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Clinical Pharmacokinetics

, Volume 58, Issue 2, pp 189–211 | Cite as

The Ontogeny of UDP-glucuronosyltransferase Enzymes, Recommendations for Future Profiling Studies and Application Through Physiologically Based Pharmacokinetic Modelling

  • Justine Badée
  • Stephen Fowler
  • Saskia N. de Wildt
  • Abby C. Collier
  • Stephan Schmidt
  • Neil ParrottEmail author
Review Article
  • 318 Downloads

Abstract

Limited understanding of drug pharmacokinetics in children is one of the major challenges in paediatric drug development. This is most critical in neonates and infants owing to rapid changes in physiological functions, especially in the activity of drug-metabolising enzymes. Paediatric physiologically based pharmacokinetic models that integrate ontogeny functions for cytochrome P450 enzymes have aided our understanding of drug exposure in children, including those under the age of 2 years. Paediatric physiologically based pharmacokinetic models have consequently been recognised by the European Medicines Agency and the US Food and Drug Administration as innovative tools in paediatric drug development and regulatory decision making. However, little is currently known about age-related changes in UDP-glucuronosyltransferase-mediated metabolism, which represents the most important conjugation reaction for xenobiotics. Therefore, the objective of the review was to conduct a thorough literature survey to summarise our current understanding of age-related changes in UDP-glucuronosyltransferases as well as associated clinical and experimental sources of variance. Our findings indicate that there are distinct differences in UDP-glucuronosyltransferase expression and activity between isoforms for different age groups. In addition, there is substantial variability between individuals and laboratories reported for human liver microsomes, which results in part from a lack of standardised experimental conditions. Therefore, we provide a number of best practice recommendations for experimental conditions, which ultimately may help improve the quality of data used for quantitative clinical pharmacology approaches, and thus for safe and effective pharmacotherapy in children.

Abbreviations

BSA

Bovine serum albumin

CLint

Intrinsic clearance

CYP

Cytochrome P450

DME

Drug-metabolizing enzymes

HLM

Human liver microsomes

IVIVE

In vitro–in vivo extrapolation

Km

Michaelis–Menten constant

PBPK

Physiologically-based pharmacokinetic

UDPGA

Uridine diphosphate-glucuronic acid

UGT

UDP-glucuronosyltransferases

Vmax

Maximum velocity

Notes

Compliance with Ethical Standards

Funding

This work was supported by the Roche Postdoc Fellowship Program.

Conflict of interest

Justine Badée, Stephen Fowler, Saskia N. de Wildt, Abby C. Collier, Stephan Schmidt and Neil Parrott have no conflicts of interest that are directly relevant to the content of this article.

Supplementary material

40262_2018_681_MOESM1_ESM.docx (319 kb)
Supplementary material 1 (DOCX 319 kb)

