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- Title
Targeted and global pharmacometabolomics in everolimus-based immunosuppression: association of co-medication and lysophosphatidylcholines with dose requirement.
- Authors
Lesche, Dorothea; Sigurdardottir, Vilborg; Leichtle, Alexander B.; Nakas, Christos T.; Christians, Uwe; Englberger, Lars; Fiedler, Martin; Largiadèr, Carlo R.; Mohacsi, Paul; Sistonen, Johanna
- Abstract
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.
- Subjects
HEART transplantation; METABOLOMICS; DRUG metabolism; EVEROLIMUS; LECITHIN; IMMUNOSUPPRESSIVE agents
- Publication
Metabolomics, 2018, Vol 14, Issue 1, p1
- ISSN
1573-3882
- Publication type
Article
- DOI
10.1007/s11306-017-1294-8