R E Ranney’s research while affiliated with United States Drug Testing Laboratories and other places

Aspartame (3-amino-N-(alpha-carboxyphenethyl) succinamic acid, methyl ester; the methyl ester of aspartylphenylalanine, SC-18862) is hydrolyzed in the gut to yield aspartic acid, phenylalanine, and methanol. This review of the literature describes the metabolic paths followed by aspartate in its conversion to CO2 or its incorporation into body constituents. About 70 percent of 14C from [asp-14C]-aspartame is converted in the monkey to 14CO2. Some of the aspartate is converted at the intestinal mucosal level to alanine by decarboxylation. This amino acid may be oxidized to CO2 by entering the tricarboxylic acid cycle via pyruvate and acetyl CoA. In addition, transamination of aspartate to oxaloacetate permits this product also to enter the tricarboxylic acid cycle. Aspartate may also be incorporated into body constitutents such as other amino acids, proteins, pyrimidines, asparagine, and N-acetylaspartic acid. It is concluded that the aspartate moiety of aspartame is metabolized in a manner similar to that of dietary aspartic acid.

Plasma concentrations of aspartic acid were determined after the oral or intraperitoneal (ip) administration of 0, 10, 100 and 1000 mg/kg L-aspartate to 15-day-old and adult mice. Plasma concentrations of aspartic acid were elevated 30 min after 1000 mg/kg L-aspartate (oral or ip) to 15-day-old and adult mice. Thereafter, plasma concentrations rapidly declined exponentially (log concentration versus time) with a half-life of approximately 0.2 hr in both age groups. Aspartic acid plasma concentrations were not appreciably altered after the oral or ip administration of 10 and 100 mg/kg L-aspartate. After oral administration of 1000 mg/kg L-aspartate, the area under the plasma aspartic acid concentration curve was much greater for 15-day-old mice than that for adult mice. Since plasma concentrations of aspartic acid in both age groups declined with similar rates after ip administration of L-aspartate, this difference cannot be accounted for by differences in the systemic metabolism of aspartate. However the systematic availability of orally aspartic acid may differ with age because of differences in the rates of metabolism of aspartic acid in the gut. The rates of 14CO2 excretion were also determined after the oral or ip administration of [14C]-L-aspartate, to 15-day-old and adult mice. After the oral or ip administration of 10 and 100 mg/kg [14C]-L-aspartate, these rates were similar in both 15-day-old and adult mice. However at 1000 mg/kg, the rates of 14CO2 excretion, as percent of dose, were depressed during the first 30 min after both oral and ip administration of the compound to both age groups. This inability to metabolize high doses of aspartate at the same rates as lower doses, may contribute to the elevated plasma concentrations of aspartic acid in animals given 100 mg/kg.

Aspartame [SC-18862; 3-amino-N-(alpha-carboxyphenethyl) succinamic acid, methyl ester, the methyl ester of aspartylphenylalanine] is a sweetening agent that organoleptically has about 180 times the sweetness of sugar. The metabolism of aspartame has been studied in mice, rats, rabbits, dogs, monkeys, and humans. The compound was digested in all species in the same way as are natural constituents of the diet. Hydrolysis of the methyl group by intestinal esterases yielded methanol, which was oxidized in the one-carbon metabolic pool to CO2. The resultant dipeptide was split at the mucosal surface by dipeptidases and the free amino acids were absorbed. The aspartic acid moiety was transformed in large part to CO2 through its entry into the tricarboxylic acid cycle. Phenylalanine was primarily incorporated into body protein either unchanged or as its major metabolite, tyrosine.

The methyl ester of aspartylphenylalanine (aspartame; SC-18862; 3-amino-N-(α-carboxyphenethyl)-succinamic acid, methyl ester) is a sweetening agent which organoleptically has about 180 times the sweetness of sugar. Since this compounds is a food additive its metabolism in pregnancy has been evaluated. Pregnant female rabbits were fed aspartame at a level of 6% in the diet beginning on day 6 of pregnancy. Maternal plasma samples taken at days 6, 9, 16, and 20 were analyzed for phenylalanine and tyrosine. Fetal amniotic fluids were similarly analyzed on days 16 and 20 as were fetal plasma samples at day 20. Maternal plasma phenylalanine and tyrosine increased as a result of the treatment, reaching a peak on day 9. These values returned toward normal levels by day 20. The ratios of fetal/maternal plasma phenylalanine and tyrosine concentrations were unaffected by the treatment. No evidence of substrate inhibition of phenylalanine hydroxylase was seen in maternal or fetal plasma analyses or in in vitro studies of maternal liver homogenates. Tyrosine concentrations in maternal and fetal plasma rose higher with treatment than phenylalanine concentrations. Both amino acids accumulated in the amniotic fluid in amounts greater than, but proportional to, plasma concentrations.

