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

Autor: Elke H. J. Krekels, Amin Rostami-Hodjegan, Margreke J. E. Brill, Janneke M. Brussee, Catherijne A. J. Knibbe, Jeffrey S. Barrett, Semra Palic, Saskia N. de Wildt, Huixin Yu
Přispěvatelé: Pediatric Surgery
Rok vydání: 2018
Předmět:
Male
CYP3A
Pharmaceutical Science
first-pass metabolism
030226 pharmacology & pharmacy
Pharmaceutical Sciences
0302 clinical medicine
Oral administration
Medicine
Cytochrome P-450 CYP3A
Pharmacology (medical)
Intestinal Mucosa
Child
education.field_of_study
3. Good health
030220 oncology & carcinogenesis
Child
Preschool
Molecular Medicine
Female
Algorithms
Anesthetics
Intravenous
Biotechnology
medicine.drug
Research Paper
medicine.medical_specialty
gut wall
Adolescent
pediatrics
Midazolam
Population
liver
Models
Biological
03 medical and health sciences
First pass effect
All institutes and research themes of the Radboud University Medical Center
Pharmacokinetics
Internal medicine
extraction ratio
Humans
education
Pharmacology
business.industry
Organic Chemistry
Infant
Metabolism
Farmaceutiska vetenskaper
Bioavailability
Endocrinology
Renal disorders Radboud Institute for Health Sciences [Radboudumc 11]
business
absorption
Zdroj: Pharmaceutical Research
Pharmaceutical Research, 35, 182
Pharmaceutical Research, 35, 9, pp.
Pharmaceutical Research, 35,
Brussee, J M, Yu, H, Krekels, E H J, Palić, S, Brill, M J E, Barrett, J S, Rostami-hodjegan, A, De Wildt, S N & Knibbe, C A J 2018, ' Characterization of Intestinal and Hepatic CYP3A-Mediated Metabolism of Midazolam in Children Using a Physiological Population Pharmacokinetic Modelling Approach ', Pharmaceutical Research, vol. 35, no. 9 . https://doi.org/10.1007/s11095-018-2458-6
Pharmaceutical Research, 35(9):Unsp 182. Springer New York
ISSN: 0724-8741
DOI: 10.1007/s11095-018-2458-6
Popis: 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 clearance (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. Electronic supplementary material The online version of this article (10.1007/s11095-018-2458-6) contains, which is available to authorized users.
Databáze: OpenAIRE
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