Abstract
Plasma binding protein levels are lower in the newborn than in the adult and gradually increase with age. At birth, human serum albumin (HSA) concentrations are close to adult levels (75%–80%), while alpha 1-acid glycoprotein (AAG) is initially half the adult concentration. As a result, the extent of drug binding to HSA is closer to that of the adult than are those drugs bound largely to AAG. A model that incorporates the fraction unbound in adults and the ratio of the binding protein concentration between infants and adults successfully predicted the fraction unbound in infants and children.
Similar content being viewed by others
References
Alcorn J, McNamara PJ. The ontogeny of hepatic and renal systemic clearance pathways in infants: a review (Part I). Clin Pharmacokinet. In press.
Alcorn J, McNamara PJ. The ontogeny of hepatic and renal systemic clearance pathways in infants: model predictions (Part II). Clin Pharmacokinet. In press.
Curry S, Brick P, Franks NP. Fatty acid binding to human serum albumin: new insights from crystallographic studies. Biochim Biophys Acta. 1999;1441(2–3):131–140.
Fournier T, Medjoubi NN, Porquet D. Alpha 1-acid glycoprotein. Biochim Biophys Acta. 2000;1482(1–2):157–171.
Kremer JM, Wilting J, Janssen LH. Drug binding to human alpha-1-acid glycoprotein in health and disease. Pharmacol Rev. 1988;40(1):1–47.
Muller WE. Drug binding sites on human alpha-1-acid glycoprotein. Prog Clin Biol Res. 1989;300:363–378.
Routledge PA. Clinical relevance of alpha 1 acid glycoprotein in health and disease. Prog Clin Biol Res. 1989;300:185–198.
Eap CB, Baumann P. The genetic polymorphism of human alpha 1-acid glycoprotein. Prog Clin Biol Res. 1989;300:111–125.
Herve F, Gomas E, Duche JC, Tillement JP. Fractionation of the genetic variants of human alpha 1-acid glycoprotein in the native form by chromatography on an immobilized copper(II) affinity adsorbent. Heterogeneity of the separate variants by isoelectrofocusing and by concanavalin A affinity chromatography. J Chromatogr. 1993;615(1):47–57.
Herve F, Gomas E, Duche JC, Tillement JP. Evidence for differences in the binding of drugs to the two main genetic variants of human alpha 1-acid glycoprotein. Br J Clin Pharmacol. 1993;36(3):241–249.
Herve F, Duche JC, d Athis P, Marche C, Barre J, Tillement JP. Binding of disopyramide, methadone, dipyridamole, chlorpromazine, lignocaine and progesterone to the two main genetic variants of human alpha 1-acid glycoprotein: evidence for drug-binding differences between the variants and for the presence of two separate drug-binding sites on alpha 1-acid glycoprotein. Pharmacogenetics. 1996;6(5):403–415.
Wilkinson GR, Shand DG. Commentary: a physiological approach to hepatic drug clearance. Clin Pharmacol Ther. 1975;18(4):377–390.
Pang KS, Rowland M. 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. J Pharmacokinet Biopharm. 1977;5(6):625–653.
Herngren L, Ehrnebo M, Boreus LO. Drug binding to plasma proteins during human pregnancy and in the perinatal period: studies on cloxacillin and alprenolol. Dev Pharmacol Ther. 1983;6(2):110–124.
Colon AR. Textbook of Pediatric Hepatology. 2nd ed. Chicago, IL: Year Book Medical Publishers; 1990:31.
Asali LA, Brown KF. Naloxone protein binding in adult and foetal plasma. Eur J Clin Pharmacol. 1984;27(4):459–463.
Pacifici GM, Viani A, Taddeucci-Brunelli G, Rizzo G, Carrai M, Schulz HU. Effects of development, aging, and renal and hepatic insufficiency as well as hemodialysis on the plasma concentrations of albumin and alpha 1-acid glycoprotein: implications for binding of drugs. Ther Drug Monit. 1986;8(3):259–263.
Kanakoudi F, Drossou V, Tzimouli V, et al. Serum concentrations of 10 acute-phase proteins in healthy term and preterm infants from birth to age 6 months. Clin Chem. 1995;41(4):605–608.
