Targeted and global pharmacometabolomics in everolimus-based immunosuppression: association of co-medication and lysophosphatidylcholines with dose requirement.

Autor: Lesche D; University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland., Sigurdardottir V; Department of Cardiology, Swiss Cardiovascular Centre, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland., Leichtle AB; University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland., Nakas CT; University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.; Laboratory of Biometry, University of Thessaly, Volos, Greece., Christians U; iC42 Clinical Research and Development, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA., Englberger L; Department of Cardiovascular Surgery, Swiss Cardiovascular Centre, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland., Fiedler M; University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland., Largiadèr CR; University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland., Mohacsi P; Department of Cardiovascular Surgery, Swiss Cardiovascular Centre, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. paul.mohacsi@insel.ch., Sistonen J; University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Jazyk: angličtina
Zdroj: Metabolomics : Official journal of the Metabolomic Society [Metabolomics] 2017 Nov 25; Vol. 14 (1), pp. 3. Date of Electronic Publication: 2017 Nov 25.
DOI: 10.1007/s11306-017-1294-8
Abstrakt: Introduction: The immunosuppressive therapy with everolimus (ERL) after heart transplantation is characterized by a narrow therapeutic window and a substantial variability in dose requirement. Factors explaining this variability are largely unknown.
Objectives: Our aim was to evaluate factors affecting ERL metabolism and to identify novel metabolites associated with the individual ERL dose requirement to elucidate mechanisms underlying ERL dose response variability.
Method: We used liquid chromatography coupled with mass spectrometry for quantification of ERL metabolites in 41 heart transplant patients and evaluated the effect of clinical and genetic factors on ERL pharmacokinetics. Non-targeted plasma metabolic profiling by ultra-performance liquid chromatography and high resolution quadrupole-time-of-flight mass spectrometry was used to identify novel metabolites associated with ERL dose requirement.
Results: The determination of ERL metabolites revealed differences in metabolite patterns that were independent from clinical or genetic factors. Whereas higher ERL dose requirement was associated with co-administration of sodium-mycophenolic acid and the CYP3A5 expressor genotype, lower dose was required for patients receiving vitamin K antagonists. Global metabolic profiling revealed several novel metabolites associated with ERL dose requirement. One of them was identified as lysophosphatidylcholine (lysoPC) (16:0/0:0). Subsequent targeted analysis revealed that high levels of several lysoPCs were significantly associated with higher ERL dose requirement.
Conclusion: For the first time, this study describes distinct ERL metabolite patterns in heart transplant patients and detected potentially new drug-drug interactions. The global metabolic profiling facilitated the discovery of novel metabolites associated with ERL dose requirement that might represent new clinically valuable biomarkers to guide ERL therapy.
Databáze: MEDLINE
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