Clinical Pharmacokinetics

, Volume 36, Issue 6, pp 439–452 | Cite as

Glucuronidation in Humans

Pharmacogenetic and Developmental Aspects
  • Saskia N. de Wildt
  • Gregory L. Kearns
  • J. Steven Leeder
  • John N. van den Anker
Review Article Concepts

Abstract

During human development impressive changes in drug disposition occur. An important determinant of drug clearance is metabolism, something that is not only determined by ontogenic regulation but also by genetic processes which add to the variability of drug metabolism during different stages of childhood. Therefore, an understanding of the developmental regulation of different metabolic pathways, together with information on the genetic determinants of drug metabolism, will increase the knowledge of inter- and intraindividual variability in drug disposition during childhood.

Conjugation has historically received less attention than cytochrome P450 metabolism. An important group of conjugation reactions are catalysed by the uridine 5′-diphosphate (UDP)-glucuronosyltransferases (UGTs); to date at least 10 different UGT isoforms have been identified. The UGTs are not only involved in the metabolism of many drugs [e.g. morphine, paracetamol (acetaminophen)] but also capable of the biotransformation of important endogenous substrates (e.g. bilirubin, ethinylestradiol) and several xenobiotics. Isoform specificity for these substrates has, however, not been fully characterised.

Serious adverse events associated with chloramphenicol toxicity in the neonate have highlighted the importance of developmental changes in UGT activity. However, isoform-specific differences preclude the generalisation of a simple developmental pattern for UGT activity. UGT2B7 is the only UGT isoform for which ontogeny has been characterised both in vitro and in vivo, using morphine as the probe drug. However, no general developmental pattern for the individual UGT isoforms which might be of value for the clinician is currently available.

Genetic polymorphisms have been identified for the UGT family. Not only for the UGT1A gene, which reduces bilirubin glucuronidation, leading to genetic hyperbilirubinaemia (the Crigler-Najjar and Gilbert’s syndromes), but also for 3 other UGT isoforms. However, the impact of these genetic differences on drug metabolism remains to be established because of overlapping isoform specificity of the drugs studied, as well as a lack of specific probe substrates to test the activity of individual UGT isoforms in relation to these gene mutations.

Clearly, an information gap exists regarding the developmental and genetic aspects of UGT regulation and its potential impact on therapy. More research is needed on the pharmacogenetics and ontogeny of the UGTs for effective translation of scientific information into clinically applicable knowledge.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Morselli PL, Franco-Morselli R, Bossi L. Clinical pharmacokinetics in newborns and infants: age-related differences and therapeutic implications. Clin Pharmacokinet 1980; 5: 485–527.PubMedCrossRefGoogle Scholar
  2. 2.
    Sutherland JM. Fatal cardiovascular collaps of infants receiving large amounts of chloramphenicol. Am J Dis Child 1959; 97: 761–7.Google Scholar
  3. 3.
    Meyer UA. Genotype or phenotype: the definition of a pharmacogenetic polymorphism. Pharmacogenetics 1991; 1 (2): 66–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Kauffman FC. Conjugation-deconjugation reactions in drug metabolism and toxicity [review]. Fed Proc 1987; 46 (7): 2434–45.PubMedGoogle Scholar
  5. 5.
    Jansen PL, Mulder GJ, Burchell B, et al. New developments in glucuronidation research: report of a workshop on ‘glucuronidation, its role in health and disease’ [review]. Hepatology 1992; 15 (3): 532–44.PubMedCrossRefGoogle Scholar
  6. 6.
    Mulder GJ. Glucuronidation and its role in regulation of biological activity of drugs [review]. Annu Rev Pharmacol Toxicol 1992; 32: 25–49.PubMedCrossRefGoogle Scholar
  7. 7.
    Miners JO, Mackenzie PI. Drug glucuronidation in humans. Pharmacol Ther 1991; 51: 347–69.PubMedCrossRefGoogle Scholar
  8. 8.
    Kroemer HK, Klotz U. Glucuronidation of drugs: are-evaluation of the pharmacological significance of the conjugates and modulating factors. Clin Pharmacokinet 1992; 23 (4): 292–310.PubMedCrossRefGoogle Scholar
  9. 9.
