Disposition of propargyl alcohol in rat and mouse after intravenous, oral, dermal and inhalation exposure.

1. The disposition of propargyl alcohol (PAL) radiolabelled with carbon-14 ([2,3-14C]PAL) was determined in the F344 rat and B6C3F1 mouse following intravenous (i.v.), oral, inhalation and dermal exposure. 2. By 72h following an i.v. (1 mg kg(-1) or oral (50 mg kg(-1) dose, 76-90% of the dose was excreted. Major routes of excretion by rat were urine (50-62%), CO2 (19-26%) and faeces (6-14%). Major routes of exerection by mouse were urine (30-40%), CO2 (22-26%) and faeces (10-20%). Less than 6% of the dose remained in tissues at 72 h. Biliary exeretion of radioactity by rat (62% in 4 h) was much greater than elimination in faeces (6% in 72 h), indicating that PAL metabolites underwent extensive enterohepatic recycling. 3. Dermal exposure studies demonstrated that dermal absorption of PAL was minimal due to its inherent volatility. 4. In the inhalation studies (1, 10 or 100 ppm for 6 h), 23-68% of the radioactivity to which animals were exposed was absorbed. The primary route of excretion was urine (23-53%), and significant portion was exhaled as volatile organics (15-30%). 5. PAL was extensively metabolized by both species. One metabolite was identified as 3,3-bis[(2-(acetylamino)-2-carboxyethyl)thio]-1-propanol, which is consistent with Banijamali et al. (1999).

Identification of metabolites of [1,2,3-(13)C]Propargyl alcohol in mouse urine by (13)C NMR and mass spectrometry and comparison to rat.

Species differences in the metabolism of acetylenic compounds commonly used in the formulation of pharmaceuticals and pesticides have not been investigated. To better understand the in vivo reactivity of this bond, the metabolism of propargyl alcohol (PA), 2-propyn-1-ol, was examined in rats and mice. An earlier study (Banijamali, A. R.; Xu, Y.; Strunk, R. J.; Gay, M. H.; Ellis, M. C.; Putterman, G. J. J. Agric. Food Chem. 1999, 47, 1717-1729) in rats revealed that PA undergoes extensive metabolism primarily via glutathione conjugation. The current research describes the metabolism of PA in CD-1 mice and compares results for the mice to those obtained for rats. [1,2,3-(13)C;2,3-(14)C]PA was administered orally to the mice. Approximately 60% of the dose was excreted in urine by 96 h. Metabolites were identified, directly, in whole urine by 1- and 2-D (13)C NMR and HPLC/MS and by comparison with the available reference compounds. The proposed metabolic pathway involves glucuronide conjugation of PA to form 2-propyn-1-ol-glucuronide as well as oxidation of PA to the proposed intermediate 2-propynal. The aldehyde undergoes conjugation with glutathione followed by further metabolism to yield as final products 3,3-bis[(2-acetylamino-2-carboxyethyl)thio]-1-propanol, 3-[(2-acetylamino-2-carboxyethyl)thio]-3-[(2-amino-2-carboxyethyl)thi o]-1-propanol, 3,3-bis[(2-amino-2-carboxyethyl)thio]-1-propanol, 3-[(2-amino-2-carboxyethyl)thio]-2-propenoic acid, and 3-[(2-formylamino-2-carboxyethyl)thio]-2-propenoic acid. A small portion of 2-propynal is also oxidized to result in the excretion of 2-propynoic acid. On the basis of urinary metabolite data, qualitative and quantitative differences are noted between rats and mice in the formation of the glucuronide conjugate of PA and in the formation of 2-propynoic acid and metabolites derived from glutathione. These metabolites represent further variation on glutathione metabolism following its addition to the carbon-carbon triple bond compared to those described for the rat.

Identification of metabolites of [1,2,3-(13)C]Propargyl alcohol in rat urine by (13)C NMR and mass spectrometry.

