, inducers, inhibitors and structure-activity relationships of human cytochrome P450 2C9 and implications in drug development. Curr Med Chem 16:34803675Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Nestlé Skin Health R&D, Les TempliersSophia-AntipolisFrance
  2. 2.Evotec (UK) LtdAbingdonUK
  3. 3.Evotec International GmbHHamburgGermany
  4. 4.Yecuris CorporationTualatinUSA
  5. 5.CEVEC Pharmaceuticals GmbHCologneGermany
  6. 6.Department of Surgery and CancerImperial CollegeLondonUK
  7. 7.Evotec (UK) LtdNether AlderleyUK

Personalised recommendations