editorial on ADME studies.
Abstract
Frank Orlowski
?-Polylysine is a homopolymer of L-lysine, containing approximately 30 L-lysine subunits, as synthesized in aerobic bacterial fermentation by Streptomyces albulus. ?-Polylysine is approved for food use in Japan as an antimicrobial preservative. A series of pharmacokinetic and metabolic profile studies on ?-polylysine have been conducted in rats in order to provide a better understanding of the reason for its lack of toxicological effects in subchronic and chronic feeding bioassays using relatively high concentrations in the diet up to 50,000 ppm. As reported in this article, ?-polylysine was practically non-toxic in an acute oral toxicity study in rats, with no mortality up to 5 g/kg and was not mutagenic in bacterial reversion assays. Absorption, distribution, metabolism and excretion (ADME) studies on 14C-radiolabeled ?-polylysine, given in a single dose to fasted male rats at 100 mg/kg, revealed low absorption from the gastrointestinal tract. All but trace amounts of the dosed radioactivity was eliminated by excretion within 168 h and over 97% was accounted for in urine (1.2%), feces (92.9%), or expired air (3%) by 48 h. The sum of the cumulative excretion with routes associated with absorption in urine, expired air and carcass was 6.4% of total recovered radioactivity; approximately 94% of the dose of ?-polylysine passed unabsorbed through the gastrointestinal tract in the feces. Whole body autoradiography did not show concentration of absorbed ?-polylysine in any tissue or organ. Excretion half-lives of ?-polylysine equivalents in blood and plasma were 20 and 3.9 days, likely prolonged by the incorporation into protein of cleaved L-lysine. Metabolic profiles by HPLC analysis of plasma samples suggest that L-lysine is the predominant early metabolic by-product, likely from protease activity in the upper GI tract; only 0.2% of the administered parent compound was found in plasma. At 8???72 h, HPLC profiles show diminishing levels of ?-polylysine and L-lysine in plasma, accompanied by a shift to larger peaks of homopolymer fragments of varying subunit length, presumably from microbial degradation of ?-polylysine in the lower gut. HPLC profiles of urine and feces collected from 0 to 24 h post-dosing revealed three distinct peaks in urine, the first peak likely to be ?-polylysine and ?-polylysine less a few amino acid subunits, and the second, L-lysine and the third, a metabolite of L-lysine. Radiolabeled L-lysine was reduced from 67.2% of the radioactivity in plasma at 30 min to 7.5% at 4 h, indicating that L-lysine is readily removed from plasma from essential amino acid incorporation into protein. Based on the findings of the ADME studies and lack of toxicity in safety studies, the proposed use of ?-polylysine as a preservative in foods is considered to be safe.
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