Impact of impurity on kinetic estimates from transport and inhibition studies

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dc.contributor.authorGonzalez, Pablo
dc.contributor.authorPolli, James E.
dc.date.accessioned2024-01-10T12:39:37Z
dc.date.available2024-01-10T12:39:37Z
dc.date.issued2008
dc.description.abstractAlthough in vitro transport/inhibition studies are commonly performed on impure drug candidates to screen for pharmacokinetic properties in early development, quantitative guidelines concerning acceptable impurity levels are lacking. The broad goal was to derive models for the effect of impurity on transport and inhibition studies and identify the maximum allowable impurity level that does not bias assay results. Models were derived, and simulations were performed to assess the impact of impurity on substrate properties K-t and J(max) and inhibition K-i. Simulation results were experimentally challenged with a known amount of impurity, using the intestinal bile acid transporter as a model system. For substrate uptake studies, glycocholate served as substrate and was contaminated with either a very strong, strong, or moderate impurity (i.e., taurolithocholate, chenodeoxycholate, or ursodeoxycholate, respectively). For inhibition studies, taurocholate and glycocholate together was the substrate/inhibitor pair, where glycocholate was contaminated with taurolithocholate. There was high agreement between simulation results and experimental observations. It is not surprising that, in the inhibition assay, potent impurity caused test compound to appear more potent than the true potency of the test compound (i.e., reduced inhibitory K-i). However, results in the transport scenario surprisingly indicated that potent impurity did not diminish test compound potency but, rather, increased substrate potency (i.e., reduced Michaelis-Menten substrate K-t). In general, less than 2.5% impurity is a reasonable target, provided the impurity is less than 10-fold more potent than test compound. Study results indicate that careful consideration of possible impurity effect is needed when quantitative structure-activity relationship analysis cannot explain high compound potency from transport or inhibition studies.
dc.description.funderFOOD AND DRUG ADMINISTRATION
dc.description.funderNATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
dc.description.funderNIDDK NIH HHS
dc.description.funderFDA HHS
dc.fechaingreso.objetodigital2024-05-14
dc.format.extent10 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1124/jpet.107.135863
dc.identifier.eissn1521-0103
dc.identifier.issn0022-3565
dc.identifier.pubmedidMEDLINE:18443216
dc.identifier.urihttps://doi.org/10.1124/jpet.107.135863
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/77215
dc.identifier.wosidWOS:000256889300033
dc.information.autorucQuímica;González P;S/I;18216
dc.issue.numero1
dc.language.isoen
dc.nota.accesocontenido parcial
dc.pagina.final305
dc.pagina.inicio296
dc.publisherAMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
dc.revistaJOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
dc.rightsacceso restringido
dc.subjectBILE-ACID TRANSPORTER
dc.subjectCONJUGATION
dc.subjectSYSTEMS
dc.subjectLIVER
dc.subjectHASBT
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleImpact of impurity on kinetic estimates from transport and inhibition studies
dc.typeartículo
dc.volumen326
sipa.codpersvinculados18216
sipa.indexWOS
sipa.indexScopus
sipa.trazabilidadCarga SIPA;09-01-2024
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