    Burchell B, Coughtrie MW. UDP-glucuronosyltransferases [review]. Pharmacol Ther 1989; 43 (2): 261–89.PubMedCrossRefGoogle Scholar
  10. 10.
    Mackenzie PI, Owens IS, Burchell B, et al. The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics 1997; 7 (4): 255–69.PubMedCrossRefGoogle Scholar
  11. 11.
    Burchell B, Brierley CH, Rance D. Specificity of human UDP-glucuronosyltransferases and xenobiotic glucuronidation [review]. Life Sci 1995; 57 (20): 1819–31.PubMedCrossRefGoogle Scholar
  12. 12.
    Paul D, Standifer KM, Inturrisi CE, et al. Pharmacological characterization of morphine-6-beta-glucuronide, a very potent morphine metabolite. J Pharmacol Exp Ther 1989; 251 (2): 477–83.PubMedGoogle Scholar
  13. 13.
    Kretz-Rommel A, Boelsterli UA. Diclofenac covalent protein binding is dependent on acyl glucuronide formation and is inversely related to P450-mediated acute cell injury in cultured rat hepatocytes. Toxicol Appl Pharmacol 1993; 120 (1): 155–61.PubMedCrossRefGoogle Scholar
  14. 14.
    Ding A, Ojingwa JC, McDonagh AF, et al. Evidence for covalent binding of acyl glucuronides to serum albumin via an imine mechanism as revealed by tandem mass spectrometry. Proc Natl Acad Sci U S A 1993; 90 (9): 3797–801.PubMedCrossRefGoogle Scholar
  15. 15.
    Burchell B, Coughtrie WH. Genetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation. Environ Health Perspect 1997; 105 Suppl. 4: 739–47.Google Scholar
  16. 16.
    Ebner T, Remmel RP, Burchell B. Human bilirubin UDP-glucuronosyltransferase catalyzes the glucuronidation of ethinylestradiol. Mol Pharmacol 1993; 43: 649–54.PubMedGoogle Scholar
  17. 17.
    Ritter JK, Chen F, Sheen YY, et al. Two human liver cDNAs encode UDP-glucuronosyltransferases with 2 log differences in activity toward parallel substrates including hyodeoxycholic acid and certain estrogen derivatives. Biochemistry 1992; 31 (13): 3409–14.PubMedCrossRefGoogle Scholar
  18. 18.
    Sutherland L, bin Senafi S, Ebner T, et al. Characterisation of a human bilirubin UDP-glucuronosyltransferase stably expressed in hamster lung fibroblast cell cultures. FEBS Lett 1992; 308 (2): 161–4.PubMedCrossRefGoogle Scholar
  19. 19.
    Iyer L, King CD, Whitington PF, et al. Genetic predisposition to the metabolism of irinotecan (CPT-11): role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 1998; 101 (4): 847–54.PubMedCrossRefGoogle Scholar
  20. 20.
    Green MD, King CD, Mojarrabi B, et al. Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3. Drug Metab Dispos 1998; 26 (6): 507–12.PubMedGoogle Scholar
  21. 21.
    Green MD, Tephly TR. Glucuronidation of amines and hydroxylated xenobiotics and endobiotics catalyzed by expressed human UGT1.4 protein. Drug Metab Dispos 1996; 24 (3): 356–63.PubMedGoogle Scholar
  22. 22.
    Ebner T, Burchell B. Substrate specificities of two stably expressed human liver UDP-glucuronosyltransferases of the UGT1 gene family. Drug Metab Dispos 1993; 21: 50–5.PubMedGoogle Scholar
  23. 23.
    Harding D, Fournel-Gigleux S, Jackson MR, et al. Cloning and substrate specificity of a human phenol UDP-glucuronosyltransferase expressed in COS-7 cells. Proc Natl Acad Sci U S A 1988; 85 (22): 8381–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Bock KW, Forster A, Gsaidmeier H, et al. Paracetamol glucuronidation by recombinant rat and human phenol UDP-glucuronosyltransferases. Biochem Pharmacol 1993; 45 (9): 1809–14.PubMedCrossRefGoogle Scholar
  25. 25.
