Pharmacokinetics in the newborn.

In addition to differences in the pharmacodynamic response in the infant, the dose and the pharmacokinetic processes acting upon that dose principally determine the efficacy and/or safety of a therapeutic or inadvertent exposure. At a given dose, significant differences in therapeutic efficacy and toxicant susceptibility exist between the newborn and adult. Immature pharmacokinetic processes in the newborn predominantly explain such differences. With infant development, the physiological and biochemical processes that govern absorption, distribution, metabolism, and excretion undergo significant growth and maturational changes. Therefore, any assessment of the safety associated with an exposure must consider the impact of these maturational changes on drug pharmacokinetics and response in the developing infant. This paper reviews the current data concerning the growth and maturation of the physiological and biochemical factors governing absorption, distribution, metabolism, and excretion. The review also provides some insight into how these developmental changes alter the efficiency of pharmacokinetics in the infant. Such information may help clarify why dynamic changes in therapeutic efficacy and toxicant susceptibility occur through infancy.

[1]  M. Cappiello,et al.  Differential distribution of phenol and catechol sulphotransferases in human liver and intestinal mucosa. , 1990, Pharmacology.

[2]  J. Kasik,et al.  Postconceptional age and gentamicin elimination half-life. , 1985, The Journal of pediatrics.

[3]  J. Guignard,et al.  Glomerular filtration rate in the first three weeks of life. , 1975, The Journal of pediatrics.

[4]  T. Cresteil,et al.  Delayed ontogenesis of CYP1A2 in the human liver. , 1998, European journal of biochemistry.

[5]  A. Aperia,et al.  Correlation between fluid reabsorption and proximal tubule ultrastructure during development of the rat kidney. , 1979, Acta physiologica Scandinavica.

[6]  R. Obach,et al.  Metabolic characterization of the major human small intestinal cytochrome p450s. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[7]  J. Kolars,et al.  Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. , 1992, The Journal of clinical investigation.

[8]  A. Rane,et al.  Morphine glucuronidation in human fetal and adult liver , 2004, European Journal of Clinical Pharmacology.

[9]  G. Kearns,et al.  Clinical Pharmacokinetics in Infants and Children , 1989, Clinical pharmacokinetics.

[10]  L. Herngren,et al.  Drug binding to plasma proteins during human pregnancy and in the perinatal period. Studies on cloxacillin and alprenolol. , 1983, Developmental pharmacology and therapeutics.

[11]  E. Tanaka Update: genetic polymorphism of drug metabolizing enzymes in humans , 1999, Journal of clinical pharmacy and therapeutics.

[12]  D. G. McCarver,et al.  The ontogeny of human drug-metabolizing enzymes: phase II conjugation enzymes and regulatory mechanisms. , 2002, The Journal of pharmacology and experimental therapeutics.

[13]  H. Michels,et al.  Differences in the binding of drugs to plasma proteins from newborn and adult man. II , 1977, European Journal of Clinical Pharmacology.

[14]  J. Randolph,et al.  Gastric acidity in the first day of life. , 1966, Pediatrics.

[15]  D. G. McCarver,et al.  The ontogeny of human drug-metabolizing enzymes: phase I oxidative enzymes. , 2002, The Journal of pharmacology and experimental therapeutics.

[16]  J. Magny,et al.  Population pharmacokinetics of midazolam in neonates , 1994, Clinical pharmacology and therapeutics.

[17]  G. Gibbs,et al.  Gastric acidity on the first day of life. , 1956, Pediatrics.

[18]  A. Rane,et al.  Development of the glucuronyltransferase and sulphotransferase towards 2-naphthol in human fetus. , 1989, Developmental pharmacology and therapeutics.

[19]  W. Peters,et al.  Expression of Glutathione S‐Transfer α, P1–1 and T1–1 in the Human Gastrointestinal Tract , 2000, Japanese journal of cancer research : Gann.

[20]  D. Dunbar,et al.  Characterization of human small intestinal cytochromes P-450. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[21]  G. Heimann Enteral absorption and bioavailability in children in relation to age , 1980, European Journal of Clinical Pharmacology.

[22]  William J. Jusko,et al.  Berichten , 2005, Pharmaceutisch weekblad.

