Pharmacokinetics and metabolism of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame) in the rat, dog, and man.
The pharmacokinetics and metabolism of advantame were evaluated in rats, dogs, and humans. The oral pharmacokinetic studies using (14)C-advantame showed that advantame undergoes rapid but incomplete absorption, with an oral bioavailability of total radioactivity in the range of 4-23%. Data indicated that absorption was mainly as ANS9801-acid (de-esterified advantame), which was formed in the gastrointestinal tract as a result of the hydrolysis of the methyl ester group of the parent compound. In the dog, plasma ANS9801-acid was present largely in the form of an unidentified conjugate. Advantame (chiefly in the form of metabolites) was mainly excreted in the feces in rats, dogs, and humans (>80% in each species), with urinary excretion representing a minor route. The predominant metabolite of (14)C-advantame detected in the feces and the urine of rats, dogs, and humans was ANS9801-acid, with lower amounts of 3-[3-hydroxy-4-methoxyphenyl]-1-propylamine (termed HU-1) or N-(3-(3-hydroxy-4-methoxy phenyl))propyl-L-aspartic acid (termed HF-1) present, as well as other minor metabolites and areas of indistinct radioactivity. ANS9801-acid, HU-1, and HF-1 were detected and identified in the urine of rats, humans, and dogs, while ANS9801-acid and HF-1 were identified in the feces of humans and dogs. In the feces of rats, in addition to ANS9801-acid, other additional metabolites were detected, including demethylated ANS9801-acid (designated as RF-1) and another unidentified metabolite (designated as RF-2). Overall, the data show generally similar pharmacokinetics of advantame and ANS9801-acid in animals and in humans and close similarity with neotame. Metabolites of advantame that occur in humans are also found in the 2 species utilized in the toxicology studies, and the metabolism studies support the interpretation of safety data from studies conducted in rats and dogs.
Ajinomoto Pharmaceuticals Co. Ltd., 1-1 Suzuki-cho, Kanagawa Kawasaki-ku, Kawasaki-shi 210-8681, Japan. kazuyuki_ubukata@ajinomoto.com
K
K
Ubukata
A
A
Nakayama
R
R
Mihara
D000284:Administration, Oral; D000328:Adult; D000818:Animals; D019540:Area Under Curve; D004151:Dipeptides / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008665:Metalloporphyrins / Q000737:chemistry; D008875:Middle Aged; D051381:Rats; D013045:Species Specificity; D013549:Sweetening Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*
D004151:Dipeptides; D008665:Metalloporphyrins; D013549:Sweetening Agents; C446505:iron chlorin e(6); C570172:N-(N-(3-(3-hydroxy-4-methoxyphenyl) propyl)-alpha-aspartyl)-L-phenylalanine 1-methyl ester