    Jin C, Miners Jo, Lillywhite KJ, et al. Complementary deoxyribonucleic acid cloning and expression of a human liver uridine diphosphate-glucuronosyltransferase glucuronidating carboxylic acid-containing drugs. J Pharmacol Exp Ther 1993; 264 (1): 475–9.PubMedGoogle Scholar
  26. 26.
    Le Guellec C, Lacarelle B, Villard PH, et al. Glucuronidation of propofol in microsomal fractions from various tissues and species including humans: effect of different drugs. Anesth Analg 1995; 81 (4): 855–61.PubMedGoogle Scholar
  27. 27.
    Mojarrabi B, Mackenzie PI. The human UDP-glucuronosyltransferase, UGT1A10, glucuronidates mycophenolic acid. Biochem Biophys Res Commun 1997; 238: 775–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Fournel-Gigleux S, Jackson MR, Wooster R, et al. Expression of a human liver cDNA encoding a UDP-glucuronosyltransferase catalysing the glucuronidation of hyodeoxycholic acid in cell culture. FEBS Lett 1989; 243 (2): 119–22.PubMedCrossRefGoogle Scholar
  29. 29.
    Pillot T, Ouzzine M, Fournel-Gigleux S, et al. Glucuronidation of hyodeoxycholic acid in human liver. J Biol Chem 1993; 268 (34): 25626–42.Google Scholar
  30. 30.
    Miners JO, Valente L, Lillywhite KJ, et al. Preclinical prediction of factors influencing the elimination of 5,6-dimethylxanthenone-4-acetic acid, a new anticancer drug. Cancer Res 1997; 57 (2): 284–9.PubMedGoogle Scholar
  31. 31.
    Coffman BL, Rios GR, King CD, et al. Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos 1997; 25 (1): 1–4.PubMedGoogle Scholar
  32. 32.
    Coughtrie MW, Ask B, Rane A, et al. The enantioselective glucuronidation of morphine in rats and humans. Evidence for the involvement of more than one UDP-glucuronosyltransferase isoenzyme. Biochem Pharmacol 1989; 38 (19): 3273–80.PubMedCrossRefGoogle Scholar
  33. 33.
    Coffman B, King CD, Rios GR, et al. The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268). Drug Metab Dispos 1998; 26 (1): 73–7.PubMedGoogle Scholar
  34. 34.
    Chen F, Ritter JK, Wang MG, et al. Characterization of a cloned human dihydrotestosterone/androstanediol UDP-glucuronosyltransferase and its comparison to steroid isoforms. Biochemistry 1993; 32 (40): 10648–57.PubMedCrossRefGoogle Scholar
  35. 35.
    Green MD, Oturu EM, Tephly TR. Stable expression of a human liver UDP-glucuronosyltransferase (UGT2B15) with activity toward steroid and xenobiotic substrates. Drug Metab Dispos 1994; 22 (5): 799–805.PubMedGoogle Scholar
  36. 36.
    Beaulieu M, Levesque E, Hum DW, et al. Isolation and characterization of a novel cDNA encoding a human UDP-glucuronosyltransferase active on C19 steroids. J Biol Chem 1996; 271 (37): 22855–62.PubMedCrossRefGoogle Scholar
  37. 37.
    Moghrabi N, Clarke DJ, Boxer M, et al. Identification of an A-to-G missense mutation in exon 2 of the UGT1 gene complex that causes Crigler-Najjar syndrome type 2. Genomics 1993; 18(1): 171–3.CrossRefGoogle Scholar
  38. 38.
    Ritter JK, Chen F, Sheen YY, et al. A novel complex locus UGT1 encodes human bilirubin, phenol and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini. J Biol Chem 1992; 267 (5): 3257–61.PubMedGoogle Scholar
  39. 39.
    Meech R, Mackenzie PI. Structure and function of uridine diphosphate glucuronosyltransferases. Clin Exp Pharmacol Physiol 1997; 24: 907–15.PubMedCrossRefGoogle Scholar
  40. 40.