References

  1. 1.
    Frattarelli DA, Galinkin JL, Green TP, Johnson TD, Neville KA, Paul IM, et al. Off-label use of drugs in children. Pediatrics. 2014;133(3):563–7.CrossRefPubMedGoogle Scholar
  2. 2.
    General clinical pharmacology considerations for pediatric studies for drugs and biological products guidance for industry. 2014. https://www.fda.gov/downloads/drugs/guidances/ucm425885.pdf. Accessed 25 May 2018.
  3. 3.
    Hoppu K, Anabwani G, Garcia-Bournissen F, Gazarian M, Kearns GL, Nakamura H, et al. The status of paediatric medicines initiatives around the world-what has happened and what has not? Eur J Clin Pharmacol. 2012;68(1):1–10.CrossRefPubMedGoogle Scholar
  4. 4.
    Dunne J, Rodriguez WJ, Murphy MD, Beasley BN, Burckart GJ, Filie JD, et al. Extrapolation of adult data and other data in pediatric drug-development programs. Pediatrics. 2011;128(5):e1242–9.CrossRefPubMedGoogle Scholar
  5. 5.
    de Zwart LL, Haenen HEMG, Versantvoort CHM, Wolterink G, Van Engelen JGM, Sips AJAM. Role of biokinetics in risk assessment of drugs and chemicals in children. Regul Toxicol Pharmacol. 2004;39(3):282–309.CrossRefPubMedGoogle Scholar
  6. 6.
    Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, et al. Drug–drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUC 1/AUC) ratios. Drug Metab Dispos. 2004;32(11):1201–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Momper JD, Mulugeta Y, Green DJ, Karesh A, Krudys KM, Sachs HC, et al. Adolescent dosing and labeling since the food and drug administration amendments act of 2007. JAMA Pediatr. 2013;167(10):926–32.CrossRefPubMedGoogle Scholar
  8. 8.
    Mahmood I. Prediction of drug clearance in children from adults: a comparison of several allometric methods. Br J Clin Pharmacol. 2006;61(5):545–57.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Germovsek E, Barker CIS, Sharland M, Standing JF. Scaling clearance in paediatric pharmacokinetics: all models are wrong, which are useful? Br J Clin Pharmacol. 2017;83(4):777–90.CrossRefPubMedGoogle Scholar
  10. 10.
    Anderson BJ, McKee AD, Holford NH. Size, myths and the clinical pharmacokinetics of analgesia in paediatric patients. Clin Pharmacokinet. 1997;33(5):313–27.CrossRefPubMedGoogle Scholar
  11. 11.
    Holford NHG, Ma SC, Anderson BJ. Prediction of morphine dose in humans. Paediatr Anaesth. 2012;22(3):209–22.CrossRefPubMedGoogle Scholar
  12. 12.
    Liu T, Lewis T, Gauda E, Gobburu J, Ivaturi V. Mechanistic population pharmacokinetics of morphine in neonates with abstinence syndrome after oral administration of diluted tincture of opium. J Clin Pharmacol. 2016;56(8):1009–18.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Björkman S. Prediction of cytochrome P450-mediated hepatic drug clearance in neonates, infants and children: how accurate are available scaling methods? Clin Pharmacokinet. 2006;45(1):1–11.CrossRefPubMedGoogle Scholar
  14. 14.
    Mahmood I, Staschen C-M, Goteti K. Prediction of drug clearance in children: an evaluation of the predictive performance of several models. AAPS J. 2014;16(6):1334–43.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin Pharmacokinet. 2006;45(9):931–56.CrossRefPubMedGoogle Scholar
  16. 16.
    de Wildt SN. Profound changes in drug metabolism enzymes and possible effects on drug therapy in neonates and children. Expert Opin Drug Metab Toxicol. 2011;7(8):935–48.CrossRefPubMedGoogle Scholar
  17. 17.
    Di L, Obach RS. Addressing the challenges of low clearance in drug research. AAPS J. 2015;17(2):352–7.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Rowland A, Miners JO, Mackenzie PI. The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification. Int J Biochem Cell Biol. 2013;45(6):1121–32.CrossRefPubMedGoogle Scholar
  19. 19.
    Kassahun K, McIntosh I, Cui D, Hreniuk D, Merschman S, Lasseter K, et al. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dispos. 2007;35(9):1657–63.CrossRefPubMedGoogle Scholar
  20. 20.
    Strassburg CP. Pharmacogenetics of Gilbert’s syndrome. Pharmacogenomics. 2008;9(6):703–15.CrossRefPubMedGoogle Scholar
  21. 21.
    Mukai M, Tanaka S, Yamamoto K, Murata M, Okada K, Isobe T, et al. In vitro glucuronidation of propofol in microsomal fractions from human liver, intestine and kidney: tissue distribution and physiological role of UGT1A9. Pharmazie. 2014;69(11):829–32.PubMedGoogle Scholar
  22. 22.
    Coffman BL, Rios GR, King CD, Tephly TR. Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos. 1997;25(1):1–4.PubMedGoogle Scholar
  23. 23.
    Di Marco A, D’Antoni M, Attaccalite S, Carotenuto P, Laufer R. Determination of drug glucuronidation and UDP-glucuronosyltransferase selectivity using a 96-well radiometric assay. Drug Metab Dispos. 2005;33(6):812–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Radominska-Pandya A, Little JM, Czernik PJ. Human UDP-glucuronosyltransferase 2B7. Curr Drug Metab. 2001;2(3):283–98.CrossRefPubMedGoogle Scholar
  25. 25.
    Burchell B, Coughtrie M, Jackson M, Harding D, Fournel-Gigleux S, Leakey J, et al. Development of human liver UDP-glucuronosyltransferases. Dev Pharmacol Ther. 1989;13(2–4):70–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Fujiwara R, Maruo Y, Chen S, Tukey RH. Role of extrahepatic UDP-glucuronosyltransferase 1A1: advances in understanding breast milk-induced neonatal hyperbilirubinemia. Toxicol Appl Pharmacol. 2015;289(1):124–32.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kawade N, Onishi S. The prenatal and postnatal development of UDP-glucuronyltransferase activity towards bilirubin and the effect of premature birth on this activity in the human liver. Biochem J. 1981;196(1):257–60.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Shapiro SM. Chronic bilirubin encephalopathy: diagnosis and outcome. Semin Fetal Neonatal Med. 2010;15(3):157–63.CrossRefPubMedGoogle Scholar
  29. 29.
    Ostrow JD, Pascolo L, Tiribelli C. Mechanisms of bilirubin neurotoxicity. Hepatology. 2002;35(5):1277–80.CrossRefPubMedGoogle Scholar
  30. 30.
    Mazur-Kominek K, Romanowski T, Bielawski K, Kiełbratowska B, Preis K, Domżalska-Popadiuk I, et al. Association between uridin diphosphate glucuronosylotransferase 1A1 (UGT1A1) gene polymorphism and neonatal hyperbilirubinemia. Acta Biochim Pol. 2017;64(2):351–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Yusoff S, Van Rostenberghe H, Yusoff NM, Talib NA, Ramli N, Ismail NZAN, et al. Frequencies of A(TA)7TAA, G71R, and G493R mutations of the UGT1A1 gene in the Malaysian population. Biol Neonate. 2006;89(3):171–6.CrossRefPubMedGoogle Scholar
  32. 32.
    Sarici SU, Saldir M. Genetic factors in neonatal hyperbilirubinemia and kernicterus. Turk J Pediatr. 2007;49(3):245–9.PubMedGoogle Scholar
  33. 33.
