title: Biomarkers for toxicodynamic monitoring of immunosuppressants: NMR-based quantitative metabonomics of the blood.
abstract: Metabonomics is the latest "omics" science and provides metabolic endpoints of drug toxicity, drug efficacy, and pathophysiology. With high-resolution 'H-NMR (nuclear magnetic resonance)spectroscopy on body fluids (eg, urine, blood samples) used in combination with statistical tools, metabolic biomarkers of drug toxicity can be distinguished and validated. For 2 decades, immuno-suppressant cyclosporine (CsA) has been used in transplantation medicine as a potent calcineurin inhibitor with well-known nephrotoxic side effects. The combination of CsA with novel macrolide immunosuppressants-sirolimus (SRL) or everolimus (RAD)-has proved to have a beneficial synergistic immunosuppressive effect but may also possess an increased nephrotoxic potential. 1H-NMR spectroscopy was performed on the blood from CsA-, SRL-, and RAD (alone and in combination)-treated rats to predict metabolic toxicity and to identify and quantify specific metabolic biomarkers. After 6 days of treatment with 10 mg/kg CsA, a significant increase in blood glucose, hydroxybutyrate, creatine+creatinine, trimethylamine-N-oxide (TMAO), and cholesterol as well as a decrease in total glutathione concentrations were observed. SRL (3 mg/kg) enhanced the magnitude of CsA metabolic changes (enhanced toxicity),whereas combination with RAD (3 mg/kg) partly curtailed them. Together with pharmacokinetic studies, quantitative NMR-based metabonomics represents a powerful tool for pharmacokinetic-pharmacodynamic-toxicodynamic evaluation in drug research.
authors.affiliation: Department of Anesthesiology, Clinical Research and Development, MRI/MRS Cancer Center Core, University of Colorado Health Sciences Center, Denver 80262, USA. Natalie.Serkova@UCHSC.edu
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Serkova
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood*; D001786:Blood Glucose; D002784:Cholesterol / Q000097:blood; D003401:Creatine / Q000097:blood; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D003903:Deuterium; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods*; D000068338:Everolimus; D005978:Glutathione / Q000097:blood; D006885:Hydroxybutyrates / Q000097:blood; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D007773:Lactates / Q000097:blood; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008744:Methylamines / Q000097:blood; D051381:Rats; D015203:Reproducibility of Results; D020123:Sirolimus / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D013997:Time Factors
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D006885:Hydroxybutyrates; D007166:Immunosuppressive Agents; D007773:Lactates; D008744:Methylamines; D016572:Cyclosporine; D002784:Cholesterol; D000068338:Everolimus; D003903:Deuterium; D003404:Creatinine; C005855:trimethyloxamine; D005978:Glutathione; D003401:Creatine; D020123:Sirolimus