Title |
In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia
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Published in |
Therapeutic Drug Monitoring, April 2016
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DOI | 10.1097/ftd.0000000000000268 |
Pubmed ID | |
Authors |
Karin Skoglund, Johan Richter, Ulla Olsson-Strömberg, Jonas Bergquist, Warunika Aluthgedara, S. J. Kumari A. Ubhayasekera, Svante Vikingsson, Anna Svedberg, Stina Söderlund, Anna Sandstedt, Anders Johnsson, Jesper Aagesen, Jonas Alsenhed, Staffan Hägg, Curt Peterson, Kourosh Lotfi, Henrik Gréen |
Abstract |
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. 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. 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. 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. |
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United States | 1 | 25% |
Unknown | 1 | 25% |
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Researcher | 3 | 19% |
Other | 2 | 13% |
Professor | 2 | 13% |
Unspecified | 1 | 6% |
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Other | 2 | 13% |
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Immunology and Microbiology | 1 | 6% |
Other | 0 | 0% |
Unknown | 4 | 25% |