    Anderson GD. Children versus adults: pharmacokinetic and adverse-effect differences. Epilepsia. 2002;43(Suppl. 3):53–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Guberman AH, Besag FM, Brodie MJ, Dooley JM, Duchowny MS, Pellock JM, et al. Lamotrigine-associated rash: risk/benefit considerations in adults and children. Epilepsia. 1999;40(7):985–91.CrossRefPubMedGoogle Scholar
  35. 35.
    Chen M, LeDuc B, Kerr S, Howe D, Williams DA. Identification of human UGT2B7 as the major isoform involved in the O-glucuronidation of chloramphenicol. Drug Metab Dispos. 2010;38(3):368–75.CrossRefPubMedGoogle Scholar
  36. 36.
    Chen Z, Somogyi A, Reynolds G, Bochner F. Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. Br J Clin Pharmacol. 1991;31(4):381–90.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Yue Q, Hasselstrom J, Svensson J, Sawe J. Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine. Br J Clin Pharmacol. 1991;31(6):635–42.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Johnson TN, Tucker GT, Rostami-Hodjegan A. Development of CYP2D6 and CYP3A4 in the first year of life. Clin Pharmacol Ther. 2008;83(5):670–1.CrossRefPubMedGoogle Scholar
  39. 39.
    Crews KR, Gaedigk A, Dunnenberger HM, Klein TE, Shen DD, Callaghan JT, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther. 2012;91(2):321–6.CrossRefPubMedGoogle Scholar
  40. 40.
    Krekels EHJ, Tibboel D, De Wildt SN, Ceelie I, Dahan A, Van Dijk M, et al. Evidence-based morphine dosing for postoperative neonates and infants. Clin Pharmacokinet. 2014;53(6):553–63.CrossRefPubMedGoogle Scholar
  41. 41.
    Krekels EHJ, DeJongh J, Van Lingen RA, Van Der Marel CD, Choonara I, Lynn AM, et al. Predictive performance of a recently developed population pharmacokinetic model for morphine and its metabolites in new datasets of (preterm) neonates, infants and children. Clin Pharmacokinet. 2011;50(1):51–63.CrossRefPubMedGoogle Scholar
  42. 42.
    Stevens JC, Marsh SA, Zaya MJ, Regina KJ, Divakaran K, Le M, et al. Developmental changes in human liver CYP2D6 expression. Drug Metab Dispos. 2008;36(8):1587–93.CrossRefPubMedGoogle Scholar
  43. 43.
    Fukuda T, Goebel J, Cox S, Maseck D, Zhang K, Sherbotie JR, et al. UGT1A9, UGT2B7, and MRP2 genotypes can predict mycophenolic acid pharmacokinetic variability in pediatric kidney transplant recipients. Ther Drug Monit. 2012;34(6):671–9.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Edginton Schmitt W, Voith B, Willmann S. A mechanistic approach for the scaling of clearance in children. Clin Pharmacokinet. 2006;45(7):683–704.CrossRefPubMedGoogle Scholar
  45. 45.
    Milne RW, Nation RL, Somogyi AA, Bochner F, Griggs WM. The influence of renal function on the renal clearance of morphine and its glucuronide metabolites in intensive-care patients. Br J Clin Pharmacol. 1992;34(1):53–9.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Ohtsuki S, Schaefer O, Kawakami H, Inoue T, Liehner S, Saito A, et al. Simultaneous absolute protein quantification of transporters, cytochromes P450, and UDP-glucuronosyltransferases as a novel approach for the characterization of individual human liver: comparison with mRNA levels and activities. Drug Metab Dispos. 2012;40(1):83–92.CrossRefPubMedGoogle Scholar
  47. 47.
    Gröer C, Busch D, Patrzyk M, Beyer K, Busemann A, Heidecke CD, et al. Absolute protein quantification of clinically relevant cytochrome P450 enzymes and UDP-glucuronosyltransferases by mass spectrometry-based targeted proteomics. J Pharm Biomed Anal. 2014;100:393–401.CrossRefPubMedGoogle Scholar
  48. 48.
    Achour B, Dantonio A, Niosi M, Novak JJ, Fallon JK, Barber J, et al. Quantitative characterization of major hepatic UDP-glucuronosyltransferase enzymes in human liver microsomes: comparison of two proteomic methods and correlation with catalytic activity. Drug Metab Dispos. 2017;45(10):1102–12.CrossRefPubMedGoogle Scholar
  49. 49.
    Margaillan G, Rouleau M, Klein K, Fallon JK, Caron P, Villeneuve L, et al. Multiplexed targeted quantitative proteomics predicts hepatic glucuronidation potential. Drug Metab Dispos. 2015;43(9):1331–5.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Fallon JK, Neubert H, Hyland R, Goosen TC, Smith PC. Targeted quantitative proteomics for the analysis of 14 UGT1As and -2Bs in human liver using NanoUPLC–MS/MS with selected reaction monitoring. J Proteome Res. 2013;12(10):4402–13.CrossRefPubMedGoogle Scholar
  51. 51.
    Bustin SA, Nolan T. Pitfalls of quantitative real-time reverse-transcription polymerase chain reaction. J Biomol Tech. 2004;15(3):155–66.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Dluzen DF, Sun D, Salzberg AC, Jones N, Bushey RT, Robertson GP, et al. Regulation of UDP-glucuronosyltransferase 1A1 expression and activity by microRNA 491-3p. J Pharmacol Exp Ther. 2014;348(3):465–77.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Harbourt DE, Fallon JK, Ito S, Baba T, Ritter JK, Glish GL, et al. Quantification of human uridine-diphosphate glucuronosyl transferase 1A isoforms in liver, intestine, and kidney using nanobore liquid chromatography–tandem mass spectrometry. Anal Chem. 2012;84(1):98–105.CrossRefPubMedGoogle Scholar
  54. 54.
    Sato Y, Nagata M, Kawamura A, Miyashita A, Usui T. Protein quantification of UDP-glucuronosyltransferases 1A1 and 2B7 in human liver microsomes by LC–MS/MS and correlation with glucuronidation activities. Xenobiotica. 2012;42(9):823–9.CrossRefPubMedGoogle Scholar
  55. 55.
    Sridar C, Hanna I, Hollenberg PF. Quantitation of UGT1A1 in human liver microsomes using stable isotope-labelled peptides and mass spectrometry based proteomic approaches. Xenobiotica. 2013;43(4):336–45.CrossRefPubMedGoogle Scholar
  56. 56.
    Achour B, Russell MR, Barber J, Rostami-Hodjegan A. Simultaneous quantification of the abundance of several cytochrome P450 and uridine 5UDP-diphospho-glucuronosyltransferase enzymes in human liver microsomes using multiplexed targeted proteomics. Drug Metab Dispos. 2014;42(4):500–10.CrossRefPubMedGoogle Scholar
  57. 57.
    Sato Y, Nagata M, Tetsuka K, Tamura K, Miyashita A, Kawamura A, et al. Optimized methods for targeted peptide-based quantification of human uridine 5′-diphosphate-glucuronosyltransferases in biological specimens using liquid chromatography–tandem mass spectrometry. Drug Metab Dispos. 2014;42(5):885–9.CrossRefPubMedGoogle Scholar
  58. 58.
    Yan T, Gao S, Peng X, Shi J, Xie C, Li Q, et al. Significantly decreased and more variable expression of major CYPs and UGTs in liver microsomes prepared from HBV-positive human hepatocellular carcinoma and matched pericarcinomatous tissues determined using an isotope label-free UPLC–MS/MS method. Pharm Res. 2015;32(3):1141–57.CrossRefPubMedGoogle Scholar
  59. 59.
    Wegler C, Gaugaz FZ, Andersson TB, Wiśniewski JR, Busch D, Gröer C, et al. Variability in mass spectrometry-based quantification of clinically relevant drug transporters and drug metabolizing enzymes. Mol Pharm. 2017;14(9):3142–51.CrossRefPubMedGoogle Scholar
