Case study 5. deconvoluting hyperbilirubinemia: Differentiating between hepatotoxicity and reversible inhibition of UGT1A1, MRP2, or OATP1B1 in drug development

Methods in Molecular Biology

Volumn 1113, Issue , 2014, Pages 471-483

  Templeton, Ian ^a   Eichenbaum, Gary ^b   Sane, Rucha ^c   Zhou, Jin ^c  

^a JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

^b JANSSEN RESEARCH AND DEVELOPMENT   (United States)

^c BOEHRINGER INGELHEIM PHARMACEUTICALS INC   (United States)

Author keywords

Bilirubin; Hyperbilirubinemia; MRP2; OATP1B1; OATP1B3; UGT1A1

Indexed keywords

ATAZANAVIR; BILIRUBIN; BILIRUBIN GLUCURONIDE; GLUCURONOSYLTRANSFERASE 1A1; INDINAVIR; JNJ 01; LOPINAVIR PLUS RITONAVIR; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 2; NELFINAVIR; SAQUINAVIR; SOLUTE CARRIER ORGANIC ANION TRANSPORTER 1B1; UNCLASSIFIED DRUG;

ARTICLE; BILIRUBIN BINDING; BILIRUBIN BLOOD LEVEL; BILIRUBIN METABOLISM; DIFFUSION; DRUG DEVELOPMENT; ENZYME INHIBITION; ENZYME KINETICS; GLUCURONIDATION; HUMAN; HYPERBILIRUBINEMIA; LIVER MICROSOME; LIVER TOXICITY; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; RISK ASSESSMENT;

ANIMALS; BILIRUBIN; BIOLOGICAL TRANSPORT; DOGS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; ENZYME ASSAYS; ENZYME INHIBITORS; GLUCURONOSYLTRANSFERASE; HUMANS; HYPERBILIRUBINEMIA; KINETICS; LIVER; MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS; ORGANIC ANION TRANSPORTERS; RATS; RISK;

EID: 84934440871     PISSN: 10643745     EISSN: None     Source Type: Book Series    
DOI: 10.1007/978-1-62703-758-7_22     Document Type: Article

References (31)