[23]  T. Deguchi,et al.  Cloning and expression of cDNAs for polymorphic and monomorphic arylamine N-acetyltransferases from human liver. , 1990, The Journal of biological chemistry.

[24]  F. Gallini,et al.  Cardiac Adverse Effects of Early Dexamethasone Treatment in Preterm Infants: A Randomized Clinical Trial , 2001, Journal of clinical pharmacology.

[25]  R. Hume,et al.  The development expression of alpha-, mu- and pi-class glutathione S-transferases in human liver. , 1989, Biochimica et biophysica acta.

[26]  W. Stigelman,et al.  Goodman and Gilman's the Pharmacological Basis of Therapeutics , 1986 .

[27]  J. Emery,et al.  The late intrauterine and postnatal development of human renal glomeruli. , 1959, Journal of anatomy.

[28]  J. Koup,et al.  Relationship between plasma and whole blood theophylline concentration in neonates. , 1979, The Journal of pediatrics.

[29]  M. Kuo,et al.  Postnatal development of organic cation transport and mdr gene expression in mouse kidney. , 1992, The Journal of pharmacology and experimental therapeutics.

[30]  U. Schumacher,et al.  The multidrug-resistance P-glycoprotein (Pgp, MDR1) is an early marker of blood-brain barrier development in the microvessels of the developing human brain , 1997, Histochemistry and Cell Biology.

[31]  P. Brick,et al.  Fatty acid binding to human serum albumin: new insights from crystallographic studies. , 1999, Biochimica et biophysica acta.

[32]  D. Holt,et al.  Metabolism of chloramphenicol by glutathione S-transferase in human fetal and neonatal liver. , 1995, Biology of the neonate.

[33]  R. Pildes,et al.  Effect of posture on the pattern of stomach emptying in the newborn. , 1979, Pediatrics.

[34]  W. Oh,et al.  Inulin Clearance in the Newborn Infant: Relationship to Gestational and Postnatal Age , 1976, Pediatric Research.

[35]  M. Manns,et al.  UDP-glucuronosyltransferase activity in human liver and colon. , 1999, Gastroenterology.

[36]  A. Rane,et al.  Prenatal and neonatal drug metabolism in man , 1980, European Journal of Clinical Pharmacology.

[37]  T. Cresteil,et al.  Developmental expression of CYP2C and CYP2C-dependent activities in the human liver: in-vivo/in-vitro correlation and inducibility. , 1997, Pharmacogenetics.

[38]  J. Hook,et al.  Perinatal renal pharmacology. , 1979, Annual review of pharmacology and toxicology.

[39]  H. Yamazaki,et al.  Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. , 1994, The Journal of pharmacology and experimental therapeutics.

[40]  D. Grant,et al.  Monomorphic and polymorphic human arylamine N-acetyltransferases: a comparison of liver isozymes and expressed products of two cloned genes. , 1991, Molecular pharmacology.

[41]  W. Hop,et al.  Ceftazidime pharmacokinetics in preterm infants: Effects of renal function and gestational age , 1995, Clinical pharmacology and therapeutics.

[42]  Kelly L. Lundstrom,et al.  Morphine pharmacokinetics in premature and mature newborn infants , 1994, Acta paediatrica.

[43]  P. Gow,et al.  Neonatal hepatic drug elimination. , 2001, Pharmacology & toxicology.

[44]  S. Wrighton,et al.  Tissue distribution and interindividual variation in human UDP-glucuronosyltransferase activity: relationship between UGT1A1 promoter genotype and variability in a liver bank. , 2000, Pharmacogenetics.

[45]  G. Haycock Development of glomerular filtration and tubular sodium reabsorption in the human fetus and newborn. , 1998, British journal of urology.

[46]  A. Rane,et al.  Plasma protein binding of diphenylhydantoin in normal and hyperbilirubinemic infants. , 1971, The Journal of pediatrics.

[47]  A. Pession,et al.  Extracorporeal photochemotherapy for treatmentof acute and chronic GVHD in childhood , 2001, Transfusion.

[48]  G. Glass,et al.  Correlative study of hydrochloric acid, pepsin, and intrinsic factor secretion in newborns and infants , 1969, The American Journal of Digestive Diseases.

[49]  J. Hakkola,et al.  Developmental expression of cytochrome P450 enzymes in human liver. , 1998, Pharmacology & toxicology.

