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An Observational Study of Blood Concentrations and Kinetics of Methyl- and Propyl-Parabens in Neonates

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ABSTRACT

Purpose

Systemic exposure to parabens in the neonatal population, in particular propyl-parabens (PPB), remains a concern. Blood concentrations and kinetics of methyl-parabens (MPB) and PPB were therefore determined in neonates receiving medicines containing these excipients.

Methods

A multi-centre, non-interventional, observational study of excipient-kinetics in neonates. ‘Dried Blood Spot’ samples were collected opportunistically at the same time as routine samples and the observations modelled using a non-linear mixed effects approach.

Results

A total of 841 blood MPB and PPB concentration data were available for evaluation from 181 pre- and term-neonates. Quantifiable blood concentrations of MPB and PPB were observed in 99% and 49% of patients, and 55% and 25% of all concentrations were above limit of detection (10 ng/ml), respectively. Only MPB data was amenable to modelling. Oral bioavailability was influenced by type of formulation and disposition was best described by a two compartment model with clearance (CL) influenced by post natal age (PNA); CLPNA<21 days 0.57 versus CLPNA>21days 0.88 L/h.

Conclusions

Daily repeated administration of parabens containing medicines can result in prolonged systemic exposure to the parent compound in neonates. Animal toxicology studies of PPB that specifically address the neonatal period are required before a permitted daily exposure for this age group can be established.

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References

  1. Pifferi G, Santoro P, Pedrani M. Quality and functionality of excipients. Farmaco. 1999;54(1–2):1–14.

    Article  CAS  PubMed  Google Scholar 

  2. MacDonald MG, Getson PR, Glasgow AM, et al. Propylene glycol: increased incidence of seizures in low birth weight infants. Pediatrics. 1987;79:622–5.

    CAS  PubMed  Google Scholar 

  3. Gershanik J, Boecler B, Ensley H, et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med. 1982;307:1384–8.

    Article  CAS  PubMed  Google Scholar 

  4. Lopez-Herce J, Bonet C, Meana A, et al. Benzyl alcohol poisoning following diazepam intravenous infusion (letter). Ann Pharmacother. 1995;29:632.

    CAS  PubMed  Google Scholar 

  5. Drug Safety Communication: Serious health problems seen in premature babies given Kaletra (lopinavir/ritonavir) oral solution.; FDA (2011) . Available from : http://www.fda.gov/Drugs/DrugSafety/ucm246002.htm. Accessed 12/15/2014.

  6. Shehab N, Lewis CL, Streetman DD, et al. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. Pediatr Crit Care Med. 2009;10:256–9.

    Article  PubMed  Google Scholar 

  7. Whittaker A, Currie AE, Turner MA, et al. Toxic additives in medications for preterm infants. Arch Dis Child Fetal Neonatal Ed. 2009;94:236–40.

    Article  Google Scholar 

  8. Souza A Jr, Santos D, Fonseca S, Medeiros M, Batista L, Turner M, Coelho H. Toxic excipients in medications for neonates in Brazil. Eur J Pediatr. 2014 Feb 6. [Epub ahead of print].

  9. EMEA/CHMP/PEG/194810/2005 (2006) Reflection paper: formulations of choice for the paediatric population. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003782.pdf. Accessed 12 May 2013.

  10. Rowe RC, Sheskey PJ, Quinn ME. Handbook of pharmaceutical excipients. 6th ed. London: Pharmaceutical Press; 2009.

    Google Scholar 

  11. Routledge EJ, Parker J, Odum J, Ashby J, Sumpter JP. Some Alkyl Hydroxy Benzoate Preservatives (Parabens) Are Estrogenic. Toxicol Appl Pharmacol. 1998;153:12–9.

    Article  CAS  PubMed  Google Scholar 

  12. Oishi S. Effects of butylparaben on the male reproductive system in rats. Toxicol Indust Health J. 2001;17:31–9.

    Article  CAS  Google Scholar 

  13. Oishi S. Effects of butyl paraben on the male reproductive system in mice. Arch Toxicol. 2002;76:423–9.

    Article  CAS  PubMed  Google Scholar 

  14. Oishi S. Effects of propyl paraben on the male reproductive system. Food Chem Toxicol. 2002;40:1807–13.

    Article  CAS  PubMed  Google Scholar 

  15. Oishi S. Lack of spermatotoxic effects of methyl and ethyl esters of p-hydroxybenzoic acid in rats. Food Chem Toxicol. 2004;42:1845–9.