    Monaghan G, Clarke DJ, Povey S, et al. Isolation of a human YAC contig encompassing a cluster of UGT2 genes and its regional localization to chromosome 4ql3. Genomics 1994; 23 (2): 496–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Beaulieu M, Levesque E, Tchernof A, et al. Chromosomal localization, structure, and regulation of the UGT2B17 gene, encoding a C19 steroid metabolizing enzyme. DNA Cell Biol 1997; 16 (10): 1143–54.PubMedCrossRefGoogle Scholar
  42. 42.
    Schmid R, Hammaker L. Glucuronide formation in patients with constitutional hepatic dysfunction (Gilbert’s disease). N Engl J Med 1959; 260 (26): 1310–4.PubMedCrossRefGoogle Scholar
  43. 43.
    Arias IM. Chronic unconjugated hyperbilirubinemia without overt signs of hemolysis in adolescents and adults. J Clin Invest 1962; 41 (12): 2233–45.PubMedCrossRefGoogle Scholar
  44. 44.
    Bosnia PJ, Seppen J, Goldhoorn B, et al. Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. J Biol Chem 1994; 269 (27): 17960–4.Google Scholar
  45. 45.
    Seppen J, Bosnia BJ, Goldhoorn BG, et al. Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase. J Clin Invest 1994; 94 (6): 2385–91.PubMedCrossRefGoogle Scholar
  46. 46.
    Ciotti M, Yeatman MT, Sokol RJ, et al. Altered coding for a strictly conserved di-glycine in the major bilirubin UDP-glucuronosyltransferase of a Crigler-Najjar type 1 patient. J Biol Chem 1995; 270 (7): 3284–91.PubMedCrossRefGoogle Scholar
  47. 47.
    Koiwai O, Nishizawa M, Hasada K, et al. Gilbert’s syndrome is caused by a heterozygous missense mutation in the gene for bilirubin UDP-glucuronosyltransferase. Hum Mol Genet 1995; 4 (7): 1183–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Sato H, Adachi Y, Koiwai O. The genetic basis of Gilbert’s syndrome [comment]. Lancet 1996; 347 (9001): 557–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Erps LT, Ritter JK, Hersh JH, et al. Identification of two single base substitutions in the UGTl gene locus which abolish bilirubin uridine diphosphate glucuronosyltransferase activity in vitro. J Clin Invest 1994; 93 (2): 564–70.PubMedCrossRefGoogle Scholar
  50. 50.
    Clarke DJ, Moghrabi N, Monaghan G, et al. Genetic defects of the UDP-glucuronosyltransferase-1 (UGT1) gene that cause familial non-haemolytic unconjugated hyperbilirubinaemias. Clin Chim Acta 1997; 266 (1): 63–74.PubMedCrossRefGoogle Scholar
  51. 51.
    Monaghan G, Ryan M, Seddon R, et al. Genetic variation in bilirubin UDP-glucuronosyltransferase gene promotor and Gilbert’s syndrome. Lancet 1996; 347 (9001): 578–81.PubMedCrossRefGoogle Scholar
  52. 52.
    Bosnia PJ, Chowdhury JR, Bakker C, 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.CrossRefGoogle Scholar
  53. 53.
    Monaghan G, Foster B, Jurima-Romet M, et al. UGT1*1 genotyping in a Canadian Inuit population. Pharmacogenetics 1997; 7 (2): 153–6.PubMedCrossRefGoogle Scholar
  54. 54.
    Ando Y, Chida M, Nakayama K, et al. The UGT1A1*28 allele is relatively rare in a Japanese population. Pharmacogenetics 1998; 8 (4): 357–60.PubMedCrossRefGoogle Scholar
  55. 55.
    Maruo Y, Sato H, Yamano T, et al. Gilbert syndrome caused by a homozygous missense mutation (Tyr486Asp) of bilirubin UDP-glucuronosyltransferase gene. J Pediatr 1998; 132 (6): 1045–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Ciotti M, Marrone A, Potter C, et al. Genetic polymorphism in the human UGT1A6 (planar phenol) UDP-glucuronosyltransferase: pharmacological implications. Pharmacogenetics 1997; 7 (6): 485–95.PubMedCrossRefGoogle Scholar
  57. 57.