[50]  S. Yaffe DEVELOPMENTAL FACTORS INFLUENCING INTERACTIONS OF DRUGS * , 1976, Annals of the New York Academy of Sciences.

[51]  B. Nichols,et al.  Comparison of patterns of fecal bile acid and neutral sterol between children and adults. , 1976, The American journal of clinical nutrition.

[52]  P. Beaune,et al.  Intralobular distribution and quantitation of cytochrome P‐450 enzymes in human liver as a function of age , 1991, Hepatology.

[53]  J. Hakkola,et al.  Expression of xenobiotic-metabolizing cytochrome P450 forms in human adult and fetal liver. , 1994, Biochemical pharmacology.

[54]  W. Oldendorf,et al.  Increased Blood—Brain Barrier Transport of Protein-Bound Anticonvulsant Drugs in the Newborn , 1983, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[55]  W. Hop,et al.  Ceftazidime pharmacokinetics in preterm infants: effect of postnatal age and postnatal exposure to indomethacin. , 1995, British journal of clinical pharmacology.

[56]  Y. Suzuki,et al.  Developmental changes in the regional Na+/glucose transporter mRNA along the small intestine of suckling rats. , 1999, Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology.

[57]  A. Hess THE GASTRIC SECRETION OF INFANTS AT BIRTH , 1913 .

[58]  W. Pearson,et al.  Nomenclature for human glutathione transferases. , 1992, The Biochemical journal.

[59]  V. Drossou,et al.  Serum concentrations of 10 acute-phase proteins in healthy term and preterm infants from birth to age 6 months. , 1995, Clinical chemistry.

[60]  B. Friis‐Hansen Body composition during growth. In vivo measurements and biochemical data correlated to differential anatomical growth. , 1971, Pediatrics.

[61]  J. Glickstein,et al.  Developmental changes in renal blood flow velocity. , 1997, Jornal de Pediatria.

[62]  B. Assael Pharmacokinetics and drug distribution during postnatal development. , 1982, Pharmacology & therapeutics.

[63]  S. Imaoka,et al.  A comparison of hepatic cytochrome P450 protein expression between infancy and postinfancy. , 1997, Life sciences.

[64]  Routledge Pa Clinical relevance of alpha 1 acid glycoprotein in health and disease. , 1989 .

[65]  A. Fantel,et al.  Human embryonic cytochrome P450S: phenoxazone ethers as probes for expression of functional isoforms during organogenesis. , 1991, Biochemical pharmacology.

[66]  L. Weaver,et al.  Ontogeny of human pancreatic exocrine function. , 1993, Archives of disease in childhood.

[67]  D W Nebert,et al.  The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. , 1997, Pharmacogenetics.

[68]  G. Fetterman,et al.  THE GROWTH AND MATURATION OF HUMAN GLOMERULI AND PROXIMAL CONVOLUTIONS FROM TERM TO ADULTHOOD: STUDIES BY MICRODISSECTION. , 1965, Pediatrics.

[69]  T. Visser,et al.  Sulfation of thyroid hormone and dopamine during human development: ontogeny of phenol sulfotransferases and arylsulfatase in liver, lung, and brain. , 2001, The Journal of clinical endocrinology and metabolism.

[70]  M. Rubin,et al.  Maturation of renal function in childhood; clearance studies. , 1949, The Journal of clinical investigation.

[71]  O. Pelkonen,et al.  Characterization of human fetal hepatic cytochrome P-450-associated 7-ethoxyresorufin O-deethylase and aryl hydrocarbon hydroxylase activities by monoclonal antibodies. , 1987, Developmental pharmacology and therapeutics.

[72]  D. Beier,et al.  Developmentally regulated expression of organic ion transporters NKT (OAT1), OCT1, NLT (OAT2), and Roct. , 2000, American journal of physiology. Renal physiology.

[73]  M. Ehrnebo,et al.  Age differences in drug binding by plasma proteins: Studies on human foetuses, neonates and adults , 1971, European Journal of Clinical Pharmacology.

[74]  M Rowland,et al.  Differentiation of absorption and first‐pass gut and hepatic metabolism in humans: Studies with cyclosporine , 1995, Clinical pharmacology and therapeutics.

