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Characterization of...
Characterization of Intestinal and Hepatic CYP3A-Mediated Metabolism of Midazolam in Children Using a Physiological Population Pharmacokinetic Modelling Approach
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- Brussee, Janneke M. (författare)
- Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands
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- Yu, Huixin (författare)
- Novartis, Basel, Switzerland;Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands
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- Krekels, Elke H. J. (författare)
- Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands
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- Palic, Semra (författare)
- Netherlands Canc Inst NKI, Amsterdam, Netherlands;Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands
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- Brill, Margreke J.E. (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Barrett, Jeffrey S. (författare)
- Sanofi, Translat Informat, Bridgewater, NJ USA;Childrens Hosp Philadelphia, Dept Pediat, Div Clin Pharmacol & Therapeut, Philadelphia, PA 19104 USA
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- Rostami-Hodjegan, Amin (författare)
- Univ Manchester, Ctr Appl Pharmacokinet Res, Manchester, Lancs, England;Simcyp Ltd, Sheffield, S Yorkshire, England
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- de Wildt, Saskia N. (författare)
- 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
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- Knibbe, Catherijne A. J. (författare)
- St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands;Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands
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(creator_code:org_t)
- 2018-07-30
- 2018
- Engelska.
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Ingår i: Pharmaceutical research. - : Springer. - 0724-8741 .- 1573-904X. ; 35:9
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- CYP3A
- extraction ratio
- absorption
- first-pass metabolism
- gut wall
- liver
- pediatrics
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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