title: Detection of ECG effects of (2R,4R)-monatin, a sweet flavored isomer of a component first identified in the root bark of the Sclerochitin ilicifolius plant.
abstract: Enzymatically-synthesized (2R,4R)-monatin has, due to its pure sweet taste, been evaluated for potential use in foods. Non-clinical studies have shown that (2R,4R)-monatin is well tolerated at high dietary concentrations, is not genotoxic/mutagenic, carcinogenic, or overtly toxic. In a pharmacokinetic and metabolism study involving 12 healthy males, consumption of a single oral dose (2 mg/kg) of (2R,4R)-monatin resulted in a small reduction of heart rate and prolongation of the QTcF interval of 20-24 ms, corresponding to the time of peak plasma levels (t(max)). These findings were evaluated in a cross-over thorough QT/QTc study with single doses of 150 mg (2R,4R)-monatin, placebo and positive control (moxifloxacin) in 56 healthy males. Peak (2R,4R)-monatin plasma concentration (1720 ± 538 ng/mL) was reached at 3.1 h (mean tmax). The placebo-corrected, change-from-baseline QTcF (ΔΔQTcF) reached 25 ms three hours after dosing, with ΔΔQTcF of 23 ms at two and four hours. Using exposure response (QTc) analysis, a significant slope of the relationship between (2R,4R)-monatin plasma levels and ΔΔQTcF was demonstrated with a predicted mean QT effect of 0.016 ms per ng/mL. While similarly high plasma levels are unlikely to be achieved by consumption of (2R,4R)-monatin in foods, QTc prolongation at this level is a significant finding.
authors.affiliation: Karolinska Institutet, Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd's Hospital, Stockholm, Sweden; iCardiac Technologies, Inc., 150 Allens Creek Road, Rochester, NY 14618, USA. Electronic address: borje.darpo@icardiac.com.
authors.forename: Borje
authors.initials: B
authors.lastname: Darpo
authors.affiliation: Bjornsson Associates, LLC, Saint Davids, PA, USA. Electronic address: thorir.bjornsson@verizon.net.
authors.forename: Thorir D
authors.initials: TD
authors.lastname: Bjornsson
authors.affiliation: Cargill, Limited, 300-240 Graham Avenue, Winnipeg, Manitoba R3C 4C5, Canada. Electronic address: witty_brathwaite@cargill.com.
authors.forename: Witty A
authors.initials: WA
authors.lastname: Brathwaite
authors.affiliation: Cargill, Incorporated, 15407 McGinty Road W., MS 163 Wayzata, MN, USA. Electronic address: christine_crincoli@cargill.com.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Crincoli
authors.affiliation: Cargill, Incorporated, 15407 McGinty Road W., MS 163 Wayzata, MN, USA. Electronic address: alex_eapen@cargill.com.
authors.forename: Alex K
authors.initials: AK
authors.lastname: Eapen
authors.affiliation: GL Fisher Consulting, LLC, 146 Davis Rd., Malvern, PA, USA. Electronic address: geraldfisher@hotmail.com.
authors.forename: Gerald L
authors.initials: GL
authors.lastname: Fisher
authors.affiliation: Lankenau Medical Center, Philadelphia, PA, USA; Jefferson Medical College, Philadelphia, PA, USA. Electronic address: koweyp@mlhs.org.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Kowey
authors.affiliation: Cargill, Incorporated, 15407 McGinty Road W., MS 163 Wayzata, MN, USA. Electronic address: marv_miller@cargill.com.
authors.forename: Marvin P
authors.initials: MP
authors.lastname: Miller
authors.affiliation: Toxicology Regulatory Services, 2365 Hunters Way, Charlottesville, VA, USA. Electronic address: anikiforov@toxregserv.com.
authors.forename: Andrey I
authors.initials: AI
authors.lastname: Nikiforov
authors.affiliation: Toxicology Regulatory Services, 2365 Hunters Way, Charlottesville, VA, USA. Electronic address: mrihner@toxregserv.com.
authors.forename: Marisa O
authors.initials: MO
authors.lastname: Rihner
authors.affiliation: iCardiac Technologies, Inc., 150 Allens Creek Road, Rochester, NY 14618, USA. Electronic address: meijian.zhou@icardiac.com.
authors.forename: Meijian
authors.initials: M
authors.lastname: Zhou
mesh_terms: D027901:Acanthaceae / Q000737:chemistry*; D004562:Electrocardiography; D005260:Female; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007536:Isomerism; D008297:Male; D024301:Plant Bark / Q000737:chemistry*
chemical_list: C414924:4-hydroxy-4-(indol-3-ylmethyl)glutamic acid; D007211:Indoles; D018698:Glutamic Acid
keywords: (2R,4R)-Monatin; Food ingredient; QT prolongation; QTc; TQT study