[75]  F. Mattheyse,et al.  The pharmacokinetics of midazolam in paediatric patients , 2004, European Journal of Clinical Pharmacology.

[76]  T. Fournier,et al.  Alpha-1-acid glycoprotein. , 2000, Biochimica et biophysica acta.

[77]  Ann Daly,et al.  Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression , 2001, Nature Genetics.

[78]  J. Lasker,et al.  Expression, induction, and catalytic activity of the ethanol-inducible cytochrome P450 (CYP2E1) in human fetal liver and hepatocytes. , 1996, Molecular pharmacology.

[79]  M. Gupta,et al.  Gastric retention in neonates. , 1978, Pediatrics.

[80]  B. Burchell,et al.  Genetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation. , 1997, Environmental health perspectives.

[81]  P. Morselli,et al.  Clinical Pharmacokinetics in Newborns and Infants , 1980 .

[82]  J. Guignard,et al.  Renal Function in Preterm Neonates , 1994, Pediatric Research.

[83]  M. Jackson,et al.  Development of human liver UDP-glucuronosyltransferases. , 1989, Developmental pharmacology and therapeutics.

[84]  A. J. Heijden,et al.  Glomerular filtration rate in the preterm infant: the relation to gestational and postnatal age , 1988, European Journal of Pediatrics.

[85]  J. Hochman,et al.  Comparative studies of drug-metabolizing enzymes in dog, monkey, and human small intestines, and in Caco-2 cells. , 1996, Drug metabolism and disposition: the biological fate of chemicals.

[86]  B. Arant,et al.  Developmental patterns of renal functional maturation compared in the human neonate. , 1978, The Journal of pediatrics.

[87]  J. Blumer,et al.  Principles of drug biodisposition in the neonate. A critical evaluation of the pharmacokinetic-pharmacodynamic interface (Part II). , 1988, Clinical pharmacokinetics.

[88]  T. Kamataki,et al.  Cytochrome P450 in human fetal liver: significance and fetal-specific expression. , 1994, Drug metabolism reviews.

[89]  P. Morselli Clinical Pharmacology of the Perinatal Period and Early Infancy , 1989, Clinical pharmacokinetics.

[90]  A. Warner Drug use in the neonate: interrelationships of pharmacokinetics, toxicity, and biochemical maturity. , 1986, Clinical chemistry.

[91]  H. L. Barnett,et al.  Renal clearances of sodium penicillin G, procaine penicillin G, and inulin in infants and children. , 1949, Pediatrics.

[92]  Y. Sugiyama,et al.  Recent Advances in Carrier-mediated Hepatic Uptake and Biliary Excretion of Xenobiotics , 1996, Pharmaceutical Research.

[93]  M. S. Ching,et al.  Fetal hepatic drug elimination. , 1999, Pharmacology & therapeutics.

[94]  P. Klein,et al.  Bile-salt metabolism in the newborn. Measurement of pool size and synthesis by stable isotope technic. , 1973, The New England journal of medicine.

[95]  B. Burchell,et al.  Development of multiple activities of UDP-glucuronyltransferase in human liver. , 1987, The Biochemical journal.

[96]  S. Salminen,et al.  Development of intestinal bacterial enzymes in infants ‐ relationship to mode of delivery and type of feeding , 1999, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[97]  L Hendeles,et al.  Theophylline A “State of the Art” Review , 1983, Pharmacotherapy.

[98]  John T. Wilson,et al.  Clinical Pharmacokinetics in Infants and Children , 1976, Clinical pharmacokinetics.

[99]  W. Charman,et al.  The Mucosa of the Small Intestine , 2002, Clinical pharmacokinetics.

[100]  E. C. Ralph,et al.  Pharmacokinetics of orally administered furosemide , 1974 .

[101]  J. Blumer,et al.  Principles of Drug Biodisposition in the Neonate , 2012 .

[102]  J. Dereń,et al.  Development of structure and function in the fetal and newborn stomach. , 1971, The American journal of clinical nutrition.

[103]  D. Heilbron,et al.  Expressing glomerular filtration rate in children , 2004, Pediatric Nephrology.

[104]  J. R. West,et al.  Glomerular filtration rate, effective renal blood flow, and maximal tubular excretory capacity in infancy. , 1948, The Journal of pediatrics.