    Article  CAS  PubMed  Google Scholar 

  16. Hoberman AM et al. Lack of effect of butylparaben and methylparaben on the reproductive system in male rats. Birth Defects Res (Part B). 2008;83:123–33.

    Article  CAS  Google Scholar 

  17. Gazin V, Marsden E, Marguerite F. Oral propylparaben administration to juvenile male Wistar rats did not induce toxicity in reproductive organs. Toxicol Sci. 2013;136(2):392–401.

    Article  CAS  PubMed  Google Scholar 

  18. EMA/CHMP/SWP/272921/2012 2. Reflection paper on the use of methyl- and propylparaben as excipients in human medicinal products for oral use. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000400.jsp&mid=WC0b01ac0580029570. Accessed 12 May 2014.

  19. 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;45:931–56.

    Article  CAS  PubMed  Google Scholar 

  20. Aubert N, Ameller T, Legrand JJ. Systemic exposure to parabens: pharmacokinetics, tissue distribution, excretion balance and plasma metabolites of [14C]-methyl-, propyl- and butylparaben in rats after oral, topical or subcutaneous administration. Food Chem Toxicol. 2012;50(3–4):445–54.

    Article  CAS  PubMed  Google Scholar 

  21. Frederiksen H, Jørgensen N, Andersson A-M. Parabens in urine, serum and seminal plasma from healthy Danish men determined by liquid chromatography–tandem mass spectrometry (LC–MS/MS). J Expo Sci Environ Epidemiol. 2011;21:262–71.

    Article  CAS  PubMed  Google Scholar 

  22. Sandanger T, Huber S, Moe MK, Braathen T, Leknes H, Lund E. Plasma concentrations of parabens in postmenopausal women and self-reported use of personal care products: the NOWAC postgenome study. J Expo Sci Environ Epidemiol. 2011;21:595–600.

    Article  CAS  PubMed  Google Scholar 

  23. Yakkundi S, McElnay J, Millership J, Mulla H, Pandya H, Shah U, et al. Use of dried blood spots to study excipient kinetics in neonates. Bioanalysis. 2011;3(24):2691–3.

    Article  CAS  PubMed  Google Scholar 

  24. Sheiner LB, Rosenberg B, Marathe V. Estimation of population characteristics of pharmacokinetic parameters from routine clinical data. J Pharmacokinet Biopharm. 1977;5:445–79.

    Article  CAS  PubMed  Google Scholar 

  25. Ahn JE, Karlsson MO, Dunne A, Ludden TM. Likelihood based approaches to handling data below the quantification limit using NONMEM VI. J Pharmacokinet Pharmacodyn. 2008;35(4):401–21.

    Article  PubMed  Google Scholar 

  26. Savic RM, Jonker DM, Kerbusch T, Karlsson MO. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn. 2007;34(5):711–26.

    Article  CAS  PubMed  Google Scholar 

  27. Patel P, Mulla H, Kairamkonda V, Spooner N, Gade S, Della Pasqua O, et al. Dried blood spots and sparse sampling: a practical approach to estimating pharmacokinetic parameters of caffeine in preterm infants. Br J Clin Pharmacol. 2013;75(3):805–13.

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Schlumpf M, Kypke K, Wittassek M, Angerer J, Mascher H, Mascher D, et al. Exposure patterns of UV filters, fragrances, parabens, phthalates, organochlor pesticides, PBDEs, and PCBs in human milk: correction of UV filters with use of cosmetics. Chemosphere. 2010;81:1171–83.

    Article  CAS  PubMed  Google Scholar 

  29. Darbre PD, Aljarrah A, Miller WR, Coldham NG, Sauer MJ, Pope GS. Concentrations of parabens in human breast tumours. J Appl Toxicol. 2004;24:5–13.