1. ICH ExpertWorking Group (2009) The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH); Multidisciplinary Guidelines; Nonclinical Safety Studies (M3). http://www.ich.org/fileadmin/Public-Web-Site/ICH-Products/Guidelines/ Multidisciplinary/M3-R2/Step4/M3-R2-Guideline.pdf. Accessed 20 June 2013
2. Sedlak TW, Snyder SH (2004) Bilirubin benefits: Cellular protection by a biliverdin reductase antioxidant cycle. Pediatrics 113(6):1776-1782
3. Keogh JP (2012) Membrane transporters in drug development. Adv Pharmacol 63:1-42. doi:10.1016/B978-0-12-398339-8.00001-X, B978-0-12-398339-8.00001-X [pii]
4. FDA/CDER (2012) Guidance for industry drug-induced liver injury: Premarketing clinical evaluation. http://www.fda.gov/downloads/Drugs/. . ./Guidances/UCM174090.pdf. Accessed 27 Aug 2012
5. London IM, West R, Shemin D, Rittenberg D (1950) On the origin of bile pigment in normal man. J Biol Chem 184(1):351-358
6. Billing BH, Black M (1969) Bilirubin metabolism. Gut 10(4):250-254
7. van de Steeg E, Stranecky V, Hartmannova H, Noskova L, Hrebicek M,Wagenaar E, van Esch A, deWaart DR, Oude Elferink RP, Kenworthy KE, Sticova E, al-Edreesi M, Knisely AS, Kmoch S, Jirsa M, Schinkel AH (2012) Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest 122(2):519-528. doi:10.1172/JCI59526, 59526 [pii]
8. Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RP, Chowdhury JR, Chowdhury NR, Jansen PL (1994) Bilirubin UDPglucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. J Biol Chem 269(27):17960-17964
9. Tukey RH, Strassburg CP (2000) Human UDP-glucuronosyltransferases: Metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 40:581-616. doi:10.1146/annurev. pharmtox.40.1.581
10. Harbourt DE, Fallon JK, Ito S, Baba T, Ritter JK, Glish GL, Smith PC (2012) Quantification of human uridine-diphosphate glucuronosyl transferase 1A isoforms in liver, intestine, and kidney using nanobore liquid chromatography-tandem mass spectrometry. Anal Chem 84(1):98-105. doi:10.1021/ac201704a
11. Xia Wang JR-C, Roy-Chowdhury N (2006) Bilirubin metabolism: Applied physiology. Curr Paediatr 16:70-74
12. Lengyel G, Veres Z, Szabo P, Vereczkey L, Jemnitz K (2005) Canalicular and sinusoidal disposition of bilirubin mono-and diglucuronides in sandwich-cultured human and rat primary hepatocytes. Drug Metab Dispos 33(9):1355-1360. doi:10.1124/dmd.105. 004481, dmd.105.004481 [pii]
13. Scheffer GL, Kool M, de Haas M, de Vree JM, Pijnenborg AC, Bosman DK, Elferink RP, van der Valk P, Borst P, Scheper RJ (2002) Tissue distribution and induction of human multidrug resistant protein. Lab Invest 82(2):193-201
14. Roy-Chowdhury N, Lu Y, Roy-Chowdhury J (2007) Bilirubin metabolism. In: Juan Rode?s J-PB, Blei A, Reichen J, RizzettoM(eds) Textbook of hepatology: From basic science to clinical practice, 3rd edn. Blackwell Publishing Ltd., Oxford
15. Sampietro M, Iolascon A (1999) Molecular pathology of Crigler-Najjar type I and II and Gilbert?s syndromes. Haematologica 84(2):150-157
16. Itaaho K, Mackenzie PI, Ikushiro S, Miners JO, Finel M (2008) The configuration of the 17-hydroxy group variably influences the glucuronidation of beta-estradiol and epiestradiol by human UDP-glucuronosyltransferases. Drug Metab Dispos 36(11):2307-2315. doi:10. 1124/dmd.108.022731, dmd.108.022731 [pii]
17. Soars MG, Ring BJ, Wrighton SA (2003) The effect of incubation conditions on the enzyme kinetics of udp-glucuronosyltransferases. Drug Metab Dispos 31(6):762-767, 31/6/762 [pii]
18. Walsky RL, Bauman JN, Bourcier K, Giddens G, Lapham K, Negahban A, Ryder TF, Obach RS, Hyland R, Goosen TC (2012) Optimized assays for human UDPglucuronosyltransferase (UGT) activities: Altered alamethicin concentration and utility to screen for UGT inhibitors. Drug Metab Dispos 40(5):1051-1065. doi:10.1124/dmd. 111.043117, dmd.111.043117 [pii]
19. Zhou J, Tracy TS, Remmel RP (2011) Correlation between bilirubin glucuronidation and estradiol-3-gluronidation in the presence of model UDP-glucuronosyltransferase 1A1 substrates/inhibitors. Drug Metab Dispos 39 (2):322-329. doi:10.1124/dmd.110. 035030, dmd.110.035030 [pii]
20. Cheng Y, Prusoff WH (1973) Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22(23):3099-3108
21. FDA/CDER (2012) Draft guidance for industry drug interaction studies. http://www.fda. gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm292362.pdf. Accessed 27 Aug 2012
22. Nso AP, Larru B, Bellon JM, Mellado MJ, Ramos JT, Gonzalez MI, Navarro ML, Munoz-Fernandez MA, Jose MI (2011) HIV-infected adolescents: Relationship between atazanavir plasma levels and bilirubin concentrations. J Adolesc Health 48 (1):100-102. doi:10.1016/j.jadohealth.2010. 05.009, S1054-139X(10)00251-X [pii]
23. Zhang D, Chando TJ, Everett DW, Patten CJ, Dehal SS, Humphreys WG (2005) In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug Metab Dispos 33(11):1729-1739. doi:10.1124/dmd.105. 005447, dmd.105.005447 [pii]
24. Mano Y, Usui T, Kamimura H (2008) Species differences in inhibition potential of nonsteroidal anti-inflammatory drugs against estradiol 3beta-glucuronidation between rats, dogs, and humans. J Pharm Sci 97(7):2805-2810. doi:10.1002/jps.21185
25. Soars MG, Riley RJ, Findlay KA, Coffey MJ, Burchell B (2001) Evidence for significant differences in microsomal drug glucuronidation by canine and human liver and kidney. Drug Metab Dispos 29(2):121-126
26. Sommerer U, Gordon ER, Goresky CA (1988) Microsomal specificity underlying the differing hepatic formation of bilirubin glucuronide and glucose conjugates by rat and dog. Hepatology 8(1):116-124, S027091398800014X [pii]
27. Furlan V, Demirdjian S, Bourdon O, Magdalou J, Taburet AM (1999) Glucuronidation of drugs by hepatic microsomes derived from healthy and cirrhotic human livers. J Pharmacol Exp Ther 289(2):1169-1175
28. Ishizuka H, Konno K, Shiina T, Naganuma H, Nishimura K, Ito K, Suzuki H, Sugiyama Y (1999) Species differences in the transport activity for organic anions across the bile canalicular membrane. J Pharmacol Exp Ther 290(3):1324-1330
29. Izumi T, Hosiyama K, Enomoto S, Sasahara K, Sugiyama Y (1997) Pharmacokinetics of troglitazone, an antidiabetic agent: Prediction of in vivo stereoselective sulfation and glucuronidation from in vitro data. J Pharmacol Exp Ther 280(3):1392-1400
30. Mistry M, Houston JB (1987) Glucuronidation in vitro and in vivo. Comparison of intestinal and hepatic conjugation of morphine, naloxone, and buprenorphine. Drug Metab Dispos 15(5):710-717
31. Soars MG, Burchell B, Riley RJ (2002) In vitro analysis of human drug glucuronidation and prediction of in vivo metabolic clearance. J Pharmacol Exp Ther 301(1):382-390