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Metabolism of aspartate and aspartame
ABSTRACTS AND COMMENTS FOOD ADDITIVES Metabolism
of aspartate and aspartame
The rates of 14C02 excretion after oral or ip doses of [‘4C&aspartate were also determined. In both Oppermann, J. A. & Ranney, R. E. (1979). The meta- adult and 15-day-old mice there was a pronounced bolism of aspartate in infant and adult mice. J. enuir. decrease in the rats of 14C02 excretion during the Path. Toxicol. 2, 987. 30min following oral or ip dosing at lOOOmg/kg. Such dramatic decreases were not apparent after Ranney, R. E. & Oppermann, J. A. (1979). A review of doses of 10 or lOOmg/kg. Therefore the decrease in the metabolism of the aspartyl moiety of aspartame in the rate of 14C02 excretion may reflect the saturation experimental animals and man. J. enuir. Path. Toxiof an enzyme-mediated metabolic process, and this col. 2, 979. saturation may have contributed to the elevated The first of these papers describes a pharmaco- plasma aspartic acid concentrations that were obkinetic study of the absorption and metabolism of served at the high dose level. The second paper cited above is a useful adjunct to aspartic acid after the oral or intraperitoneal (ip) administration of 0, 10, 100 or 1000mg L-aspartate/kg the first. It reviewsthe literature concerning the metabody weight to 1%day-old and adult mice. It was bolic paths followed by aspartate in its conversion to found that massive oral doses of L-aspartate led to CO2 or its incorporation into body constituents higher plasma concentrations in the young mice than (Cited in F.C.T. 1978, 16, 293). It appears that the did equivalent dosesin adults, and it is suggested that aspartate moiety of the sweetening agent aspartame is this might explain the increased susceptibility of metabolized in a similar manner to dietary’ aspartic infant mice to the hypothalamic damage produced by acid. large oral dosesof aspartate (Olney. Fd Comet. Toxico/. 1975, 13. 595; Olney & Ho, Nature, Land. 1970, Three new BHT metaboiites 227, 609; Reynolds et al. J. Toxicol. enuir. Hlth 1976, 2, 471). Yamamoto, K., Tajima, K. & Mizutani, T. (1979). At doses of up to 1OOmg monosodium L-aspart- Identification of new metabolites of butylated hyate/kg by either the oral or ip route, plasma levels of droxytoluene (BHT) in rats. J. Pharmacobic+dyn. 2, 164. aspartic acid were not appreciably altered. However, plasma aspartic acid concentrations 30 min after oral Various products of BHT metabolism have been or ip treatment with 1000 mg/kg were greatly eleva- identified in man (Cited in F.C.T. 1979, 17, 551) and ted-to 554 or 718.3 pg/ml, respectively, in the infants the rat (ibid 1973, 11, 1141; Takahashi & Hiraga, Fd and to 141 or 1435 pg/ml, respectively, in the adults. Cosmet. Toxicol. 1979, 17, 451). In the paper cited Thereafter the plasma levels declined rapidly in both above three newly identified metabolites of BHT in 15-day-old and adult mice in this dose group. The the rat are described. Urine and faecescollected from plasma concentration of aspartic acid observed male Wistar rats for 48 hr following intraperitoneal 30min after ip administration of 1OOOmgL-aspart- administration of 5OOmg BHT/kg body weight were ate/kg to infant mice was 180 times the concentration extracted with ether and fractionated on a silica-gel in the controls, which were given saline. The marked column. One fraction (I) was eluted from the column increasesin plasma aspartic acid concentrations after with hexane-benzene while the other (II) was eluted doses of 1OflOmg L-aspartate/kg suggest that the with benzene-ether. Gas chromatograms of I revealed pharmacokinetics of aspartate became altered at the the presence of the known metabolite 3,5-di-terthigh dose. Measurement of the areas under the butyl+hydroxybenzaldehyde, along with three preplasma concentration-time curves for the high oral viously unrecognized metabolites. By high-resolution and ip dosesshowed that in infants the systemicavail- ‘mass spectrometry it was indicated that these might ability of aspartic acid was similar after administra- be 2,6-di-tert-butyl-pbenzoquinone (III), 2.6-di-terrtion by either route, while in adults the bioavailability butylhydroquinone (IV) and 2,6-di-tert-butyl-4was much lessafter oral administration than after ip [(methylthio)methyl]phenol (V). These identities were injection. The authors suggest that gut-wall meta- confirmed by comparison with the authentic materials bolism in adult mice might account for this effect. A using gas chromatography-mass spectrometry. Fraclower rate of metabolism in the gastro-intestinal tract tion 11 contained no new metabolites. Metabolite III might also account for the higher peak plasma con- was predominant. During the 5 days following BHT centrations after oral doses of L-aspartate in the administration, 0048 and 1.52% of the original dose younger mice. The higher peak concentrations could was excreted as III in the urine and faeces, respectnot have resulted from slower systemic metabolism or ively. The maximum rate of excretion occurred on excretion since the decline in plasma aspartic acid day 2. During the same 5-day period, 0003% of the concentration was faster in neonates (half life 0.15 hr) initial dose was excreted in the urine as V. than that observed in the adult group (half life During the 72 hr following the ip administration of 0.26 hr). 100mg 2,6-di-terr-butyl-4-hydroperoxy-4-methyl-2,5129