    Article  CAS  PubMed  Google Scholar 

  30. Janjua NR, Frederiksen H, Skakkeback NE, Wulff HC, Andersson AM. Urinary excretion of phthalates and paraben after repeated whole-body topical application in humans. Int J Androl. 2008;31:118–30.

    Article  CAS  PubMed  Google Scholar 

  31. Tsukamoto H, Terada S. Metabolism of drugs. XXVI Metabolic fate of p-hydroxybenzoic acid and its derivatives in rabbits. Chem Pharm Bull. 1962;10:86–90.

    Article  CAS  Google Scholar 

  32. Yang D, Pearce RE, Wang X, Gaedigk R, Wan YJ, Yan B. Human carboxylesterases HCE1 and HCE2: Ontogenic expression, inter-individual variability and differential hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin. Biochem Pharmacol. 2009;77:238–47.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Zhu HJ, Appel DI, Jiang Y, Markowitz JS. Age- and sex-related expression and activity of carboxylesterase 1 and 2 in mouse and human liver. Drug Metab Dispos. 2009;37(9):1819–25.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to thank Amy Smith, Karen Harvey and all other members of the neonatal research teams in UK and Estonia who contributed to the conduct of this study.

The following are members of ESNEE (European Study of Neonatal Exposure to Excipients): Mark A. Turner (project leader, UK), Susan Graham (UK), Jennifer Duncan (UK), Anthony Nunn (UK), Utpal Shah (UK), Hussain Mulla (UK), Hitesh Pandya (UK), James McElnay (UK), Jeff Millership (UK), Shirish Yakkundi (UK), Andre Rieutord (France), Thomas Storme (France), Pascal Vaconsin (France), Irja Lutsar (Estonia), Tuuli Metsvaht (Estonia), Heili Varendi (Estonia), Georgi Nellis (Estonia).

Financial and Competing Interests

The ESNEE project has been funded via the European Research Area-Network PRIOMEDCHILD program. In the UK this is supported by Medical Research Council, in Estonia by the Estonian Science Foundation, and in France by the Agence Nationale de la Recherche. IL and AN are members of the EMA Paediatric Committee (PDCO). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Authors and Affiliations

  1. Department of Pharmacy, University Hospitals of Leicester, Leicester, UK

    H. Mulla

  2. Clinical & Practice Research Group, School of Pharmacy, Queen’s University Belfast, Belfast, UK

    S. Yakkundi & J. McElnay

  3. Institute of Microbiology, Tartu University, Tartu, Estonia

    I. Lutsar, T. Metsvaht & G. Nellis

  4. Tartu University Hospital, Clinic of Anaesthesiology and Intensive Care, Paediatric Intensive Care Unit, Tartu, Estonia

    T. Metsvaht

  5. Tartu University Hospital, Children’s Clinic, Neonatal Unit, Tartu, Estonia

    H. Varendi & G. Nellis

  6. Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

    A. Nunn & J. Duncan

  7. Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK

    H. Pandya

  8. Liverpool Women’s Hospital, Neonatal Unit, Liverpool, UK

    M. Turner

  9. Institute of Translational Medicine, University of Liverpool, Liverpool, UK

    M. Turner

  10. Department of Pharmacy, Glenfield Hospital, University Hospitals of Leicester, Groby Road, Leicester, LE3 9QP, UK

    H. Mulla

Authors
  1. H. Mulla
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  2. S. Yakkundi
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  3. J. McElnay
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  4. I. Lutsar
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  5. T. Metsvaht
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  6. H. Varendi
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  7. G. Nellis
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  8. A. Nunn
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  9. J. Duncan
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  10. H. Pandya
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  11. M. Turner
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Corresponding author

Correspondence to H. Mulla.

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Mulla, H., Yakkundi, S., McElnay, J. et al. An Observational Study of Blood Concentrations and Kinetics of Methyl- and Propyl-Parabens in Neonates. Pharm Res 32, 1084–1093 (2015). https://doi.org/10.1007/s11095-014-1520-2

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  • DOI: https://doi.org/10.1007/s11095-014-1520-2

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