  60. 60.
    Tukey RH, Strassburg CP. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol. 2000;40(1):581–616.CrossRefPubMedGoogle Scholar
  61. 61.
    Collier AC, Ganley NA, Tingle MD, Blumenstein M, Marvin KW, Paxton JW, et al. UDP-glucuronosyltransferase activity, expression and cellular localization in human placenta at term. Biochem Pharmacol. 2002;63(3):409–19.CrossRefPubMedGoogle Scholar
  62. 62.
    Sabolovic N, Heydel JM, Li X, Little JM, Humbert AC, Radominska-Pandya A, et al. Carboxyl nonsteroidal anti-inflammatory drugs are efficiently glucuronidated by microsomes of the human gastrointestinal tract. Biochim Biophys Acta. 2004;1675(1–3):120–9.CrossRefPubMedGoogle Scholar
  63. 63.
    Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human phase I metabolizing enzymes except for cytochrome P450 and phase II metabolizing enzymes. Drug Metab Pharmacokinet. 2006;21(5):357–74.CrossRefPubMedGoogle Scholar
  64. 64.
    Court MH, Zhang X, Ding X, Yee KK, Hesse LM, Finel M. Quantitative distribution of mRNAs encoding the 19 human UDP-glucuronosyltransferase enzymes in 26 adult and 3 fetal tissues. Xenobiotica. 2012;42(3):266–77.CrossRefPubMedGoogle Scholar
  65. 65.
    Margaillan G, Rouleau M, Fallon JK, Caron P, Villeneuve L, Turcotte V, et al. Quantitative profiling of human renal UDP-glucuronosyltransferases and glucuronidation activity: a comparison of normal and tumoral kidney tissues. Drug Metab Dispos. 2015;43(4):611–9.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    King CD, Rios GR, Assouline JA, Tephly TR. Expression of UDP-glucuronosyltransferases (UGTs) 2B7 and 1A6 in the human brain and Identification of 5-hydroxytryptamine as a substrate. Arch Biochem Biophys. 1999;365(1):156–62.CrossRefPubMedGoogle Scholar
  67. 67.
    Sneitz N, Court MH, Zhang X, Laajanen K, Yee KK, Dalton P, et al. Human UDP-glucuronosyltransferase UGT2A2: CDNA construction, expression, and functional characterization in comparison with UGT2A1 and UGT2A3. Pharmacogenet Genomics. 2009;19(12):923–34.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Cheng Z, Radominska-Pandya A, Tephly TR. Cloning and expression of human UDP-glucuronosyltransferase (UGT) 1A8. Arch Biochem Biophys. 1998;356(2):301–5.CrossRefPubMedGoogle Scholar
  69. 69.
    Nakamura A, Nakajima M, Yamanaka H, Fujiwara R, Yokoi T. Expression of UGT1A and UGT2B mRNA in human normal tissues and various cell lines. Drug Metab Dispos. 2008;36(8):1461–4.CrossRefPubMedGoogle Scholar
  70. 70.
    Izukawa T, Nakajima M, Fujiwara R, Yamanaka H, Fukami T, Takamiya M, Aoki Y, Ikushiro S, Sakaki T, Yokoi T. Quantitative analysis of UDP-glucuronosyltransferase (UGT) 1A and UGT2B expression levels in human livers. Drug Metab Dispos. 2009;37(8):1759–68.CrossRefPubMedGoogle Scholar
  71. 71.
    MacKenzie PI, Rogers A, Elliot DJ, Chau N, Hulin J-A, Miners JO, Meech R. The novel UDP glycosyltransferase 3A2: cloning, catalytic properties, and tissue distribution. Mol Pharmacol. 2011;79(3):472–8.CrossRefPubMedGoogle Scholar
  72. 72.
    Mizuma T. Intestinal glucuronidation metabolism may have a greater impact on oral bioavailability than hepatic glucuronidation metabolism in humans: a study with raloxifene, substrate for UGT1A1, 1A8, 1A9, and 1A10. Int J Pharm. 2009;378(1–2):140–1.CrossRefPubMedGoogle Scholar
  73. 73.
    Wells PG, Mackenzie PI, Chowdhury JR, Guillemette C, Gregory PA, Ishii Y, et al. Glucuronidation and the UDP-glucuronosyltransferases in health and disease. Drug Metab Dispos. 2004;32(3):281–90.CrossRefPubMedGoogle Scholar
  74. 74.
    Guillemette C, Levesque E, Beaulieu M, Turgeon D, Hum DW, Belanger A. Differential regulation of two uridine diphospho-glucuronosyltransferases, UGT2B15 and UGT2B17, in human prostate LNCaP cells. Endocrinology. 1997;138(0013–7227):2998–3005.CrossRefPubMedGoogle Scholar
  75. 75.
    Beaulieu M, Lévesque E, Tchernof A, Beatty BG, Bélanger A, Hum DW. Chromosomal localization, structure, and regulation of the UGT2B17 gene, encoding a C19 steroid metabolizing enzyme. DNA Cell Biol. 1997;16(10):1143–54.CrossRefPubMedGoogle Scholar
  76. 76.
    Chouinard S, Yueh MF, Tukey RH, Giton F, Fiet J, Pelletier G, et al. Inactivation by UDP-glucuronosyltransferase enzymes: the end of androgen signaling. J Steroid Biochem Mol Biol. 2008;109(3–5):247–53.CrossRefPubMedGoogle Scholar
  77. 77.
    Ohno S, Nakajin S. Determination of mRNA expression of human UDP-glucuronosyltransferases and application for localization in various human tissues by real-time reverse transcriptase-polymerase chain reaction. Drug Metab Dispos. 2009;37(1):32–40.CrossRefPubMedGoogle Scholar
  78. 78.
    Barbier O, Bélanger A. Inactivation of androgens by UDP-glucuronosyltransferases in the human prostate. Best Pract Res Clin Endocrinol Metab. 2008;22(2):259–70.CrossRefPubMedGoogle Scholar
  79. 79.
    Proctor NJ, Tucker GT, Rostami-Hodjegan A. Predicting drug clearance from recombinantly expressed CYPs: intersystem extrapolation factors. Xenobiotica. 2004;34(2):151–78.CrossRefPubMedGoogle Scholar
  80. 80.
    Chen Y, Liu L, Nguyen K, Fretland AJ. Utility of intersystem extrapolation factors in early reaction phenotyping and the quantitative extrapolation of human liver microsomal intrinsic clearance using recombinant cytochromes P450. Drug Metab Dispos. 2011;39(3):373–82.CrossRefPubMedGoogle Scholar
  81. 81.
    Donato MT, Montero S, Castell JV, Gómez-Lechón MJ, Lahoz A. Validated assay for studying activity profiles of human liver UGTs after drug exposure: inhibition and induction studies. Anal Bioanal Chem. 2010;396(6):2251–63.CrossRefPubMedGoogle Scholar
  82. 82.
    de Wildt SN, Kearns GL, Leeder JS, Van Den Anker JN. Glucuronidation in humans: pharmacogenetic and developmental aspects. Clin Pharmacokinet. 1999;36(6):439–52.CrossRefPubMedGoogle Scholar
  83. 83.
    Kato Y, Nakajima M, Oda S, Fukami T, Yokoi T. Human UDP-glucuronosyltransferase isoforms involved in haloperidol glucuronidation and quantitative estimation of their contribution. Drug Metab Dispos. 2012;40(2):240–8.CrossRefPubMedGoogle Scholar
  84. 84.
    Gibson CR, Lu P, MacIolek C, Wudarski C, Barter Z, Rowland-Yeo K, et al. Using human recombinant UDP-glucuronosyltransferase isoforms and a relative activity factor approach to model total body clearance of laropiprant (MK-0524) in humans. Xenobiotica. 2013;43(12):1027–36.CrossRefPubMedGoogle Scholar
  85. 85.
    Zientek MA, Youdim K. Reaction phenotyping: advances in the experimental strategies used to characterize the contribution of drug-metabolizing enzymes. Drug Metab Dispos. 2015;43(1):163–81.CrossRefPubMedGoogle Scholar
  86. 86.