Kurz H, Mauser-Ganshorn A, Stickel HH. Differences in the binding of drugs to plasma proteins from newborn and adult man: I. Eur J Clin Pharmacol. 1977;11(6):463–467.
Kingston HG, Kendrick A, Sommer KM, Olsen GD, Downes H. Binding of thiopental in neonatal serum. Anesthesiology. 1990;72(3): 428–431.
Notarianni LJ. Plasma protein binding of drugs in pregnancy and in neonates. Clin Pharmacokinet. 1990;18(1):20–36.
Bardy AH, Hiilesmaa VK, Teramo K, Neuvonen PJ. Protein binding of antiepileptic drugs during pregnancy, labor, and puerperium. Ther Drug Monit. 1990;12(1):40–46.
Lerman J, Strong HA, LeDez KM, Swartz J, Rieder MJ, Burrows FA. Effects of age on the serum concentration of alpha 1-acid glycoprotein and the binding of lidocaine in pediatric patients. Clin Pharmacol Ther. 1989;46(2):219–225.
Wood M, Wood AJ. Changes in plasma drug binding and alpha 1-acid glycoprotein in mother and newborn infant. Clin Pharmacol Ther. 1981;29(4):522–526.
Kurz H, Michels H, Stickel HH. Differences in the binding of drugs to plasma proteins from newborn and adult man: II. Eur J Clin Pharmacol. 1977;11(6):469–472.
Ehrnebo M, Agurell S, Jalling B, Boreus LO. Age differences in drug binding by plasma proteins: studies on human foetuses, neonates and adults. Eur J Clin Pharmacol. 1971;3(4):189–193.
Nau H, Luck W, Kuhnz W. 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. Br J Clin Pharmacol. 1984;17(1):92–98.
Brodersen R, Robertson A. Ceftriaxone binding to human serum albumin: competition with bilirubin. Mol Pharmacol. 1989;36(3):478–483.
Pacifici GM, Viani A, Taddeucci-Brunelli G. Serum protein binding of furosemide in newborn infants and children. Dev Pharmacol Ther. 1987;10(6):413–421.
Echizen H, Nakura M, Saotome T, Minoura S, Ishizaki T. Plasma protein binding of disopyramide in pregnant and postpartum women, and in neonates and their mothers. Br J Clin Pharmacol. 1990;29(4):423–430.
Pacifici GM, Taddeucci-Brunelli G, Rane A. Clonazepam serum protein binding during development. Clin Pharmacol Ther. 1984;35(3):354–359.
Schaad UB, Hayton WL, Stoeckel K. Single-dose ceftriaxone kinetics in the newborn. Clin Pharmacol Ther. 1985;37(5):522–528.
Benson JM, Boudinot FD, Pennell AT, Cunningham FE, DiPiro JT. In vitro protein binding of cefonicid and cefuroxime in adult and neonatal sera. Antimicrob Agents Chemother 1993;37(6):1343–7.
Brodersen R, Honore B. Drug binding properties of neonatal albumin. Acta Paediatr Scand. 1989;78(3):342–346.
Belpaire FM, Wynant P, Van Trappen P, Dhont M, Verstraete A, Bogaert MG. Protein binding of propranolol and verapamil enantiomers in maternal and foetal serum. Br J Clin Pharmacol. 1995;39(2):190–193.
Hamar C, Levy G. Factors affecting the serum protein binding of salicylic acid in newborn infants and their mothers. Pediatr Pharmacol. 1980;1(1):31–43.
Wilson AS, Stiller RL, Davis PJ, et al. Fentanyl and alfentanil plasma protein binding in preterm and term neonates. Anesth Analg. 1997;84(2):315–318.
Meuldermans W, Woestenborghs R, Noorduin H, Camu F, van Steenberge A, Heykants J. Protein binding of the analgesics alfentanil and sufentanil in maternal and neonatal plasma. Eur J Clin Pharmacol. 1986;30(2):217–219.
Bodenham A, Park GR. Alfentanil infusions in patients requiring intensive care. Clin Pharmacokinet. 1988;15(4):216–226.
Olkkola KT, Hamunen K, Maunuksela EL. Clinical pharmacokinetics and pharmacodynamics of opioid analgesics in infants and children. Clin Pharmacokinet. 1995;28(5):385–404.