[105]  T. Cresteil,et al.  Cytochrome P-450 expression in sudden infant death syndrome. , 1996, Biochemical pharmacology.

[106]  M. Richard,et al.  Caffeine Acetylator Phenotyping during Maturation in Infants , 1990, Pediatric Research.

[107]  E. L. Potter Normal and abnormal development of the kidney , 1972 .

[108]  R. Leake,et al.  Glomerular Filtration Rate during the Period of Adaptation to Extrauterine Life , 1977, Pediatric Research.

[109]  S. Ohmori,et al.  Steroid hydroxylation by human fetal CYP3A7 and human NADPH-cytochrome P450 reductase coexpressed in insect cells using baculovirus. , 1998, Research communications in molecular pathology and pharmacology.

[110]  H. Yamazaki,et al.  Characterization of microsomal cytochrome P450 enzymes involved in the oxidation of xenobiotic chemicals in human fetal liver and adult lungs. , 1996, Drug metabolism and disposition: the biological fate of chemicals.

[111]  A. Aperia,et al.  POSTNATAL DEVELOPMENT OF RENAL FUNCTION IN PRE‐TERM AND FULL‐TERM INFANTS , 1981, Acta paediatrica Scandinavica.

[112]  E. Hiatt,et al.  Development of Renal Function in Fetal and Neo-Natal Rabbits Using Phenolsulfonphthalein.∗ , 1947, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[113]  H. Nau,et al.  Decreased serum protein binding of diazepam and its major metabolite in the neonate during the first postnatal week relate to increased free fatty acid levels. , 1984, British journal of clinical pharmacology.

[114]  E. Lumbers,et al.  The secretion of organic acids and bases by the ovine fetal kidney , 1990, Experimental physiology.

[115]  L. Cousins,et al.  Increased serum gastrin concentrations and gastric acid hyposecretion in the immediate newborn period. , 1977, Gastroenterology.

[116]  J. Raufman,et al.  Glucuronidation of estrogens and retinoic acid and expression of UDP-glucuronosyltransferase 2B7 in human intestinal mucosa. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[117]  A. Rettie,et al.  Functional cytochrome P4503A isoforms in human embryonic tissues: expression during organogenesis. , 1994, Molecular pharmacology.

[118]  O. Pelkonen Biotransformation of xenobiotics in the fetus. , 1980, Pharmacology & therapeutics.

[119]  C. Berseth Gestational evolution of small intestine motility in preterm and term infants. , 1989, The Journal of pediatrics.

[120]  S. Conroy,et al.  Unlicensed and Off-Label Drug Use in Children , 2002, Drug safety.

[121]  C. S. Yang,et al.  Modulation of cytochrome P450 isozymes in human liver, by ethanol and drug intake , 1989, European journal of clinical investigation.

[122]  F. Smith,et al.  Interrelationship between glomerular filtration rate and renal transport of sodium and chloride during fetal life. , 1977, American journal of obstetrics and gynecology.

[123]  Malcolm Rowland,et al.  Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance , 1977, Journal of Pharmacokinetics and Biopharmaceutics.

[124]  U. Klotz,et al.  Extrahepatic Metabolism of Drugs in Humans , 1994, Clinical pharmacokinetics.

[125]  E. Lebenthal,et al.  Development of functional responses in human exocrine pancreas. , 1980, Pediatrics.

[126]  G. Dutton Developmental aspects of drug conjugation, with special reference to glucuronidation. , 1978, Annual review of pharmacology and toxicology.

[127]  J. Steven Leeder,et al.  Glucuronidation in Humans , 1999, Clinical pharmacokinetics.

[128]  E. Signer,et al.  Bile acid metabolism in infants and children. , 1974, Gut.

[129]  C. Berseth Effect of early feeding on maturation of the preterm infant's small intestine. , 1992, The Journal of pediatrics.

[130]  A. Rane,et al.  Glutathione-S-transferase in human fetal liver. , 1981, Biochemical pharmacology.

[131]  J. Hook,et al.  Development of mechanisms for drug excretion. , 1977, The American journal of medicine.

[132]  N. Huang,et al.  Comparison of serum levels following the administration of oral and parenteral preparations of penicillin to infants and children of various age groups. , 1953, The Journal of pediatrics.

