Biomedical subjects
Publications and source records attributed to B K Tang.
Amobarbital is almost completely metabolized in animals and man. The major metabolite is 3'-hydroxyamobarbital. The second major metabolite in dog, mice, hamsters, guinea pigs, and rats could be identified as 3',4'-dihydroxyamobarbital. A striking contrast between man and animals is the virtual absence of the diol in man and absence of amobarbital-N-glucoside in animals.
The two main metabolites of amobarbital excreted in urine are 3'-hydroxyamobarbital (C-OH) and 1-(beta-D-glucopyranosyl) amobarbital (N-glu). When testing the metabolite ratio in small single samples of urine, it was found that the urine in a Caucasian population contained about one-third glucose conjugation and two-thirds hydroxylation product, while an Oriental population excreted both metabolites in equal proportion. Attempts to learn the causes for the different metabolite ratios led to an investigation of metabolite concentrations in urine. The sums of the average urinary concentration of C-OH was greater in Caucasians than in Orientals, no matter how the data were expressed; the reverse was true for the N-glu metabolite. C-OH data was scattered more widely among Orientals than Caucasians; this might indicate bimodality of the distribution curves. There also was a trend toward more N-glu metabolite in urine of females than of males. Measuring the metabolite/creatinine ratios narrowed the distribution range of the data, particularly after correction for sex difference in creatinine, but population differences were not changed. Expected relationships between metabolite content of urine, sampling times, and plasma half-life (t1/2) were established by calculation. A Caucasian female with no capacity for N-glucosidation was found during the first part of this population survey. An Oriental male with only trace capacity for amobarbital hydroxylation was found in the second part.
This paper establishes that the relative proportion of amobarbital metabolites in urine is highly variable from person to person and that observations of plasma half-life give no indication of this variability, but it shows that a valid estimate of a given person's metabolite pattern can be obtained by studying a single urine specimen in the postdistributive phase. The two metabolites which were measured in urine accounted on the average of 9 subjects for 80% +/- 3% of the dose with a range from 66% to 94%. The two metabolites were the well known 3'-hydroxyamobarbital (COH) as a product of side chain hydroxylation and N-beta-D-glucopyranosyl amobarbital (N-glu), a glucose conjugate which at some earlier time had been mistaken for an N-hydroxylation product. Among 129 volunteer subjects, the metabolite ratio N-glu/COH showed a median value of about 0.5 with a range from 0 to 2.8. A virtual absence of N-glu was observed in one of the 129 subjects and confirmed by a second administration of amobarbital 3 mo later. Of the 14 subjects with predominant N-glu excretion 4 were of Chinese origin, while there were 6 Chinese among the 115 other subjects (p less than 0.02).
N-Hydroxyamobarbital, the compound previously proposed as the second major metabolite of amobarbital was synthesized. The metabolite was shown not to be N-hydroxyamobarbital. NMR and MS analyses on the metabolite suggested it could be a derivative of N-beta-D-glucopyranoside. This proposed structure was confirmed by comparison with the spectral data of synthetic amobarbital-N-methyl-N-2,3,4,6-tetraacetyl-beta-D-glucopyranoside.
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It has been shown recently that the overall metabolism of amobarbital in man is essentially under genetic control. The drug normally undergoes two hydroxylation reactions, leading to 3'-hydroxyamobarbital (C-OH) and N-hydroxyamobarbital (N-OH). This paper describes a sibship in which two mothers who are identical twins show a gross deficiency on N-OH elimination in urine. The whole set of sibship data suggests that this deficiency represents a recessive trait controlled by a single pair of allelic autosomal genes which regulate N-OH formation. Several methodical approaches to assess an individual's capacity for N-OH formation are illustrated. There was no evidence of compensatory or concordant regulation of the two hydroxylation reactions. The case of this family illustrates that the functional lack of a biotransformation reaction is almost certain to be overlooked if one measures only the disappearance of a multimetabolized drug and not the appearance of metabolites.
Some aspects of the fate of amobarbital were investigated since this drug is being used as a probe to gauge drug oxidation in man. The mean ratio of orally available over intravenously injected amobarbital was established as 0.99 +/- 0.11 (SD), by comparing integrated concentration-time curves, indicating complete absorption and absence of a first-pass effect. One subject ingested 200 mg of amobarbital sodium, and amobarbital concentrations in serum were monitored for 5 days thereafter. Elimination of amobarbital under these conditions followed first-order kinetics. One subject ingested amobarbital 7 times over a period of 3 yr; plasma clearances (32.1 +/- 1.8 [SD]ml/min) exhibited remarkable constancy, while biologic half-lives (26.5 +/- 3.1 hr) and distribution volumes (73.6 +/- 8.0 L) showed some fluctuation. The distribution of parameters of amobarbital elimination was investigated in 36 unrelated subjects. Amobarbital half-lives (23.8 +/- 6.7 hr) appeared to be normally distributed, while the clearances (36.7 +/- 10.0 ml/min) might not follow a normal distribution.