Furst DE, Tozer TN, Melmon KL. Salicylate clearance, the resultant of protein binding and metabolism. Clin Pharmacol Ther. 1979;26(3):380–389.
Sallee FR, Pollock BG. Clinical pharmacokinetics of imipramine and desipramine. Clin Pharmacokinet. 1990;18(5):346–364.
Siddoway LA, Woosley RL. Clinical pharmacokinetics of disopyramide. Clin Pharmacokinet. 1986;11(3):214–222.
Nattel S, Gagne G, Pineau M. The pharmacokinetics of lignocaine and beta-adrenoceptor antagonists in patients with acute myocardial infarction. Clin Pharmacokinet. 1987;13(5):293–316.
Kearns GL, Kemp SF, Turley CP, Nelson DL. Protein binding of phenytoin and lidocaine in pediatric patients with type I diabetes mellitus. Dev Pharmacol Ther. 1988;11(1):14–23.
Handal KA, Schauben JL, Salamone FR. Naloxone. Ann Emerg Med. 1983;12(7):438–445.
Bendayan R, Pieper JA, Stewart RB, Caranasos GJ. Influence of age on serum protein binding of propranolol. Eur J Clin Pharmacol. 1984;26(2):251–254.
Colangelo PM, Blouin RA, Steinmetz JE, McNamara PJ, DeMaria AN, Wedlund PJ. Age and propranolol stereoselective disposition in humans. Clin Pharmacol Ther. 1992;51(5):489–494.
Pickoff AS, Kessler KM, Singh S, et al. Age-related differences in the protein binding of quinidine. Dev Pharmacol Ther. 1981;3(2):108–115.
Verme CN, Ludden TM, Clementi WA, Harris SC. Pharmacokinetics of quinidine in male patients: a population analysis. Clin Pharmacokinet. 1992;22(6):468–480. [Published erratum appears in Clin Pharmacokinet. 1992;23(1):68.]
Meistelman C, Benhamou D, Barre J, et al. Effects of age on plasma protein binding of sufentanil. Anesthesiology. 1990;72(3):470–473.
Bovill JG, Sebel PS, Blackburn CL, Oei-Lim V, Heykants JJ. The pharmacokinetics of sufentanil in surgical patients. Anesthesiology. 1984;61(5):502–506.
McTavish D, Sorkin EM. Verapamil: an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension. Drugs. 1989;38(1):19–76.
Ehrnebo M, Nilsson SO, Boreus LO. Pharmacokinetics of ampicillin and its prodrugs bacampicillin and pivampicillin in man. J Pharmacokinet Biopharm. 1979;7(5):429–451.
Kentala E, Kaila T, Iisalo E, Kanto J. Intramuscular atropine in healthy volunteers: a pharmacokinetic and pharmacodynamic study. Int J Clin Pharmacol Ther Toxicol. 1990;28(9):399–404.
Kuhnz W, Steldinger R, Nau H. Protein binding of carbamazepine and its epoxide in maternal and fetal plasma at delivery: comparison to other anticonvulsants. Dev Pharmacol Ther. 1984;7(1):61–72.
Bertilsson L, Tomson T. Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11-epoxide: an update. Clin Pharmacokinet. 1986;11(3):177–198.
Ambrose PJ. Clinical pharmacokinetics of chloramphenicol and chloramphenicol succinate. Clin Pharmacokinet. 1984;9(3):222–238.
Greenblatt DJ, Shader RI, MacLeod SM, Sellers EM. Clinical pharmacokinetics of chlordiazepoxide. Clin Pharmacokinet. 1978;3(5):381–394.
Zemlickis D, Klein J, Moselhy G, Koren G. Cisplatin protein binding in pregnancy and the neonatal period. Med Pediatr Oncol. 1994;23(6):476–479.
Berlin A, Dahistrom H. Pharmacokinetics of the anticonvulsant drug clonazepam evaluated from single oral and intravenous doses and by repeated oral administration. Eur J Clin Pharmacol. 1975;9(2–3):155–159.
Spino M, Chai RP, Isles AF, et al. Cloxacillin absorption and disposition in cystic fibrosis. J Pediatr. 1984;105(5):829–835.