[133]  F. Bazzoli,et al.  Serum Bile Acids in Newborns and Children , 1980, Pediatric Research.

[134]  W. Balistreri Immaturity of hepatic excretory function and the ontogeny of bile acid metabolism. , 1983, Journal of pediatric gastroenterology and nutrition.

[135]  P. Milla,et al.  Intestinal motility during ontogeny and intestinal pseudo-obstruction in children. , 1996, Pediatric clinics of North America.

[136]  A. Rane,et al.  Polymorphic acetylation of 7-amino-clonazepam in human liver cytosol. , 1984, Pediatric pharmacology.

[137]  M. Reed,et al.  Developmental pharmacology: ontogenic basis of drug disposition. , 1989, Pediatric clinics of North America.

[138]  R Hume,et al.  Sulfation of endogenous compounds and xenobiotics--interactions and function in health and disease. , 1994, Chemico-biological interactions.

[139]  D. Shen,et al.  Oral first‐pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A‐mediated metabolism , 1996, Clinical pharmacology and therapeutics.

[140]  A. Rane,et al.  Sulphation and glucuronidation of ritodrine in human foetal and adult tissues , 2004, European Journal of Clinical Pharmacology.

[141]  R. Fontana,et al.  Molecular and physical mechanisms of first-pass extraction. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[142]  T. Cresteil,et al.  Developmental expression of CYP2E1 in the human liver. Hypermethylation control of gene expression during the neonatal period. , 1996, European journal of biochemistry.

[143]  T. Rosen,et al.  A short review of perinatal pharmacology. , 1983, Bulletin of the New York Academy of Medicine.

[144]  D. Shen,et al.  First‐pass metabolism of midazolam by the human intestine , 1996, Clinical pharmacology and therapeutics.

[145]  C. Rudolph,et al.  Development of gastrointestinal motility in the infant and child. , 1994, Gastroenterology clinics of North America.

[146]  J. Anker Pharmacokinetics and renal function in preterm infants , 1996 .

[147]  I. Szórády,et al.  Drug acetylator phenotypes in newborn infants. , 1987, Biological research in pregnancy and perinatology.

[148]  B. Rumack,et al.  Pharmacology of furosemide in the premature newborn infant. , 1980, The Journal of pediatrics.

[149]  P. Moldéus,et al.  Acetaminophen: potentially toxic metabolite formed by human fetal and adult liver microsomes and isolated fetal liver cells. , 1979, Science.

[150]  A. Rane,et al.  Acetyltransferase in humans: development and tissue distribution. , 1986, Pharmacology.

[151]  B. Burchell,et al.  The inadequacy of perinatal glucuronidation: immunoblot analysis of the developmental expression of individual UDP-glucuronosyltransferase isoenzymes in rat and human liver microsomes. , 1988, Molecular pharmacology.

[152]  P. Beaune,et al.  Immunoquantification of epoxide hydrolase and cytochrome P-450 isozymes in fetal and adult human liver microsomes. , 1985, European journal of biochemistry.

[153]  R. A. Miller Observations on the gastric acidity during the first month of life , 1941, Archives of disease in childhood.

[154]  T. Cresteil Onset of xenobiotic metabolism in children: toxicological implications. , 1998, Food additives and contaminants.

[155]  R. Hume,et al.  Studies of the development of basic, neutral and acidic isoenzymes of glutathione S-transferase in human liver, adrenal, kidney and spleen. , 1987, The Biochemical journal.

[156]  Jane Alcorn,et al.  Ontogeny of Hepatic and Renal Systemic Clearance Pathways in Infants Part I , 2002, Clinical pharmacokinetics.

[157]  Akira Tsuji,et al.  Carrier-Mediated Intestinal Transport of Drugs , 1996, Pharmaceutical Research.

[158]  S. Cagen,et al.  Characteristics of hepatic excretory function during development. , 1979, The Journal of pharmacology and experimental therapeutics.

[159]  M. Coulthard,et al.  Maturation of glomerular filtration in preterm and mature babies. , 1985, Early human development.

[160]  P. van Bladeren,et al.  Glutathione S-transferases in relation to their role in the biotransformation of xenobiotics. , 1990, Chemico-biological interactions.