    Miners JO, Mackenzie PI, Knights KM. The prediction of drug-glucuronidation parameters in humans: UDP-glucuronosyltransferase enzyme-selective substrate and inhibitor probes for reaction phenotyping and in vitro–in vivo extrapolation of drug clearance and drug–drug interaction potential. Drug Metab Rev. 2010;42(1):196–208.CrossRefPubMedGoogle Scholar
  87. 87.
    Naritomi Y, Nakamori F, Furukawa T, Tabata K. Prediction of hepatic and intestinal glucuronidation using in vitro–in vivo extrapolation. Drug Metab Pharmacokinet. 2015;30(1):21–9.CrossRefPubMedGoogle Scholar
  88. 88.
    Barter Z, Bayliss M, Beaune P, Boobis A, Carlile D, Edwards R, et al. Scaling factors for the extrapolation of in vivo metabolic drug clearance from in vitro data: reaching a consensus on values of human micro-somal protein and hepatocellularity per gram of liver. Curr Drug Metab. 2007;8(1):33–45.CrossRefPubMedGoogle Scholar
  89. 89.
    Ito K, Houston JB. Prediction of human drug clearance from in vitro and preclinical data using physiologically based and empirical approaches. Pharm Res. 2005;22(1):103–12.CrossRefPubMedGoogle Scholar
  90. 90.
    Mistry M, Houston JB. Glucuronidation in vitro and in vivo. Comparison of intestinal and hepatic conjugation of morphine, naloxone, and buprenorphine. Drug Metab Dispos. 1987;15(5):710–7.PubMedGoogle Scholar
  91. 91.
    Nakamori F, Naritomi Y, Furutani M, Takamura F, Miura H, Murai H, et al. Correlation of intrinsic in vitro and in vivo clearance for drugs metabolized by hepatic UDP-glucuronosyltransferases in rats. Drug Metab Pharmacokinet. 2011;26(5):465–73.CrossRefPubMedGoogle Scholar
  92. 92.
    Gill KL, Houston JB, Galetin A. Characterization of in vitro glucuronidation clearance of a range of drugs in human kidney microsomes: comparison with liver and intestinal glucuronidation and impact of albumin. Drug Metab Dispos. 2012;40(4):825–35.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Kilford PJ, Stringer R, Sohal B, Houston JB, Galetin A. Prediction of drug clearance by glucuronidation from in vitro data: use of combined cytochrome P450 and UDP-glucuronosyltransferase cofactors in alamethicin-activated human liver microsomes. Drug Metab Dispos. 2009;37(1):82–9.CrossRefPubMedGoogle Scholar
  94. 94.
    de Wildt SN, Tibboel D, Leeder JS. Drug metabolism for the paediatrician. Arch Dis Child. 2014;99(12):1137–42.CrossRefPubMedGoogle Scholar
  95. 95.
    Coughtrie MW, Burchell B, Leakey JE, Hume R. The inadequacy of perinatal glucuronidation: immunoblot analysis of the developmental expression of individual UDP-glucuronosyltransferase isoenzymes in rat and human liver microsomes. Mol Pharmacol. 1988;34(6):729–35.PubMedGoogle Scholar
  96. 96.
    Zaya MJ, Hines RN, Stevens JC. Epirubicin glucuronidation and UGT2B7 developmental expression. Drug Metab Dispos. 2006;34(12):2097–101.CrossRefPubMedGoogle Scholar
  97. 97.
    Miyagi SJ, Milne AM, Coughtrie MWH, Collier AC. Neonatal development of hepatic UGT1A9: implications of pediatric pharmacokinetics. Drug Metab Dispos. 2012;40(7):1321–7.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Miyagi SJ, Collier AC. Pediatric development of glucuronidation: the ontogeny of hepatic UGT1A4. Drug Metab Dispos. 2007;35(9):1587–92.CrossRefPubMedGoogle Scholar
  99. 99.
    Miyagi SJ, Collier AC. The development of UDP-glucuronosyltransferases 1A1 and 1A6 in the pediatric liver. Drug Metab Dispos. 2011;39(5):912–9.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Neumann E, Mehboob H, Ramírez J, Mirkov S, Zhang M, Liu W. Age-dependent hepatic UDP-glucuronosyltransferase gene expression and activity in children. Front Pharmacol. 2016;16(7):437.Google Scholar
  101. 101.
    Pasha YZ, Kacho MA, Niaki HA, Tarighati M, Alaee E. The association between prolonged jaundice and TATA box dinucleotide repeats in Gilbert’s syndrome. J Clin Diagn Res. 2017;11(9):GC05–7.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Skierka JM, Kotzer KE, Lagerstedt SA, O’Kane DJ, Baudhuin LM. UGT1A1 genetic analysis as a diagnostic aid for individuals with unconjugated hyperbilirubinemia. J Pediatr. 2013;162(6):1146–52 (1152.e1–2).CrossRefPubMedGoogle Scholar
  103. 103.
    Mackenzie PI, Owens IS, Burchell B, Bock KW, Bairoch A, Bélanger A, et al. The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics. 1997;7(4):255–69.CrossRefPubMedGoogle Scholar
  104. 104.
    Kraemer D, Scheurlen M. Gilbert disease and type I and II Crigler–Najjar syndrome due to mutations in the same UGT1A1 gene locus (in German). Med Klin (Munich). 2002;97(9):528–32.CrossRefPubMedGoogle Scholar
  105. 105.
    Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med. 1995;333(18):1171–5.CrossRefPubMedGoogle Scholar
  106. 106.
    Kaniwa N, Kurose K, Jinno H, Tanaka-Kagawa T, Saito Y, Saeki M, et al. Racial variability in haplotype frequencies of UGT1A1 and glucuronidation activity of a novel single nucleotide polymorphism 686C>T (P229L) found in an African–American. Drug Metab Dispos. 2005;33(3):458–65.CrossRefPubMedGoogle Scholar
  107. 107.
    Minami H, Sai K, Saeki M, Saito Y, Ozawa S, Suzuki K, et al. Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: roles of UGT1A1*6 and *28. Pharmacogenet Genom. 2007;17(7):497–504.CrossRefGoogle Scholar
  108. 108.
    Zhang J, Yang C, Liu Y, Xi W, Zhou C, Jiang J, et al. Relationship between UGT1A1*6/*28 polymorphisms and severe toxicities in Chinese patients with pancreatic or biliary tract cancer treated with irinotecan-containing regimens. Drug Des Dev Ther. 2015;9:3677.CrossRefGoogle Scholar
  109. 109.
    Nie Y-L, He H, Li J-F, Meng X-G, Yan L, Wang P, et al. Hepatic expression of transcription factors affecting developmental regulation of UGT1A1 in the Han Chinese population. Eur J Clin Pharmacol. 2017;73(1):29–37.CrossRefPubMedGoogle Scholar
  110. 110.
    Pasternak AL, Crews KR, Caudle KE, Smith C, Pei D, Cheng C, et al. The impact of the UGT1A1*60 allele on bilirubin serum concentrations. Pharmacogenomics. 2017;18(1):5–16.CrossRefPubMedGoogle Scholar
  111. 111.
    Munisamy M, Tripathi M, Behari M, Raghavan S, Jain DC, Ramanujam B, et al. The effect of uridine diphosphate glucuronosyltransferase (UGT)1A6 genetic polymorphism on valproic acid pharmacokinetics in Indian patients with epilepsy: a pharmacogenetic approach. Mol Diagn Ther. 2013;17(5):319–26.CrossRefPubMedGoogle Scholar
  112. 112.
    Guo Y, Hu C, He X, Qiu F, Zhao L. Effects of UGT1A6, UGT2B7, and CYP2C9 genotypes on plasma concentrations of valproic acid in Chinese children with epilepsy. Drug Metab Pharmacokinet. 2012;27(5):536–42.CrossRefPubMedGoogle Scholar
  113. 113.
    Shirzadi M, Reimers A, Helde G, Sjursen W, Brodtkorb E. No association between non-bullous skin reactions from lamotrigine and heterozygosity of UGT1A4 genetic variants *2(P24T) or *3(L48V) in Norwegian patients. Seizure. 2017;45:169–71.CrossRefPubMedGoogle Scholar
  114. 114.