Greenblatt DJ, Allen MD, Harmatz JS, Shader RI. Diazepam disposition determinants. Clin Pharmacol Ther. 1980;27(3):301–312.
Mooradian AD. Digitalis: an update of clinical pharmacokinetics, therapeutic monitoring techniques and treatment recommendations. Clin Pharmacokinet. 1988;15(3):165–179.
Herve F, Duche JC, d Athis P, Marche C, Barre J, Tillement JP. Binding of disopyramide, methadone, dipyridamole, chlorpromazine, lignocaine and progesterone to the two main genetic variants of human alpha 1-acid glycoprotein: evidence for drug-binding differences between the variants and for the presence of two separate drug-binding sites on alpha 1-acid glycoprotein. Pharmacogenetics. 1996;6(5):403–415.
Gorodischer R, Krasner J, Yaffe SJ. Serum protein binding of digoxin in newborn infants. Res Commun Chem Pathol Pharmacol. 1974;9(2):387–390.
Hammarlund-Udenaes M, Benet LZ. Furosemide pharmacokinetics and pharmacodynamics in health and disease-an update. J Pharmacokinet Biopharm. 1989;17(1):1–46.
Glare PA, Walsh TD. Clinical pharmacokinetics of morphine. Ther Drug Monit. 1991;13(1):1–23.
Hoener B, Patterson SE. Nitrofurantoin disposition. Clin Pharmacol Ther. 1981;29(6):808–816.
Browne TR, Evans JE, Szabo GK, Evans BA, Greenblatt DJ. Studies with stable isotopes: II. Phenobarbital pharmacokinetics during monotherapy. J Clin Pharmacol. 1985;25(1):51–58.
Loughnan PM, Greenwald A, Purton WW, Aranda JV, Watters G, Neims AH. Pharmacokinetic observations of phenytoin disposition in the newborn and young infant. Arch Dis Child. 1977;52(4):302–309.
Levine M, Chang T. Therapeutic drug monitoring of phenytoin: rationale and current status. Clin Pharmacokinet. 1990;19(5):341–358.
Homer TD, Stanski DR. The effect of increasing age on thiopental disposition and anesthetic requirement. Anesthesiology. 1985;62(6):714–724.
Sorbo S, Hudson RJ, Loomis JC. The pharmacokinetics of thiopental in pediatric surgical patients. Anesthesiology. 1984;61(6):666–670.
Fisher DM, O Keeffe C, Stanski DR, Cronnelly R, Miller RD, Gregory GA. Pharmacokinetics and pharmacodynamics of d-tubocurarine in infants, children, and adults. Anesthesiology. 1982;57(3):203–208.
Battino D, Estienne M, Avanzini G. Clinical pharmacokinetics of antiepileptic drugs in paediatric patients: Part I. Phenobarbital, primidone, valproic acid, ethosuximide and mesuximide. Clin Pharmacokinet. 1995;29(4):257–286.
Nau H, Rating D, Koch S, Hauser I, Helge H. Valproic acid and its metabolites: placental transfer, neonatal pharmacokinetics, transfer via mothers milk and clinical status in neonates of epileptic mothers. J Pharmacol Exp Ther. 1981;219(3):768–777.
Zaccara G, Messori A, Moroni F. Clinical pharmacokinetics of valproic acid—1988. Clin Pharmacokinet. 1988;15(6):367–389.
Hayton WL, Stoeckel K. Age-associated changes in ceftriaxone pharmacokinetics. Clin Pharmacokinet. 1986;11(1):76–86.
Yuk JH, Nightingale CH, Quintiliani R. Clinical pharmacokinetics of ceftriaxone. Clin Pharmacokinet. 1989;17(4):223–235.
Herngren L, Lundberg B, Nergardh A. Pharmacokinetics of total and free valproic acid during monotherapy in infants. J Neurol. 1991;238(6):315–319.
Author information
Authors and Affiliations
Corresponding author
Additional information
Published: March 28, 2002
Rights and permissions
About this article
Cite this article
McNamara, P.J., Alcorn, J. Protein binding predictions in infants. AAPS PharmSci 4, 3 (2002). https://doi.org/10.1208/ps040104
Received:
Accepted:
Published:
DOI: https://doi.org/10.1208/ps040104