of aspartate and aspartame
The rates of 14C02 excretion after oral or ip doses of [‘4C&aspartate were also determined. In both Oppermann, J. A. & Ranney, R. E. (1979). The meta- adult and 15-day-old mice there was a pronounced bolism of aspartate in infant and adult mice. J. enuir. decrease in the rats of 14C02 excretion during the Path. Toxicol. 2, 987. 30min following oral or ip dosing at lOOOmg/kg. Such dramatic decreases were not apparent after Ranney, R. E. & Oppermann, J. A. (1979). A review of doses of 10 or lOOmg/kg. Therefore the decrease in the metabolism of the aspartyl moiety of aspartame in the rate of 14C02 excretion may reflect the saturation experimental animals and man. J. enuir. Path. Toxiof an enzyme-mediated metabolic process, and this col. 2, 979. saturation may have contributed to the elevated The first of these papers describes a pharmaco- plasma aspartic acid concentrations that were obkinetic study of the absorption and metabolism of served at the high dose level. The second paper cited above is a useful adjunct to aspartic acid after the oral or intraperitoneal (ip) administration of 0, 10, 100 or 1000mg L-aspartate/kg the first. It reviewsthe literature concerning the metabody weight to 1%day-old and adult mice. It was bolic paths followed by aspartate in its conversion to found that massive oral doses of L-aspartate led to CO2 or its incorporation into body constituents higher plasma concentrations in the young mice than (Cited in F.C.T. 1978, 16, 293). It appears that the did equivalent dosesin adults, and it is suggested that aspartate moiety of the sweetening agent aspartame is this might explain the increased susceptibility of metabolized in a similar manner to dietary’ aspartic infant mice to the hypothalamic damage produced by acid. large oral dosesof aspartate (Olney. Fd Comet. Toxico/. 1975, 13. 595; Olney & Ho, Nature, Land. 1970, Three new BHT metaboiites 227, 609; Reynolds et al. J. Toxicol. enuir. Hlth 1976, 2, 471). Yamamoto, K., Tajima, K. & Mizutani, T. (1979). At doses of up to 1OOmg monosodium L-aspart- Identification of new metabolites of butylated hyate/kg by either the oral or ip route, plasma levels of droxytoluene (BHT) in rats. J. Pharmacobic+dyn. 2, 164. aspartic acid were not appreciably altered. However, plasma aspartic acid concentrations 30 min after oral Various products of BHT metabolism have been or ip treatment with 1000 mg/kg were greatly eleva- identified in man (Cited in F.C.T. 1979, 17, 551) and ted-to 554 or 718.3 pg/ml, respectively, in the infants the rat (ibid 1973, 11, 1141; Takahashi & Hiraga, Fd and to 141 or 1435 pg/ml, respectively, in the adults. Cosmet. Toxicol. 1979, 17, 451). In the paper cited Thereafter the plasma levels declined rapidly in both above three newly identified metabolites of BHT in 15-day-old and adult mice in this dose group. The the rat are described. Urine and faecescollected from plasma concentration of aspartic acid observed male Wistar rats for 48 hr following intraperitoneal 30min after ip administration of 1OOOmgL-aspart- administration of 5OOmg BHT/kg body weight were ate/kg to infant mice was 180 times the concentration extracted with ether and fractionated on a silica-gel in the controls, which were given saline. The marked column. One fraction (I) was eluted from the column increasesin plasma aspartic acid concentrations after with hexane-benzene while the other (II) was eluted doses of 1OflOmg L-aspartate/kg suggest that the with benzene-ether. Gas chromatograms of I revealed pharmacokinetics of aspartate became altered at the the presence of the known metabolite 3,5-di-terthigh dose. Measurement of the areas under the butyl+hydroxybenzaldehyde, along with three preplasma concentration-time curves for the high oral viously unrecognized metabolites. By high-resolution and ip dosesshowed that in infants the systemicavail- ‘mass spectrometry it was indicated that these might ability of aspartic acid was similar after administra- be 2,6-di-tert-butyl-pbenzoquinone (III), 2.6-di-terrtion by either route, while in adults the bioavailability butylhydroquinone (IV) and 2,6-di-tert-butyl-4was much lessafter oral administration than after ip [(methylthio)methyl]phenol (V). These identities were injection. The authors suggest that gut-wall meta- confirmed by comparison with the authentic materials bolism in adult mice might account for this effect. A using gas chromatography-mass spectrometry. Fraclower rate of metabolism in the gastro-intestinal tract tion 11 contained no new metabolites. Metabolite III might also account for the higher peak plasma con- was predominant. During the 5 days following BHT centrations after oral doses of L-aspartate in the administration, 0048 and 1.52% of the original dose younger mice. The higher peak concentrations could was excreted as III in the urine and faeces, respectnot have resulted from slower systemic metabolism or ively. The maximum rate of excretion occurred on excretion since the decline in plasma aspartic acid day 2. During the same 5-day period, 0003% of the concentration was faster in neonates (half life 0.15 hr) initial dose was excreted in the urine as V. than that observed in the adult group (half life During the 72 hr following the ip administration of 0.26 hr). 100mg 2,6-di-terr-butyl-4-hydroperoxy-4-methyl-2,5129