dc.contributor.author
Olafuyi, Olusola
dc.contributor.author
Michelet, Robin
dc.contributor.author
Garle, Michael
dc.contributor.author
Allegaert, Karel
dc.date.accessioned
2025-03-05T11:28:16Z
dc.date.available
2025-03-05T11:28:16Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/45540
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-45252
dc.description.abstract
Propylene glycol (PG) is a pharmaceutical excipient which is generally regarded as safe (GRAS), though clinical toxicity has been reported. PG toxicity has been attributed to accumulation due to saturation of the alcohol dehydrogenase (ADH)-mediated clearance pathway. This study aims to explore the impact of the saturation of ADH-mediated PG metabolism on its developmental clearance in adults and neonates and assess the impact of a range of doses on PG clearance saturation and toxicity. Physiologically based pharmacokinetic (PBPK) models for PG in adults and term neonates were developed using maximum velocity (Vmax) and Michaelis–Menten's constant (Km) of ADH-mediated metabolism determined in vitro in human liver cytosol, published physicochemical, drug-related and ADH ontogeny parameters. The models were validated and used to determine the impact of dosing regimen on PG clearance saturation and toxicity in adults and neonates. The Vmax and Km of PG in human liver cytosol were 1.57 nmol/min/mg protein and 25.1 mM, respectively. The PG PBPK model adequately described PG PK profiles in adults and neonates. The PG dosing regimens associated with saturation and toxicity were dependent on both dose amount and cumulative in standard dosing frequencies. Doses resulting in saturation were higher than those associated with clinically observed toxicity. In individuals without impaired clearance or when PG exposure is through formulations that contain excipients with possible interaction with PG, a total daily dose of 100–200 mg/kg/day in adults and 25–50 mg/kg/day in neonates is unlikely to result in toxic PG levels or PG clearance saturation.
en
dc.format.extent
13 Seiten
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
physiologically based pharmacokinetics
en
dc.subject
propylene glycol
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::615 Pharmakologie, Therapeutik
dc.title
Exploring the Impact of Developmental Clearance Saturation on Propylene Glycol Exposure in Adults and Term Neonates Using Physiologically Based Pharmacokinetic Modeling
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.doi
10.1002/jcph.6150
dcterms.bibliographicCitation.journaltitle
The Journal of Clinical Pharmacology
dcterms.bibliographicCitation.number
3
dcterms.bibliographicCitation.pagestart
272
dcterms.bibliographicCitation.pageend
284
dcterms.bibliographicCitation.volume
65
dcterms.bibliographicCitation.url
https://doi.org/10.1002/jcph.6150
refubium.affiliation
Biologie, Chemie, Pharmazie
refubium.affiliation.other
Institut für Pharmazie

refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.isPartOf.eissn
1552-4604
refubium.resourceType.provider
WoS-Alert