An improved synthesis of 3-hydroxymethylantipyrine using antipyrine as starting material.

A partly new synthesis of 3-hydroxymethylantipyrine, an important metabolite of antipyrine in man and therefore frequently used as a reference substance, is described. The use of tri-n-butyltin hydride to reduce the vinyl bromide system in 3-hydroxymethyl-4-bromoantipyrine is the main improvement, since it enables the isolation of salt-free 3-hydroxymethylantipyrine in an almost quantitative yield.

Biotransformation of 1,2-dibromopropane in rats into four mercapturic acid derivatives.

1,2-Dibromopropane was administered orally in doses of 50-350 mg/kg to male Wistar rats. Four mercapturic acids were identified in urine by GC/MS, viz. N-acetyl-S-(2-oxopropyl)-L-cysteine (I), N-acetyl-S-(2-hydroxypropyl)-L-cysteine (II), N-acetyl-S-(1-carboxyethyl)-L-cysteine (III), and N-acetyl-S-(2-bromo-2-propenyl)-L-cysteine (IV). Mercapturic acid IV was a minor metabolite which could only be measured at doses of 200 mg/kg or higher. In 24 hr, urinary excretion of mercapturic acids amounted to about 36% of the dose (11% I, 21% II, 4% III, 0.2% IV). No dose dependency was found up to the highest dose. A unified scheme is proposed for the metabolism of 1,2-dibromopropane in the rat, which accounts for the identified mercapturic acids. The role of direct glutathione conjugation in the route leading to the major metabolite II, presumably involving thiiranium ion formation, is discussed. This route probably is biologically not very important because of the absence of detectable activity of 1,2-dibromopropane toward glutathione S-transferases in vitro, the very low mutagenicity of 1,2-dibromopropane, and the high mutagenic activity of N-acetyl-S-(2-bromopropyl)-L-cysteine methyl ester which was studied as a model compound for direct conjugation.

Glutathione conjugation of 1,2-dibromo-1-phenylethane in rats in vivo.

The metabolism of 1,2-dibromo-1-phenylethane (DBPE) was studied in rats. Administration of DBPE orally, in doses of 0.25-1.25 mmol/kg (66-330 mg/kg), to male Wistar rats resulted in the excretion of a single mercapturic acid in urine. The methyl esters of three potential mercapturic acid metabolites were synthesized: N-acetyl-S-(2-oxo-2-phenylethyl)-L-cysteine methyl ester (O),N-acetyl-S-(2-hydroxy-1-phenylethyl)-L-cysteine methyl ester (I), and N-acetyl-S-(2-hydroxy-2-phenylethyl)-L-cysteine methyl ester (II). GC/MS analysis showed that the methyl ester of the excreted mercapturic acid was identical with II. Quantitative measurement of II in urine by GLC showed that, after 24 hr, excretion of the mercapturic acid was almost complete and amounted to 41% of the administered dose. At doses higher than 1.00 mmol/kg, the excretion no longer increased. Inhibition of the oxidative pathways by ip injection of 1-phenylimidazole resulted in an excretion decrease of about 40%. (Pre)treatment with diethyl maleate lowered the excretion of mercapturic acid by 30-60%. Glutathione conjugates synthesized from DBPE and styrene oxide were separated by HPLC. Both compounds can produce the same two pairs of diastereomers, viz. (R)- and (S)-(2-hydroxy-1-phenyl-ethyl)glutathione ((R)-1 and (S)-1), and (R)- and (S)-(2-hydroxy-2-phenylethyl)glutathione ((R)-2 and (S)-2). These could be separated in the order (R)-2, (R)-1, (S)-1, and (S)-2 within 20 min. This method was also applied to examine glutathione conjugates excreted in bile after DBPE administration.(ABSTRACT TRUNCATED AT 250 WORDS)