The Personalization of Clopidogrel Antiplatelet Therapy: The Role of Integrative Pharmacogenetics and Pharmacometabolomics

Table 3

Examples of pharmacometabolomics studies in humans.

Study	Drug	Analytical method	Specimen	Main findings
Holmes et al., 2006 [136]	Antipsychotic drugs	^1HNMR	CSF	A metabotype of schizophrenia which discriminated antipsychotic drug naive patients from healthy control. This metabotype was alleviated in half of the patients to normal after short term treatment with antipsychotic drugs.
Kim et al., 2010 [146]	Cyclosporine A (CsA) & Tacrolimus (TAC)	^1HNMR	Serum	Time dependent metabolites changes in response to different treatment. The difference in the level of trimethylamine-N-oxide (TMAO) which is associated with graft dysfunction, between 2 groups of immunosuppressant drugs treatment; CsA & TAC were not significant. Lipid metabolites were higher in CsA group increasing the risk of cardiovascular diseases.
Wang et al., 2012 [147]	Methotrexate	^1HNMR	Serum	Identification of 11 metabolites which can discriminate between methotrexate efficacy groups in patients with early rheumatoid arthritis.
Kaddurah-Daouk et al., 2013 [148]	Sertraline	GC-TOF-MS	Serum	Discriminating metabotypes of symptoms reduction between sertraline and placebo in MDD patients on one week and 4 weeks of treatment. Symptoms reduction after one week of sertraline treatment was associated with the reduction of 5-methoxytryptamine levels, while it was associated with lower levels of branched chain amino acids at four weeks of sertraline treatment.
Yerges-Armstrong et al., 2013 [164]	Aspirin	GC-MS	Serum	Identification of aspirin exposure metabotype of 18 metabolites in healthy volunteers who were on aspirin 81 mg for 14 days (HAPI study). Aspirin exposure metabotype was significantly associated with purine metabolic pathway. Inosine and adenosine were significantly higher after aspirin in aspirin HTPR group.
Villaseñor et al., 2014 [149]	Ketamine	LC-QTOF-MS	Plasma	Identification of discriminating metabolites between responders and nonresponders of ketamine among bipolar depression patients. The discriminating metabolites were related to mitochondrial β-oxidation of fatty acid.
Ellero-Simatos et al., 2014 [166]	Aspirin	LC-MS	Serum	Elevated level of baseline serum serotonin is associated with aspirin HTPR based on collagen induced PFT assessment of healthy subjects who were on aspirin 81 mg for 14 days (HAPI study).

HNMR: proton nuclear magnetic resonance, GC: gas chromatography, TOF: time of flight, MS: mass spectroscopy, QTOF: quadrupole time of flight, LC: liquid chromatography, CSF: cerebrospinal fluid, CVDs: cardiovascular diseases, CsA: Cyclosporine A, TAC: Tacrolimus, TMAO: trimethylamine-N-oxide, MDD: major depressive disorder, HAPI: Heredity and Phenotype Intervention, and HTPR: high on treatment platelets reactivity.
Antipsychotic drugs: atypical antipsychotic drug such as amisulpride, clozapine, olanzapine, risperidone, quetiapine, and ziprasidone.