    Levesque E, Beaulieu M, Green MD, et al. Isolation and characterization of UGT2B15(Y85): a UDP-glucuronosyltransferase encoded by a polymorphic gene. Pharmacogenetics 1997; 7 (4): 317–25.PubMedCrossRefGoogle Scholar
  58. 58.
    Vincent-Viry M, Cossy C, Galteau MM, et al. Lack of a genetic polymorphism in the glucuronidation of fenofibric acid. Pharmacogenetics 1995; 5 (1): 50–2.PubMedCrossRefGoogle Scholar
  59. 59.
    Duche JC, Querol-Ferrer V, Barre J, et al. Dextromethorphan O-demethylation and dextrorphan glucuronidation in a French population. Int J Clin Pharmacol Ther Toxicol 1993; 31 (8): 392–8.PubMedGoogle Scholar
  60. 60.
    Liu HF, Vincent-Viry M, Galteau MM, et al. Urinary glucuronide excretion of fenofibric and clofibric acid glucuronides in man: is it polymorphic? Eur J Clin Pharmacol 1991; 41 (2): 153–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Yue QY, Svensson JO, Alm C, et al. Interindividual and interethnic differences in the demethylation and glucuronidation of codeine. Br J Clin Pharmacol 1989; 28 (6): 629–37.PubMedCrossRefGoogle Scholar
  62. 62.
    Zhou HH, Sheller JR, Nu H, et al. Ethnic differences in response to morphine. Clin Pharmacol Ther 1993; 54 (5): 507–13.PubMedCrossRefGoogle Scholar
  63. 63.
    Wasserman E, Myara A, Lokiec F, et al. Severe CPT-11 toxicity in patients with Gilbert’s syndrome: two case reports. Ann Oncol 1997; 8 (10): 1049–51.PubMedCrossRefGoogle Scholar
  64. 64.
    Ullrich D, Sieg A, Blume R, et al. Normal pathways for glucuronidation, sulphation and oxidation of paracetamol in Gilbert’s syndrome. Eur J Clin Invest 1987; 17 (3): 237–40.PubMedCrossRefGoogle Scholar
  65. 65.
    Esteban A, Perez-Mateo M. Gilbert’s disease: a risk factor for paracetamol overdosage? [letter]. J Hepatol 1993; 18 (2): 257–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Weiss CF, Glazko AJ, Weston JK. Chloramphenicol in the newborn infant: a physiological explanation of its toxicity when given in excessive doses. N Engl J Med 1960; 262 (16): 787–94.PubMedCrossRefGoogle Scholar
  67. 67.
    Levy G, Khanna NN, Soda DM, et al. Pharmacokinetics of acetaminophen in the human neonate: formation of acetaminophen glucuronide and sulfate in relation to plasma bilirubin concentration and D-glucaric acid excretion. Pediatrics 1975; 55 (6): 818–25.PubMedGoogle Scholar
  68. 68.
    Reiter PD, Stiles AD. Lorazepam toxicity in a premature infant. Ann Pharmacother 1993; 27 (6): 727–9.PubMedGoogle Scholar
  69. 69.
    McRorie TI, Lynn AM, Nespeca MK, et al. The maturation of morphine clearance and metabolism. Am J Dis Child 1992; 146 (8): 972–6.PubMedGoogle Scholar
  70. 70.
    Hume R, Coughtrie MW, Burchell B. Differential localisation of UDP-glucuronosyltransferase in kidney during human embryonic and fetal development. Arch Toxicol 1995; 69 (4): 242–7.PubMedCrossRefGoogle Scholar
  71. 71.
    Hume R, Burchell A, Allan BB, et al. The ontogeny of key endoplasmic reticulum proteins in human embryonic and fetal red blood cells. Blood 1996; 87 (2): 762–70.PubMedGoogle Scholar
  72. 72.
    Onishi S, Kawade N, Itoh S, et al. Postnatal development of uridine diphosphate glucuronyltransferase activity towards bilirubin and 2-aminophenol in human liver. Biochem J 1979; 184 (3): 705–7.PubMedGoogle Scholar
  73. 73.