    Chang Y, Yang LY, Zhang MC, Liu SY. Correlation of the UGT1A4 gene polymorphism with serum concentration and therapeutic efficacy of lamotrigine in Han Chinese of Northern China. Eur J Clin Pharmacol. 2014;70(8):941–6.CrossRefPubMedGoogle Scholar
  115. 115.
    Gulcebi MI, Ozkaynakci A, Goren MZ, Aker RG, Ozkara C, Onat FY. The relationship between UGT1A4 polymorphism and serum concentration of lamotrigine in patients with epilepsy. Epilepsy Res. 2011;95(1–2):1–8.CrossRefPubMedGoogle Scholar
  116. 116.
    Reimers A, Sjursen W, Helde G, Brodtkorb E. Frequencies of UGT1A4*2 (P24T) and *3 (L48V) and their effects on serum concentrations of lamotrigine. Eur J Drug Metab Pharmacokinet. 2016;41(2):149–55.CrossRefPubMedGoogle Scholar
  117. 117.
    Wang Q, Liang M, Dong Y, Yun W, Qiu F, Zhao L, et al. Effects of UGT1A4 genetic polymorphisms on serum lamotrigine concentrations in Chinese children with epilepsy. Drug Metab Pharmacokinet. 2015;30(3):209–13.CrossRefPubMedGoogle Scholar
  118. 118.
    Lévesque E, Delage R, Benoit-Biancamano M-O, Caron P, Bernard O, Couture F, et al. The impact of UGT1A8, UGT1A9, and UGT2B7 genetic polymorphisms on the pharmacokinetic profile of mycophenolic acid after a single oral dose in healthy volunteers. Clin Pharmacol Ther. 2007;81(3):392–400.CrossRefPubMedGoogle Scholar
  119. 119.
    Djebli N, Picard N, Rérolle J-P, Le Meur Y, Marquet P. Influence of the UGT2B7 promoter region and exon 2 polymorphisms and comedications on Acyl-MPAG production in vitro and in adult renal transplant patients. Pharmacogenet Genom. 2007;17(5):321–30.CrossRefGoogle Scholar
  120. 120.
    Chen G, Blevins-Primeau AS, Dellinger RW, Muscat JE, Lazarus P. Glucuronidation of nicotine and cotinine by UGT2B10: loss of function by the UGT2B10 codon 67 (Asp>Tyr) polymorphism. Cancer Res. 2007;67(19):9024–9.CrossRefPubMedGoogle Scholar
  121. 121.
    Zhou D, Guo J, Linnenbach AJ, Booth-Genthe CL, Grimm SW. Role of human UGT2B10 in N-glucuronidation of tricyclic antidepressants, amitriptyline, imipramine, clomipramine, and trimipramine. Drug Metab Dispos. 2010;38(5):863–70.CrossRefPubMedGoogle Scholar
  122. 122.
    Fowler S, Kletzl H, Finel M, Manevski N, Schmid P, Tuerck D, et al. A UGT2B10 splicing polymorphism common in African populations may greatly increase drug exposure. J Pharmacol Exp Ther. 2015;352(2):358–67.CrossRefPubMedGoogle Scholar
  123. 123.
    Court MH, Zhu Z, Masse G, Duan SX, James LP, Harmatz JS, et al. Race, gender, and genetic polymorphism contribute to variability in acetaminophen pharmacokinetics, metabolism, and protein-adduct concentrations in healthy African–American and European–American volunteers. J Pharmacol Exp Ther. 2017;362(3):431–40.CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Wilson W, Pardo-Manuel de Villena F, Lyn-Cook BD, Chatterjee PK, Bell TA, Detwiler DA, et al. Characterization of a common deletion polymorphism of the UGT2B17 gene linked to UGT2B15. Genomics. 2004;84(4):707–14.CrossRefPubMedGoogle Scholar
  125. 125.
    Zhu AZX, Cox LS, Ahluwalia JS, Renner CC, Hatsukami DK, Benowitz NL, et al. Genetic and phenotypic variation in UGT2B17, a testosterone-metabolizing enzyme, is associated with BMI in males. Pharmacogenet Genom. 2015;25(5):263–9.CrossRefGoogle Scholar
  126. 126.
    Wang LA, Gonzalez D, Leeder JS, Tyndale RF, Pearce RE, Benjamin DK, et al. Metronidazole metabolism in neonates and the interplay between ontogeny and genetic variation. J Clin Pharmacol. 2017;57(2):230–4.CrossRefPubMedGoogle Scholar
  127. 127.
    de Wildt SN, Van Schaik RHN, Soldin OP, Soldin SJ, Brojeni PY, Van Der Heiden IP, et al. The interactions of age, genetics, and disease severity on tacrolimus dosing requirements after pediatric kidney and liver transplantation. Eur J Clin Pharmacol. 2011;67(12):1231–41.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Ward RM, Tammara B, Sullivan SE, Stewart DL, Rath N, Meng X, et al. Single-dose, multiple-dose, and population pharmacokinetics of pantoprazole in neonates and preterm infants with a clinical diagnosis of gastroesophageal reflux disease (GERD). Eur J Clin Pharmacol. 2010;66(6):555–61.CrossRefPubMedGoogle Scholar
  129. 129.
    Leeder JS, Kearns GL. Interpreting pharmacogenetic data in the developing neonate: the challenge of hitting a moving target. Clin Pharmacol Ther. 2012;92(4):434–6.PubMedGoogle Scholar
  130. 130.
    Yasar U, Greenblatt DJ, Guillemette C, Court MH. Evidence for regulation of UDP-glucuronosyltransferase (UGT) 1A1 protein expression and activity via DNA methylation in healthy human livers. J Pharm Pharmacol. 2013;65(6):874–83.CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Oda S, Fukami T, Yokoi T, Nakajima M. Epigenetic regulation of the tissue-specific expression of human UDP-glucuronosyltransferase (UGT) 1A10. Biochem Pharmacol. 2014;87(4):660–7.CrossRefPubMedGoogle Scholar
  132. 132.
    Oeser SG, Bingham J-P, Collier AC. Regulation of hepatic UGT2B15 by methylation in adults of Asian descent. Pharmaceutics. 2018;10(1):6.CrossRefPubMedCentralGoogle Scholar
  133. 133.
    Liu W, Ramírez J, Gamazon ER, Mirkov S, Chen P, Wu K, et al. Genetic factors affecting gene transcription and catalytic activity of UDP-glucuronosyltransferases in human liver. Hum Mol Genet. 2014;23(20):5558–69.CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Lee SY, Lee JY, Kim YM, Kim SK, Oh SJ. Expression of hepatic cytochrome P450s and UDP-glucuronosyltransferases in PXR and CAR double humanized mice treated with rifampicin. Toxicol Lett. 2015;235(2):107–15.CrossRefPubMedGoogle Scholar
  135. 135.
    Bock KW. Roles of human UDP-glucuronosyltransferases in clearance and homeostasis of endogenous substrates, and functional implications. Biochem Pharmacol. 2015;96(2):77–82.CrossRefPubMedGoogle Scholar
  136. 136.
    Bao B-Y, Chuang B-F, Wang Q, Sartor O, Balk SP, Brown M, et al. Androgen receptor mediates the expression of UDP-glucuronosyltransferase 2 B15 and B17 genes. Prostate. 2008;68(8):839–48.CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Papageorgiou I, Freytsis M, Court MH. Transcriptome association analysis identifies miR-375 as a major determinant of variable acetaminophen glucuronidation by human liver. Biochem Pharmacol. 2016;117:78–87.CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Papageorgiou I, Court MH. Identification and validation of microRNAs directly regulating the UDP-glucuronosyltransferase 1A subfamily enzymes by a functional genomics approach. Biochem Pharmacol. 2017;1(137):93–106.CrossRefGoogle Scholar
  139. 139.
    Basu NK, Kovarova M, Garza A, Kubota S, Saha T, Mitra PS, et al. Phosphorylation of a UDP-glucuronosyltransferase regulates substrate specificity. Proc Natl Acad Sci USA. 2005;102(18):6285–90.CrossRefPubMedGoogle Scholar
  140. 140.
