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  • Brussee, Janneke M.Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands (författare)

Characterization of Intestinal and Hepatic CYP3A-Mediated Metabolism of Midazolam in Children Using a Physiological Population Pharmacokinetic Modelling Approach

  • Artikel/kapitelEngelska2018

Förlag, utgivningsår, omfång ...

  • 2018-07-30
  • Springer,2018
  • electronicrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:uu-362025
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-362025URI
  • https://doi.org/10.1007/s11095-018-2458-6DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

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  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • Purpose Changes in drug absorption and first-pass metabolism have been reported throughout the pediatric age range. Our aim is to characterize both intestinal and hepatic CYP3A-mediated metabolism of midazolam in children in order to predict first-pass and systemic metabolism of CYP3A substrates. Methods Pharmacokinetic (PK) data of midazolam and 1-OH-midazolam from 264 post-operative children 1-18 years of age after oral administration were analyzed using a physiological population PK. modelling approach. In the model, consisting of physiological compartments representing the gastro-intestinal tract and liver,intrinsic intestinal and hepatic clearances were estimated to derive values for bioavailability and plasma clearance. Results The whole-organ intrinsic clearance in the gut wall and liver were found to increase with body weight, with a 105 (95% confidence interval (CI): 5-405) times lower intrinsic gut wall clearance than the intrinsic hepatic dearance (i.e. 5.08 L/h (relative standard error (RSE) 10%) versus 527 L/h (RSE 7%) for a 16 kg individual, respectively). When expressed per gram of organ, intrinsic clearance increases with increasing body weight in the gut wall, but decreases in the liver, indicating that CYP3A-mediated intrinsic clearance and local bioavailability in the gut wall and liver do not change with age in parallel. The resulting total bioavailability was found to be age-independent with a median of 20.8% in children (95%CI: 3.8-50.0%). Conclusion In conclusion, the intrinsic CYP3A-mediated gut wall clearance is substantially lower than the intrinsic hepatic CYP3A-mediated clearance in children from 1 to 18 years of age, and contributes less to the overall first-pass metabolism compared to adults.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Yu, HuixinNovartis, Basel, Switzerland;Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands (författare)
  • Krekels, Elke H. J.Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands (författare)
  • Palic, SemraNetherlands Canc Inst NKI, Amsterdam, Netherlands;Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands (författare)
  • Brill, Margreke J.E.Uppsala universitet,Institutionen för farmaceutisk biovetenskap(Swepub:uu)marbr178 (författare)
  • Barrett, Jeffrey S.Sanofi, Translat Informat, Bridgewater, NJ USA;Childrens Hosp Philadelphia, Dept Pediat, Div Clin Pharmacol & Therapeut, Philadelphia, PA 19104 USA (författare)
  • Rostami-Hodjegan, AminUniv Manchester, Ctr Appl Pharmacokinet Res, Manchester, Lancs, England;Simcyp Ltd, Sheffield, S Yorkshire, England (författare)
  • de Wildt, Saskia N.Erasmus MC Sophia Childrens Hosp, Dept Pediat Surg, Rotterdam, Netherlands;Radboud Univ Nijmegen, Dept Pharmacol & Toxicol, Med Ctr, Nijmegen, Netherlands;Erasmus MC Sophia Childrens Hosp, Intens Care, Rotterdam, Netherlands (författare)
  • Knibbe, Catherijne A. J.St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands;Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands (författare)
  • Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, NetherlandsNovartis, Basel, Switzerland;Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Pharmaceutical research: Springer35:90724-87411573-904X

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