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In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
Skåne University Hospital, Sweden.
Uppsala University, Sweden.
Uppsala University, Sweden.
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2016 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 38, no 2, 230-238 p.Article in journal (Refereed) PublishedText
Abstract [en]

Background: Cytochrome P450 3A (CYP3A) isoenzyme metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML). The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in patients with CML. Methods: Forty-three patients with CML were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry. Results: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to nonoptimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P = 0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity. Conclusions: The CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that although imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS , 2016. Vol. 38, no 2, 230-238 p.
Keyword [en]
pharmacokinetics; chronic myeloid leukemia; imatinib; CGP74588; CYP3A
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:liu:diva-129678DOI: 10.1097/FTD.0000000000000268ISI: 000376938000006PubMedID: 26693810OAI: diva2:943041

Funding Agencies|Swedish Research Council; Swedish Cancer Society; Medical Research Council of Southeast Sweden; Novartis

Available from: 2016-06-27 Created: 2016-06-23 Last updated: 2016-08-24

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The full text will be freely available from 2017-04-30 14:55
Available from 2017-04-30 14:55

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Skoglund, KarinVikingsson, SvanteSvedberg, AnnaSandstedt, AnnaHägg, StaffanPeterson, CurtLotfi, KouroshGreen, Henrik
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