Little is known about the metabolism of acetylenic (C&tbd1;C) compounds commonly used in the formulation of pesticides. To better understand the in vivo reactivity of this bond, we examined the metabolism of propargyl alcohol (PA), 2-propyn-1-ol, used extensively in the chemical industry. [1,2,3-(13)C, 2,3-(14)C]PA was administered orally to male Sprague-Dawley rats. Approximately 56% of the dose was excreted in urine by 96 h. Major metabolites were characterized, directly, in the whole urine by one- and two-dimensional (13)C NMR. To determine the complete structures of metabolites of PA, rat urine was also subjected to TLC followed by purification of separated TLC bands on HPLC. The purified metabolites were identified by (13)C NMR and mass spectrometry and by comparison with available synthetic standards. The proposed metabolic pathway involves oxidation of propargyl alcohol to 2-propynoic acid and further detoxification via glutathione conjugation to yield as final products: 3, 3-bis[(2-(acetylamino)-2-carboxyethyl)thio]-1-propanol, 3-(carboxymethylthio)-2-propenoic acid, 3-(methylsulfinyl)-2-(methylthio)-2-propenoic acid, 3-[[2-(acetylamino)-2-carboxyethyl]thio]-3-[(2-amino-2-carboxyethyl)t hio]-1-propanol and 3-[[2-(acetylamino)-2-carboxyethyl]sulfinyl]-3-[2-(acetylamino)-2-car boxyethyl]thio]-1-propanol. These unique metabolites have not been reported previously and represent the first example of multiple glutathione additions to the carbon-carbon triple bond.

Studies on hypoxoside and rooperol analogues from Hypoxis rooperi and Hypoxis latifolia and their biotransformation in man by using high-performance liquid chromatography with in-line sorption enrichment and diode-array detection.

Methanol extracts of the corms of Hypoxis rooperi and H. latifolia were studied for their hypoxoside content by an in-line sorption enrichment HPLC technique [Kruger et al., J. Chromatogr., 612 (1993) 191]. Hypoxoside is the trivial name for (E)-1,5-bis(3'-hydroxy-4'-O-beta-D-glucopyranosyl-phenyl) pent-1-en-4-yne and rooperol the aglucone obtained from beta-glucosidase treatment. Hypoxoside and rooperol analogues containing 4, 3 and 2 hydroxyl groups resolved as separate peaks with the proportion of the latter two markedly higher in H. latifolia than in H. rooperi. After oral ingestion of hypoxoside by humans, no hypoxoside or rooperol appeared in the serum. Only rooperol was present in the faeces. The serum and urine contained at least three phase II metabolite peaks. Selective enzyme hydrolysis showed that they represent the diglucuronide, disulfate and glucuronide-sulfate conjugates of all three rooperol analogues.

Automated sequential trace enrichment of dialysates combined with high-performance liquid chromatography and automated heart-cutting for the determination of the nucleoside 1-(beta-D-arabinofuranosyl)-5-(1-propynyl)uracil and its metabolite 5-propynyluracil in urine.

The use of a new configuration to control the automated sequential trace enrichment of dialysate (ASTED) system has been used to estimate 1-(beta-D-arabinofuranosyl)-5-(1-propynyl)uracil and its metabolite 5-propynyluracil in urine. The system employs "heart-cutting" as a means to improve the efficiency of sample preparation and reduce analysis time. Using this technique the mean within- and between-run imprecision (coefficient of variation) at three different urine analyte concentrations was found to be 1.6 and 3.6% and 1.7 and 3.3% for 5-propynyluracil and 1-(beta-D-arabinofuranosyl)-5-(1-propynyl)uracil, respectively.

Gas-liquid chromatography of methylpentynol carbamate and its metabolite 3-methylpentyne-3,4-diol.

Procedures are described for the determination of methylpentynol carbamate in serum, either by injection into the chromatograph of diluted serum or extraction of the drug into chloroform and injection of an aliquot of the concentrated organic phase; a 4% CDMS column is used. Similar assays for measuring the metabolite 3-methylpentyne-3,4-diol in urine are reported. The methods have been used for measuring methylpentynol carbamate and its metabolite in samples from rats and dogs.

5-Decynedioic acid, an acetylenic compound in human urine.

An acetylenic dicarboxylic acid, 5-decynedioic acid, has been isolated from human urine. The structure was determined by mass spectrometry of several derivatives, and by infrared spectroscopy. On osmium tetroxide oxidation, a vic-diketone was formed, the mass spectrum of which established the position of the triple bond between carbon atoms 5 and 6. Mass spectrometric evidence for the presence of a small amount of the isomeric 4-decynedioic acid was also obtained. The 24-h excretion of these acids is 0.01-0.1 mmol for healthy adults on a regular diet.

A feeding study with the herbicide, Kerb (N-(1, 1 dimethylpropynyl)-3,5-dichlorobenzamide, in the dairy cow.

The herbicide, Kerb ((N-(1,1 dimethylpropynyl)-3,5-dichlorobezamide) was fed to a lactating cow at a concentration of 5 ppm in the ration for four days. Excretion of residues of equivalent herbicide in milk, urine and feces were found to be, respectively, 0.19, 44.38 and 4.46% of the total dose.