Plasma Pharmacokinetics and Routes of Excretion of [14C]-Labeled Arruva, a High-Potency Sweetener, Following Oral Administration to Beagle Dogs.
[14C]-Labeled arruva [sodium/potassium (2R,4R)-2-amino-4-carboxy-4-hydroxy-5-(3-indolyl) pentanoate] was administered as a single gavage dose (10 mg/kg bw) to male and female Beagle dogs and 1 bile duct-cannulated male. The mean peak arruva plasma concentration equivalent of 1.2 µg/g occurred at first sampling time point of 1 hour postdosing. The mean area under the concentration versus time curve from 0 hour postdosing to the last time point was approximately 20 µg·h/g and the mean terminal plasma elimination half-life ranged from 15 hours in females to 21 hours in males. Over 168 hours postdosing, 35% to 50% of the administered arruva was eliminated in the urine with 44% to 53% eliminated in feces; 1.3% of the administered dose was recovered in bile. Arruva and its derivatives were identified using tandem mass spectrometry, and the relative percentage of each substance was quantified via radio high-performance liquid chromatography. Over a 168-hour collection period, combined urine and feces extract data from the 6 noncannulated dogs showed that approximately 91% of the dose was excreted as unchanged parent arruva (41% in urine and 50% in feces). In the cannulated male, 95.3% was excreted as unchanged parent arruva; 50.2% in urine, 43.9% in feces, and 1.3% in bile. Lactone and lactam derivatives of arruva and 1 unidentified substance were detected in urine only during the first 24 hours postdosing with the greatest amounts detected during the first 6 hours of collection; up to 1% of lactone or lactam derivatives were detected in bile samples. Plasma pharmacokinetics data indicated rapid absorption of arruva with the majority of radioactivity located in the feces collected in the first 48 hours.
Cargill, Inc, Scientific & Regulatory Affairs, Wayzata, MN, USA.
Phillip L
PL
Casterton
Cargill, Inc, Scientific & Regulatory Affairs, Wayzata, MN, USA christine_crincoli@cargill.com.
Christine M
CM
Crincoli
Cargill, Ltd, Scientific & Regulatory Affairs, Winnipeg, Manitoba, Canada.
Witty A
WA
Brathwaite
Toxicology Regulatory Services, Charlottesville, VA, USA.
Marisa O
MO
Rihner
Toxicology Regulatory Services, Charlottesville, VA, USA.
Andrey I
AI
Nikiforov
WIL Research, Ashland, OH, USA.
Jennifer A
JA
Thomas
D000818:Animals; D017849:Animals, Inbred Strains; D001646:Bile / Q000737:chemistry; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005260:Female; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D006207:Half-Life; D007211:Indoles / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D007408:Intestinal Absorption; D066237:Intestinal Elimination; D007700:Kinetics; D007769:Lactams / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D007783:Lactones / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D008297:Male; D015394:Molecular Structure; D064306:Non-Nutritive Sweeteners / Q000737:chemistry / Q000378:metabolism*; D065667:Renal Elimination; D012727:Sex Characteristics; D053719:Tandem Mass Spectrometry
C414924:4-hydroxy-4-(indol-3-ylmethyl)glutamic acid; D002250:Carbon Radioisotopes; D007211:Indoles; D007769:Lactams; D007783:Lactones; D064306:Non-Nutritive Sweeteners; D018698:Glutamic Acid
R; R-monatin salt; arruva; excretion; lactam; lactone; pharmacokinetics