[161]  L. Benet,et al.  The drug efflux-metabolism alliance: biochemical aspects. , 2001, Advanced drug delivery reviews.

[162]  G. Giaccone,et al.  Multidrug resistance gene (P-glycoprotein) expression in the human fetus. , 1992, American Journal of Pathology.

[163]  C. Calhau,et al.  Postnatal development of organic cation transport in the rat liver. , 1998, Pharmacological research.

[164]  F. Smith,et al.  Maturational changes in the fetal glomerular filtration rate. , 1975, American journal of obstetrics and gynecology.

[165]  T. Kamataki,et al.  Significance of cytochrome P-450 (P-450 HFLa) of human fetal livers in the steroid and drug oxidations. , 1987, Biochemical pharmacology.

[166]  J. Gilman Therapeutic Drug Monitoring in the Neonate and Paediatric Age Group , 1990, Clinical pharmacokinetics.

[167]  L. Larsson,et al.  The ultrastructural development of the glomerular filtration barrier in the rat kidney: a morphometric analysis. , 1980, Journal of ultrastructure research.

[168]  D. Shen,et al.  Comparison of CYP2D6 Content and Metoprolol Oxidation Between Microsomes Isolated from Human Livers and Small Intestines , 1999, Pharmaceutical Research.

[169]  Y. Kitamura,et al.  Developmental expression of P-glycoprotein (multidrug resistance gene product) in the rat brain. , 1999, Journal of neurobiology.

[170]  L. Boréus,et al.  Plasma concentrations of phenobarbital in the neonate during prophylaxis for neonatal hyperbilirubinemia. , 1974, The Journal of pediatrics.

[171]  G. Simon,et al.  Intestinal flora in health and disease. , 1984, Gastroenterology.

[172]  W. Dodson Special Pharmacokinetic Considerations in Children , 1987, Epilepsia.

[173]  J. Kremer,et al.  Drug binding to human alpha-1-acid glycoprotein in health and disease. , 1988, Pharmacological reviews.

[174]  M. Siepmann,et al.  Influence of clinical factors, diet, and drugs on the human upper gastrointestinal glutathione system , 2002, Gut.

[175]  W. Oh,et al.  RENAL FUNCTION AS A MARKER OF HUMAN FETAL MATURATION , 1976, Acta paediatrica Scandinavica.

[176]  D. Gendrel,et al.  Isoniazid acetylation metabolic ratio during maturation in children , 1997, Clinical pharmacology and therapy.

[177]  G. Tucker,et al.  Enterocytic CYP3A4 in a paediatric population: developmental changes and the effect of coeliac disease and cystic fibrosis. , 2001, British journal of clinical pharmacology.

[178]  S. Tagawa,et al.  Gene structure of CYP3A4, an adult-specific form of cytochrome P450 in human livers, and its transcriptional control. , 1993, European journal of biochemistry.

[179]  K. Sato,et al.  Purification and subunit-structural and immunological characterization of five glutathione S-transferases in human liver, and the acidic form as a hepatic tumor marker. , 1986, Biochimica et biophysica acta.

[180]  J. W. Poole,et al.  Serum concentrations of ampicillin in newborn infants after oral administration. , 1973, Pediatrics.

[181]  J. Slattery,et al.  The maturation of morphine clearance and metabolism. , 1992, American journal of diseases of children.

[182]  B. Friis‐Hansen Body water compartments in children: changes during growth and related changes in body composition. , 1961, Pediatrics.

[183]  T. Kamataki,et al.  P-450 HFLa, a form of cytochrome P-450 purified from human fetal livers, is the 16 alpha-hydroxylase of dehydroepiandrosterone 3-sulfate. , 1987, The Journal of biological chemistry.

[184]  T. Cresteil,et al.  Expression of CYP3A in the human liver--evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. , 1997, European journal of biochemistry.

[185]  T. Cresteil,et al.  Expression of CYP2D6 in developing human liver. , 1991, European journal of biochemistry.

[186]  M. Hadchouel,et al.  Ontogenic expression of the Na(+)-independent organic anion transporting polypeptide (oatp) in rat liver and kidney. , 1996, Journal of hepatology.

[187]  G. Koren,et al.  Interactions of drugs with the developing kidney. , 1995, Pediatric clinics of North America.