Aspartame (SC-18862, 3-amino-NT-(a-carboxyphenethyl)succinamic acid, methyl ester; the methyl ester of aspartyl-phenylalanine ) is a sweetening agent that organoleptically has about 180 times the sweetness of sugar. It is hydrolyzed in the gut to its constituent moieties: methanol, aspartic acid, and phenylalanine; and these are metabolized as natural constituents in the diet. Because the major fraction of phenylala nine is incorporated into body constituents, this study was carried out to determine if continued ingestion of aspartame had any effect on phenylalanine metabolism. It was found that after aspartame had been administered at doses of 15 or 60 mg/kg for 10 days, these treatments had essentially no effect on the disappearance of intravenously administered ("C) phenylalanine from the plasma. In addition, the conversion of labeled phenylalanine to tyrosine was not affected, nor was the rate of conversion to CO2 sub stantially affected, nor was the rate of incorporation of the label into protein changed by the treatments. It was concluded that these doses of aspartame had not modified phenylalanine metabolism in this species. J. Nutr. 103: 1460-1466, 1973.

Aspartame (SC-18862, 3-amino-N-(a-carboxyphenethyl)succinarnic acid, methyl ester; the methyl ester of aspartyl-phenylalanine ) is a sweetening agent that organoleptically has about 180 times the sweetness of sugar. Because it so closely resembles naturally occurring dipeptides, it was believed that it would be digested in a similar manner. To show this, the metabolism of (14C) aspartame labeled separately in the methyl, aspartyl and phenylalanine moieties was compared with the metabolism of "C-labeled methanol, aspartic acid, and phenylalanine. The metabolism of each moiety of aspartame was found to be the same as its free counterpart. Parameters measured were: conversion to "COj, incorporation of 14C into plasma proteins, and urinary and fecal excretion of the label. It was concluded that aspartame was digested to its three constituents that were then absorbed as natural constituents of the diet. J. Nutr. 103: 1454-1459, 1973.

The disposition and metabolic fate of 14C oxandrolone (17α methyl 17β hydroxy 2 oxa 5α androstan 3 one) was studied in 6 healthy male subjects. After administration of a single oral dose (10 mg containing 20 μCi of 14C in ethanolic solution), the peak concentration of 14C oxandrolone in the plasma was 417 (mean) μg per milliliter at 0.50 to 1.50 hours. Its level then declined in two phases: from 1.5 to 4.0 hours with a half life of 0.55 hour and from 4.0 to 48 hours with a half life of 9.4 hours. The ingested 14C was eliminated predominantly by urinary excretion. In the urine, 43.6% of the administered 14C was excreted in 24 hours and 60.4% in 96 hours. Recovery of 14C in the feces accounted for only 2.8% of the dose. The chloroform extractable urinary radioactivity was largely composed of the unchanged drug, which accounted for 46.1% of urinary 14C or 28.7% of the ingested 14C. Enzyme hydrolysis of the urinary conjugated fraction, which accounted for 31.3% of the urinary 14C, gave two major aglycones in the approximate ratio of 2:7. These aglycones were tentatively identified as oxandrolone and 16β hydroxyoxandrolone, respectively.

The biotransformation of disopyramide phosphate [4-diisopropylamino-2-phenyl-2-(2-pyridyl)butyramide phosphate] was studied in rats and dogs using the 14C-labeled compound and in man using the unlabeled drug. Within 72 hr., 78.7 ± 1.4% of the administered radioactivity was recovered in the urine of dogs after oral administration and 44.1 ± 3.4% was recovered in the urine of rats after intraperitoneal administration. In dogs, 17.3 ± 3.4% of the urinary radioactivity was associated with the unchanged compound, 12.4 ± 1.6% with 4-isopropylamino-2-phenyl-2-(2-pyridyl)-butyramide, and 29.2 ± 2.6% with 3-phenyl-3-(2-pyridyl)-2-pyrrolidone; 18.0 ± 3.3% was present as a water-soluble conjugate which, on acid hydrolysis, gave the pyrrolidone as the major aglycone. In rats, the urinary radioactivity was predominantly (80.9 ± 2.3%) associated with the unchanged disopyramide. In this species the major metabolic pathway was aryl hydroxylation, giving two phenolic compounds, one of which was identified as 4-diisopropylamino-2-(p-hydroxyphenyl)-2-(2-pyridyl)butyramide. These phenolic metabolites were predominantly excreted in the bile as conjugates. In man, 56% of the administered drug was excreted unchanged in the urine while 4% was present as the secondary amine. The structural assignments of the metabolites were based on their detailed spectroscopic analysis and by comparison of their chromatographic properties with authentic samples.

The absorption, excretion, and biotransformation of 14C-diphenoxylate hydrochloride (5 mg. containing 20.2 μc of 14C) when administered orally in ethanolic solution and without the presence of atropine sulfate was studied in 3 men. The mean urinary and fecal excretion of the total label in a 96 hour period was 13.65 ± 1.18 per cent and 49.20 ± 2.24 per cent, respectively. Thin-layer radiochromatographic analysis of the label in excreta indicated extensive biotransformation of the parent drug. In the urine, the major metabolites were characterized as diphenoxylic acid and hydroxydiphenoxylic acid. These acids were present in both the free and conjugated fractions. Radioactivity in the plasma was associated largely with diphenoxylic acid and to a smaller extent with the unchanged drug. Pharmacokinetic analysis using a one-compartment open model showed a rapid absorption (t 1 2 = 19.7 ± 1.7 minutes; peak level at 2.0 hours) of diphenoxylate followed by its rapid elimination (t 1 2 = 2.50 ± 0.34 hours). The plasma half-life t 1 2 = 4.38 ± 1.04 hours) of diphenoxylic acid was higher than that of diphenoxylate.