    Mitra PS, Basu NK, Owens IS. Src supports UDP-glucuronosyltransferase-2B7 detoxification of catechol estrogens associated with breast cancer. Biochem Biophys Res Commun. 2009;382(4):651–6.CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Girard-Bock C, Benoit-Biancamano MO, Villeneuve L, Desjardins S, Guillemette C. A rare UGT2B7 variant creates a novel N-glycosylation site at codon 121 with impaired enzyme activity. Drug Metab Dispos. 2016;44(12):1867–71.CrossRefPubMedGoogle Scholar
  142. 142.
    Sneitz N, Bakker CT, De Knegt RJ, Halley DJJ, Finel M, Bosma PJ. Crigler–Najjar syndrome in the Netherlands: identification of four novel UGT1A1 alleles, genotype-phenotype correlation, and functional analysis of 10 missense mutants. Hum Mutat. 2010;31(1):52–9.CrossRefPubMedGoogle Scholar
  143. 143.
    Walsky RL, Bauman JN, Bourcier K, Giddens G, Lapham K, Negahban A, et al. Optimized assays for human UDP-glucuronosyltransferase (UGT) activities: altered alamethicin concentration and utility to screen for UGT inhibitors. Drug Metab Dispos. 2012;40(5):1051–65.CrossRefPubMedGoogle Scholar
  144. 144.
    Chang JH, Yoo P, Lee T, Klopf W, Takao D. The role of pH in the glucuronidation of raloxifene, mycophenolic acid and ezetimibe. Mol Pharm. 2009;6(4):1216–27.CrossRefPubMedGoogle Scholar
  145. 145.
    Miners JO, Lillywhite KJ, Birkett DJ. In vitro evidence for the involvement of at least two forms of human liver UDP-glucuronosyltransferase in morphine 3-glucuronidation. Biochem Pharmacol. 1988;37(14):2839–45.CrossRefPubMedGoogle Scholar
  146. 146.
    Fisher MB, Campanale K, Ackermann BL, VandenBranden M, Wrighton SA. In vitro glucuronidation using human liver microsomes and the pore-forming peptide alamethicin. Drug Metab Dispos. 2000;28(5):560–6.PubMedGoogle Scholar
  147. 147.
    Shipkova M, Strassburg CP, Braun F, Streit F, Gröne HJ, Armstrong VW, et al. Glucuronide and glucoside conjugation of mycophenolic acid by human liver, kidney and intestinal microsomes. Br J Pharmacol. 2001;132(5):1027–34.CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Soars MG, Riley RJ, Findlay KAB, Coffey MJ, Burchell B. Evidence for significant differences in microsomal drug glucuronidation by canine and human liver and kidney. Drug Metab Dispos. 2001;29(2):121–6.PubMedGoogle Scholar
  149. 149.
    Vietri M, Pietrabissa A, Mosca F, Pacifici G. Inhibition of mycophenolic acid glucuronidation by niflumic acid in human liver microsomes. Eur J Clin Pharmacol. 2002;58(2):93–7.CrossRefPubMedGoogle Scholar
  150. 150.
    Soars MG, Ring BJ, Wrighton SA. The effect of incubation conditions on the enzyme kinetics of UDP-glucuronosyltransferases. Drug Metab Dispos. 2003;31(6):762–7.CrossRefPubMedGoogle Scholar
  151. 151.
    Court MH, Krishnaswamy S, Hao Q, Duan SX, Patten CJ, Von Moltke LL, et al. Evaluation of 3′-azido-3′-deoxythymidine, morphine, and codeine as probe substrates for udp-glucuronosyltransferase 2B7 (UGT2B7) in human liver microsomes: specificity and influence of the UGT2B7*2 polymorphism. Drug Metab Dispos. 2003;31(9):1125–33.CrossRefPubMedGoogle Scholar
  152. 152.
    Chau N, Elliot DJ, Lewis BC, Burns K, Johnston MR, Mackenzie PI, et al. Morphine glucuronidation and glucosidation represent complementary metabolic pathways that are both catalyzed by UDP-glucuronosyltransferase 2B7: kinetic, inhibition, and molecular modeling studies. J Pharmacol Exp Ther. 2014;349(1):126–37.CrossRefPubMedGoogle Scholar
  153. 153.
    Miles KK, Stern ST, Smith PC, Kessler FK, Ali S, Ritter JK. An investigation of human and rat liver microsomal mycophenolic acid glucuronidation: evidence for a principal role of UGT1A enzymes and species differences in UGT1A specificity. Drug Metab Dispos. 2005;33(10):1513–20.CrossRefPubMedGoogle Scholar
  154. 154.
    Picard N, Ratanasavanh D, Prémaud A, Le Meur Y, Marquet P. Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism. Drug Metab Dispos. 2005;33(1):139–46.CrossRefPubMedGoogle Scholar
  155. 155.
    Slovak JE, Mealey K, Court MH. Comparative metabolism of mycophenolic acid by glucuronic acid and glucose conjugation in human, dog, and cat liver microsomes. J Vet Pharmacol Ther. 2017;40(2):123–9.CrossRefPubMedGoogle Scholar
  156. 156.
    Rowland A, Gaganis P, Elliot DJ, Mackenzie PI, Knights KM, Miners JO. Binding of inhibitory fatty acids is responsible for the enhancement of UDP-glucuronosyltransferase 2B7 activity by albumin: implications for in vitro–in vivo extrapolation. J Pharmacol Exp Ther. 2007;321(1):137–47.CrossRefPubMedGoogle Scholar
  157. 157.
    Rowland A, Knights KM, Mackenzie PI, Miners JO. The “albumin effect” and drug glucuronidation: bovine serum albumin and fatty acid-free human serum albumin enhance the glucuronidation of UDP-glucuronosyltransferase (UGT) 1A9 substrates but not UGT1A1 and UGT1A6 activities. Drug Metab Dispos. 2008;36(6):1056–62.CrossRefPubMedGoogle Scholar
  158. 158.
    Liu X, Sheng L, Zhao M, Mi J, Liu Z, Li Y. In vitro glucuronidation of the primary metabolite of 10-chloromethyl-11-demethyl-12-oxo-calanolide A by human liver microsomes and its interactions with UDP-glucuronosyltransferase substrates. Drug Metab Pharmacokinet. 2015;30(1):89–96.CrossRefPubMedGoogle Scholar
  159. 159.
    Knights KM, Spencer SM, Fallon JK, Chau N, Smith PC, Miners JO. Scaling factors for the in vitro–in vivo extrapolation (IV–IVE) of renal drug and xenobiotic glucuronidation clearance. Br J Clin Pharmacol. 2016;81(6):1153–64.CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Gagez A-L, Rouguieg-Malki K, Sauvage F-L, Marquet P, Picard N. Simultaneous evaluation of six human glucuronidation activities in liver microsomes using liquid chromatography–tandem mass spectrometry. Anal Biochem. 2012;427(1):52–9.CrossRefPubMedGoogle Scholar
  161. 161.
    Joo J, Lee B, Lee T, Liu K-H. Screening of six UGT enzyme activities in human liver microsomes using liquid chromatography/triple quadrupole mass spectrometry. Rapid Commun Mass Spectrom. 2014;28(22):2405–14.CrossRefPubMedGoogle Scholar
  162. 162.
    Seo KA, Kim HJ, Jeong ES, Abdalla N, Choi CS, Kim DH, et al. In vitro assay of six UDP-glucuronosyltransferase isoforms in human liver microsomes, using cocktails of probe substrates and liquid chromatography–tandem mass spectrometry. Drug Metab Dispos. 2014;42(11):1803–10.CrossRefPubMedGoogle Scholar
  163. 163.
    Gradinaru J, Romand S, Geiser L, Carrupt PA, Spaggiari D, Rudaz S. Inhibition screening method of microsomal UGTs using the cocktail approach. Eur J Pharm Sci. 2015;71:35–45.CrossRefPubMedGoogle Scholar
  164. 164.
    Krishnaswamy S, Duan SX, Von Moltke LL, Greenblatt DJ, Court MH. Validation of serotonin (5-hydroxtryptamine) as an in vitro substrate probe for human UDP-glucuronosyltransferase (UGT) 1A6. Drug Metab Dispos. 2003;31(1):133–9.CrossRefPubMedGoogle Scholar
  165. 165.
    Uchaipichat V, Mackenzie PI, Elliot DJ, Miners JO. Selectivity of substrate (trifluoperazine) and inhibitor (amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone) “probes” for human UDP-glucuronosyltransferases. Drug Metab Dispos. 2006;34(3):449–56.PubMedGoogle Scholar