    Burchell B, Coughtrie M, Jackson M, et al. Development of human liver UDP-glucuronosyltransferases. Dev Pharmacol Ther 1989; 13 (2–4): 70–7.PubMedGoogle Scholar
  74. 74.
    Coughtrie MW, Burchell B, Leakey JE, et al. 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
  75. 75.
    Leakey JEA, Hume R, Burchell B. Development of multiple activities of UDP-glucuronyltransferase in human liver. Biochem J 1987; 243: 859–61.PubMedGoogle Scholar
  76. 76.
    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.PubMedGoogle Scholar
  77. 77.
    Bancroft JD, Kreamer B, Gourley GR. Gilbert syndrome accelerates development of neonatal jaundice. J Pediatr 1998; 132: 656–60.PubMedCrossRefGoogle Scholar
  78. 78.
    Kaplan M, Renbaum P, Levy-Lahad E, et al. Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc Natl Acad Sci USA 1997; 94 (22): 12128–32.PubMedCrossRefGoogle Scholar
  79. 79.
    Pacifici GM, Franchi M, Giuliani L, et al. Development of the glucuronyltransferase and sulphotransferase towards 2-naphthol in human fetus. Dev Pharmacol Ther 1989; 14(2): 108–14.Google Scholar
  80. 80.
    Pacifici GM, Sawe J, Kager L, et al. Morphine glucuronidation in human fetal and adult liver. Eur J Clin Pharmacol 1982; 22 (6): 553–8.PubMedCrossRefGoogle Scholar
  81. 81.
    Choonara IA, McKay P, Hane R, et al. Morphine metabolism in children. Br J Clin Pharmacol 1989; 28 (5): 599–604.PubMedCrossRefGoogle Scholar
  82. 82.
    Anderson BJ, McKee AD, Holford NH. Size, myths and the clinical pharmacokinetics of analgesia in paediatric patients. Clin Pharmacokinet 1997; 33 (5): 313–27.PubMedCrossRefGoogle Scholar
  83. 83.
    Koren G, Butt W, Chinyanga H, et al. Postoperative morphine infusion in newborn infants: assessment of disposition characteristics and safety. J Pediatr 1985; 107 (6): 963–7.PubMedCrossRefGoogle Scholar
  84. 84.
    Moreland TA, Brice JE, Walker CH, et al. Naloxone pharmacokinetics in the newborn. Br J Clin Pharmacol 1980; 9 (6): 609–12.PubMedCrossRefGoogle Scholar
  85. 85.
    Cummings AJ, Whitelaw AGL. A study of conjugation and drug elimination in the human neonate. Br J Clin Pharmacol 1981; 12: 511–5.PubMedCrossRefGoogle Scholar
  86. 86.
    Crom WR, Relling MV, Christensen ML, et al. Age-related differences in hepatic drug clearance in children: studies with lorazepam and antipyrine. Clin Pharmacol Ther 1991; 50 (2): 132–40.PubMedCrossRefGoogle Scholar
  87. 87.
    Tomson G, Lunell NO, Sundwall A, et al. Placental passage of oxazepam and its metabolism in mother and newborn. Clin Pharmacol Ther 1979; 25 (1): 74–81.PubMedGoogle Scholar
  88. 88.
    Patel M, Tang BK, Grant DM, et al. Interindividual variability in the glucuronidation of (S) oxazepam contrasted with that of (R) oxazepam. Pharmacogenetics 1995; 5 (5): 287–97.PubMedCrossRefGoogle Scholar
  89. 89.
    Garrettson LK, Procknal JA, Levy G. Fetal acquisition and neonatal elimination of a large amount of salicylate: study of a neonate whose mother regularly took therapeutic doses of aspirin during pregnancy. Clin Pharmacol Ther 1975; 17 (1): 98–103.PubMedGoogle Scholar
  90. 90.
    Levy G, Garrettson LK. Kinetics of salicylate elimination by newborn infants of mothers who ingested aspirin before delivery. Pediatrics 1974; 53 (2): 201–10.PubMedGoogle Scholar
  91. 91.
