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In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
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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) Published
Abstract [en]

BACKGROUND: CYP3A metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in chronic myeloid leukemia (CML) patients. The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in CML patients.

METHODS: Forty-three CML patients 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 non-optimal 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: CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that even though 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
2016. Vol. 38, no 2, 230-238 p.
Keyword [en]
pharmacokinetics; chronic myeloid leukemia; imatinib; CGP74588; CYP3A
National Category
Cancer and Oncology Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-270505DOI: 10.1097/FTD.0000000000000268ISI: 000376938000006PubMedID: 26693810OAI: oai:DiVA.org:uu-270505DiVA: diva2:889905
Swedish Research CouncilSwedish Cancer Society
Available from: 2015-12-29 Created: 2015-12-29 Last updated: 2016-07-12Bibliographically approved

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Olsson-Strömberg, UllaBergquist, JonasAluthgedara, WarunikaUbhayasekera, S J Kumari ASöderlund, Stina
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