The uropygial (preen) gland secretion of the domestic turkey resembles that of the chicken in consisting mainly of a diester wax. The esterified fatty acids are saturated; they include all members of the n-C(10)-C(20) homologous series, the C(17)-C(19) acids together accounting for 60% of the total. There are four major 2,3-n-alkanediols, C(19)-C(23), all having the erythro configuration as determined by thin-layer chromatography on boric acid-silica gel and by gas-liquid chromatography. The chicken uropygiols, by contrast, contain erythro and threo diols. It is suggested that the chicken possesses two biosynthetic enzyme systems for the diols, the turkey only one
After oral administration of 14C-labeled amobarbital to healthy subjects, most of the radioactivity was recovered in urine and only 4-5% in feces over a period of 6 days. No unchanged amobarbital was excreted. Two major metabolites were found and isolated. One was 3'-hydroxyamobarbital, which has been previously identified by Maynert. The second could be identified as N-hydroxyamobarbital on the basis of its spectral and chemical properties.
After oral administration of 14C-labeled pentobarbital to healthy subjects, most ot the radioactivity was recovered in urine over a period of 6 days. Only a minute amount (approximately 1%) of unchanged pentobarbital was found in the urine. Four major metabolites were found and isolated. One was 3'-hydroxypentobarbital, which has been previously identified by Maynert. The second could be identified as N-hydroxypentobarbital on the basis of its spectral and chemical properties. The other two metabolites were not identified.
Alcohol dehydrogenase (ADH) is genetically polymorphic, and large differences in allele frequencies exist between the major human races. Genetic variants at the ADH2 gene locus include the beta 2-ADH ("atypical" ADH) present in 85% of Orientals and the beta 1-ADH ("normal" ADH) present in 85 to 95% of whites. Although the presence of one or the other of these ADH variants does not significantly affect the rate of ethanol oxidation in the living subject, it may affect that of other substrates. The overall objective of this work was to screen in vitro for ADH substrates which might be differentially metabolized by these ADH2variants in living subjects. In an in vitro screening method using autopsy livers at pH 8.5, the formation or disappearance of NADH at 340 nm was measured before and after exposure to 4-methylpyrazole, an ADH-specific competitive inhibitor. The screening test revealed three new substrates and suggested that alcohol substrates fall into two groups. The majority of substrates belonged to a group which was oxidized at a significantly lower rate by the beta 2-ADH as compared to the beta 1-ADH, but this was not the case for a small group which included ethanol. Subsequent kinetic studies of selected alcohols tended to indicate a uniqueness of ethanol kinetics in that both KM and Vmax favored its oxidation by beta 2-ADH rather than by the beta 1 variant. None of the other seven tested alcohols showed a similar differential. Also, reduction of aldehydes and ketones tended to be moderately slower by beta 2- than by beta 1-ADH.(ABSTRACT TRUNCATED AT 250 WORDS)
1-(beta-D-Glucopyranosyl)phenobarbital was identified as the major metabolite of phenobarbital in man. Proof of structure was based on the comparison of the UV, NMR, and mass spectrometry and TLC data for the acetylated metabolite with an authentic compound. The previous erroneous structure assignment of this metabolite as N-hydroxyphenobarbital was based on insufficient data. After oral administration of 14C-labeled phenobarbital to two healthy male subjects, most of the radioactivity (87 and 78% of the dose) was recovered in urine over a period of 16 days. The N-glucopyranoside, p-hydroxyphenobarbital, and unchanged phenobarbital accounted for 30 and 24%, 18 and 19%, and 33 and 25% of the dose, respectively.
An acetylated metabolite produced in man after po administration of caffeine was detected, isolated, and purified using suitable solvent extraction and chromatographic techniques. A set of UV, NMR, and mass spectral data identify it as 5-acetylamino-6-formylamino-3-methyluracil, a structure confirmed by chemical synthesis. This metabolite was shown to be unstable in the presence of dilute base and/or methanol, giving rise to a deformylated compound, 5-acetylamino-6-amino-3-methyluracil, which had recently been reported in the literature as a major metabolite of caffeine in man.