title: Pharmacokinetic, partial pharmacodynamic and initial safety analysis of (-)-epicatechin in healthy volunteers.
abstract: (-)-Epicatechin ((-)-EPI), a naturally occurring flavanol, has emerged as a likely candidate for cocoa-based product reported reductions in cardiometabolic risk. The present study aimed to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of purified (-)-EPI administered to healthy volunteers. In this phase I, open-label, two-part single- and multiple-dose study, subjects received either a single dose (n = 9) of 50, 100 or 200 mg or multiple doses (n = 8) of 50 mg daily (q.d.) or twice daily (b.i.d) for 5 days. Blood was collected at 0, 0.5, 1, 2, 4 and 6 h after (-)-EPI administration in the single and multiple dose groups (blood collection repeated in day 5). Samples were analyzed by HPLC-HR-ESI-MS for EPI and metabolite quantification. In the q.d. and b.i.d. groups, blood samples were analyzed for NO surrogates and follistatin levels as well as, platelet mitochondrial complexes I, V and citrate synthase activity levels. (-)-EPI was well tolerated and readily absorbed with further phase 2 metabolism. On day 5, in the q.d. and b.i.d. groups, there were significant increases in plasma nitrite of 30% and 17%, respectively. In the q.d. group on day 5 vs. day 1, platelet mitochondrial complexes I, IV and citrate synthase activities demonstrated a significant increase of ∼92, 62 and 8%, respectively. Average day 5 follistatin AUC levels were ∼2.5 fold higher vs. day 1 AUC levels in the b.i.d. group. (-)-EPI was safe to use, with no observed adverse effects, and our findings suggest that increases in NO metabolites, mitochondrial enzyme function and plasma follistatin levels may underlie some of the beneficial effects of cocoa products or (-)-EPI as reported in other studies.
authors.affiliation: University of California, San Francisco, USA.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Barnett
authors.forename: Aldo
authors.initials: A
authors.lastname: Moreno-Ulloa
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.forename: Israel
authors.initials: I
authors.lastname: Ramirez-Sanchez
authors.forename: Pam R
authors.initials: PR
authors.lastname: Taub
authors.forename: Yongxuan
authors.initials: Y
authors.lastname: Su
authors.forename: Guillermo
authors.initials: G
authors.lastname: Ceballos
authors.forename: Sundeep
authors.initials: S
authors.lastname: Dugar
authors.forename: George
authors.initials: G
authors.lastname: Schreiner
authors.forename: Francisco
authors.initials: F
authors.lastname: Villarreal
mesh_terms: D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D001792:Blood Platelets / Q000201:enzymology; D002318:Cardiovascular Diseases / Q000276:immunology / Q000517:prevention & control*; D002392:Catechin / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism*; D002950:Citrate (si)-Synthase / Q000737:chemistry / Q000378:metabolism; D019587:Dietary Supplements / Q000009:adverse effects* / Q000032:analysis; D045222:Electron Transport Chain Complex Proteins / Q000819:agonists / Q000378:metabolism; D005260:Female; D038681:Follistatin / Q000097:blood / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000819:agonists / Q000097:blood / Q000378:metabolism; D059550:Toxicity Tests, Subchronic; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D045222:Electron Transport Chain Complex Proteins; D038681:Follistatin; D009569:Nitric Oxide; D002392:Catechin; D002950:Citrate (si)-Synthase