  166. 166.
    Trottier J, Verreault M, Grepper S, Monté D, Bélanger J, Kaeding J, et al. Human UDP-glucuronosyltransferase (UGT)1A3 enzyme conjugates chenodeoxycholic acid in the liver. Hepatology. 2006;44(5):1158–70.CrossRefPubMedGoogle Scholar
  167. 167.
    Divakaran K, Hines RN, McCarver DG. Human hepatic UGT2B15 developmental expression. Toxicol Sci. 2014;141(1):292–9.CrossRefPubMedPubMedCentralGoogle Scholar
  168. 168.
    Jones H, Rowland-Yeo K. Basic concepts in physiologically based pharmacokinetic modeling in drug discovery and development. CPT Pharmacomet Syst Pharmacol. 2013;2(8):e63.CrossRefGoogle Scholar
  169. 169.
    Wagner C, Zhao P, Pan Y, Hsu V, Grillo J, Huang SM, et al. Application of physiologically based pharmacokinetic (PBPK) modeling to support dose selection: report of an FDA Public Workshop on PBPK. CPT Pharmacomet Syst Pharmacol. 2015;4(4):226–30.CrossRefGoogle Scholar
  170. 170.
    Jamei M. Recent advances in development and application of physiologically-based pharmacokinetic (PBPK) models: a transition from academic curiosity to regulatory acceptance. Curr Pharmacol Rep. 2016;2(3):161–9.CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Jones H, Chen Y, Gibson C, Heimbach T, Parrott N, Peters S, et al. Physiologically based pharmacokinetic modeling in drug discovery and development: a pharmaceutical industry perspective. Clin Pharmacol Ther. 2015;97(3):247–62.CrossRefPubMedGoogle Scholar
  172. 172.
    Huang S-M, Abernethy DR, Wang Y, Zhao P, Zineh I. The utility of modeling and simulation in drug development and regulatory review. J Pharm Sci. 2013;102(9):2912–23.CrossRefPubMedGoogle Scholar
  173. 173.
    Sager JE, Yu J, Ragueneau-Majlessi I, Isoherranen N. Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches: a systematic review of published models, applications, and model verification. Drug Metab Dispos. 2015;43(11):1823–37.CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Shebley M, Sandhu P, Emami Riedmaier A, Jamei M, Narayanan R, Patel A, et al. Physiologically based pharmacokinetic model qualification and reporting procedures for regulatory submissions: a consortium perspective. Clin Pharmacol Ther. 2018.  https://doi.org/10.1002/cpt.1013 (Epub ahead of print).CrossRefPubMedPubMedCentralGoogle Scholar
  175. 175.
    Jiang X-L, Zhao P, Barrett JS, Lesko LJ, Schmidt S. Application of physiologically based pharmacokinetic modeling to predict acetaminophen metabolism and pharmacokinetics in children. CPT Pharmacomet Syst Pharmacol. 2013;2(10):e80.CrossRefGoogle Scholar
  176. 176.
    Ogungbenro K, Aarons L, CRESim & Epi-CRESim Project Groups. A physiologically based pharmacokinetic model for valproic acid in adults and children. Eur J Pharm Sci. 2014;15(63):45–52.CrossRefGoogle Scholar
  177. 177.
    Emoto C, Fukuda T, Johnson TN, Neuhoff S, Sadhasivam S, Vinks AA. Characterization of contributing factors to variability in morphine clearance through PBPK modeling implemented with OCT1 transporter. CPT Pharmacomet Syst Pharmacol. 2017;6(2):110–9.CrossRefGoogle Scholar
  178. 178.
    Maharaj AR, Barrett JS, Edginton AN. A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam. AAPS J. 2013;15(2):455–64.CrossRefPubMedPubMedCentralGoogle Scholar
  179. 179.
    Leong R, Vieira MLT, Zhao P, Mulugeta Y, Lee CS, Huang S-M, et al. Regulatory experience with physiologically based pharmacokinetic modeling for pediatric drug trials. Clin Pharmacol Ther. 2012;91(5):926–31.CrossRefPubMedGoogle Scholar
  180. 180.
    Ginsberg G, Hattis D, Russ A, Sonawane B. Physiologically based pharmacokinetic (PBPK) modeling of caffeine and theophylline in neonates and adults: implications for assessing children’s risks from environmental agents. J Toxicol Environ Health A. 2004;67(4):297–329.CrossRefPubMedGoogle Scholar
  181. 181.
    Emoto C, Fukuda T, Cox S, Christians U, Vinks AA. Development of a physiologically-based pharmacokinetic model for sirolimus: predicting bioavailability based on intestinal CYP3A content. CPT Pharmacomet Syst Pharmacol. 2013;2(7):e59.CrossRefGoogle Scholar
  182. 182.
    Lin W, Heimbach T, Jain JP, Awasthi R, Hamed K, Sunkara G, et al. A physiologically based pharmacokinetic model to describe artemether pharmacokinetics in adult and pediatric patients. J Pharm Sci. 2016;105(10):3205–13.CrossRefPubMedGoogle Scholar
  183. 183.
    Upreti VV, Wahlstrom JL. Meta-analysis of hepatic cytochrome P450 ontogeny to underwrite the prediction of pediatric pharmacokinetics using physiologically based pharmacokinetic modeling. J Clin Pharmacol. 2016;56(3):266–83.CrossRefPubMedGoogle Scholar
  184. 184.
    T’jollyn H, Snoeys J, Vermeulen A, Michelet R, Cuyckens F, Mannens G, et al. Physiologically based pharmacokinetic predictions of tramadol exposure throughout pediatric life: an analysis of the different clearance contributors with emphasis on CYP2D6 maturation. AAPS J. 2015;17(6):1376–87.CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Shangguan WN, Lian Q, Aarons L, Matthews I, Wang Z, Chen X, et al. Pharmacokinetics of a single bolus of propofol in chinese children of different ages. Anesthesiology. 2006;104(1):27–32.CrossRefPubMedGoogle Scholar
  186. 186.
    Allegaert K, Peeters MY, Verbesselt R, Tibboel D, Naulaers G, De Hoon JN, et al. Inter-individual variability in propofol pharmacokinetics in preterm and term neonates. Br J Anaesth. 2007;99(6):864–70.CrossRefPubMedGoogle Scholar
  187. 187.
    Wang C, Sadhavisvam S, Krekels EHJ, Dahan A, Tibboel D, Danhof M, et al. Developmental changes in morphine clearance across the entire paediatric age range are best described by a bodyweight-dependent exponent model. Clin Drug Investig. 2013;33(7):523–34.CrossRefPubMedGoogle Scholar
  188. 188.
    Anand KJS, Anderson BJ, Holford NHG, Hall RW, Young T, Shephard B, et al. Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial. Br J Anaesth. 2008;101(5):680–9.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Justine Badée
    • 1
  • Stephen Fowler
    • 2
  • Saskia N. de Wildt
    • 3
    • 4
  • Abby C. Collier
    • 5
  • Stephan Schmidt
    • 1
  • Neil Parrott
    • 2
    Email author
  1. 1.Department of Pharmaceutics, Center for Pharmacometrics and Systems PharmacologyUniversity of Florida at Lake NonaOrlandoUSA
  2. 2.Pharmaceutical Sciences, Roche Pharma Research and Early DevelopmentRoche Innovation Centre BaselBaselSwitzerland
  3. 3.Department of Pharmacology and ToxicologyRadboud UniversityNijmegenThe Netherlands
  4. 4.Intensive Care and Department of Paediatric SurgeryErasmus MC Sophia Children’s HospitalRotterdamThe Netherlands
  5. 5.Faculty of Pharmaceutical SciencesThe University of British ColumbiaVancouverCanada

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