    Rollins DE, von Bahr C, Glaumann H, et al. Acetaminophen: potentially toxic metabolite formed by human fetal and adult liver microsomes and isolated fetal liver cells. Science 1979; 205 (4413): 1414–6.PubMedCrossRefGoogle Scholar
  92. 92.
    Alam SN, Roberts RJ, Fischer LJ. Age-related differences in salicylamide and acetaminophen conjugation in man. J Pediatr 1977; 90 (1): 130–5.PubMedCrossRefGoogle Scholar
  93. 93.
    Murat I, Billard V, Vernois J, et al. Pharmacokinetics of propofol after a single dose in children aged 1–3 years with minor burns: comparison of three data analysis approaches. Anesthesiology 1996; 84 (3): 526–32.PubMedCrossRefGoogle Scholar
  94. 94.
    Kataria BK, Ved SA, Nicodemus HF, et al. The pharmacokinetics of propofol in children using three different data analysis approaches. Anesthesiology 1994; 80 (1): 104–22.PubMedCrossRefGoogle Scholar
  95. 95.
    Reed MD, Yamashita TS, Marx CM, et al. A pharmacokinetically based propofol dosing strategy for sedation of the critically ill mechanically ventilated pediatric patient. Crit Care Med 1996; 24 (9): 1473–81.PubMedCrossRefGoogle Scholar
  96. 96.
    Gray PA, Park GR, Cockshott ID, et al. Propofol metabolism in man during the anhepatic and reperfusion phases of liver transplantation. Xenobiotica 1992; 22 (1): 105–14.PubMedCrossRefGoogle Scholar
  97. 97.
    Rajaonarison JF, Lacarelle B, De Sousa G, et al. In vitro glucuronidation of 3′-azido-3′-deoxythymidine by human liver: role of UDP-glucuronosyltransferase 2 form. Drug Metab Dispos 1991; 19 (4): 809–15.PubMedGoogle Scholar
  98. 98.
    Boucher FD, Modlin JF, Weiler S, et al. Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus. J Pediatr 1993; 122 (1): 137–44.PubMedCrossRefGoogle Scholar
  99. 99.
    Bakshi SS, Britta P, Capparelli E, et al. Evaluation of pharmacokinetics, safety, tolerance, and activity of combination of zalcitabine and zidovudine in stable, zidovudine-treated pediatric patients with human immunodeficiency virus infection: AIDS Clinical Trials Group Protocol 190 Team. J Infect Dis 1997; 175 (5): 1039–50.PubMedCrossRefGoogle Scholar
  100. 100.
    Pacifici GM, Kubrich M, Giuliani L, et al. Sulphation and glucuronidation of ritodrine in human foetal and adult tissues. Eur J Clin Pharmacol 1993; 44 (3): 259–64.PubMedCrossRefGoogle Scholar
  101. 101.
    Brashear WT, Kuhnert BR, Wei R. Maternal and neonatal urinary excretion of sulfate and glucuronide ritodrine conjugates. Clin Pharmacol Ther 1988; 44 (6): 634–41.PubMedCrossRefGoogle Scholar
  102. 102.
    Holford NH. A size standard for pharmacokinetics. Clin Pharmacokinet 1996; 30 (5): 329–32.PubMedCrossRefGoogle Scholar
  103. 103.
    Munzel PA, Bookjans G, Mehner G, et al. Tissue-specific 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible expression of human UDP-glucuronosyltransferase UGT1A6. Arch Biochem Biophys 1996; 335 (1): 205–10.PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1999

Authors and Affiliations

  • Saskia N. de Wildt
    • 1
    • 2
  • Gregory L. Kearns
    • 3
  • J. Steven Leeder
    • 3
  • John N. van den Anker
    • 1
    • 2
  1. 1.Department of PediatricsErasmus University and University HospitalRotterdamThe Netherlands
  2. 2.Sophia Children’s HospitalRotterdamThe Netherlands
  3. 3.Section of Pediatric Clinical Pharmacology and Experimental Therapeutics, Childrens Mercy HospitalUniversity of Missouri-Kansas CityUSA

Personalised recommendations