O. Lafont

Phenobarbital metabolism by hepatocytes isolated from rat.

In order to test the validity of the use of hepatocytes as an alternative to studies of metabolism in live animals, phenobarbital (PB) was applied at 37 degrees C to isolated rat hepatocytes, which had been previously induced by PB. The metabolites were extracted by ethyl acetate, at various pH, and identified and evaluated by GC-MS. PB was not metabolized to p-hydroxyphenobarbital as is usually the case in living animals, but it was transformed into sulphoconjugated 2-phenyl-gamma-butyrolactone. This pathway, beta-hydroxylation of the ethyl side chain followed by lactonization, previously described as a secondary metabolic pathway occurring during intoxications, was here the only observed biodegradation. These results show that it is not possible to use hepatocytes as an alternative to live animals.

Competition between two metabolic pathways: oxidation and desulfuration in the thiobarbiturate series

Summary In order to study the competition between hepatic hydroxylation and desulfuration in the thiobarbiturate series, two compounds bearing a branched side chain with a tertiary carbon atom in position ω-1 were administered to rats over about one week. Urine and faeces were collected and extracted. The metabolites isolated were identified. It was shown that desulfuration was not the major metabolic pathway, and that, when it took place, it remained a minor process and was accompanied by γ-hydroxylation into a tertiary alcohol.

Mechanism of the formation in vivo of α-phenyl-γ-lactones in the glutethimide series

Abstract The isolation of γ-lactones from the urines of humans or animals treated with glutethimide or aminoglutethimide required an explanation. The question was studied on the glutethimide model. Potential metabolites such as β-hydroxymetabolite, γ-lactone amide, and γ-lactone acid were synthesized. Glutethimide was first administered to rats at high and normal doses. The corresponding γ-lactone amide, resulting from alcoholysis of β-hydroxyglutethimide, was also administered to rats. The amounts of the various γ-lactone derivatives isolated from the urine were discussed and it was concluded that the α-phenyl-γ-lactone was formed in vivo via β-hydroxylation of glutethimide followed by intramolecular alcoholysis. The lactone amide was then oxidized and dealkylated via an intramolecular mechanism leading to the corresponding α-phenyl-γ-lactone.

To publish or not to publish? That is the question

Purpose: In this lesson students will understand that a free press is the glue that binds our nation. A free press provides the information that allows us to make personal choices. If we abandon our right to know and thereby to think for ourselves, somebody else will make our choices. Students will examine how the press balances its First Amendment right to provide the public with all the news and opinion available with the responsibility to be honest and fair. At the end of the lesson students will be able to propose guidelines for journalists to follow in balancing First Amendment rights with the responsibility to be ethical.

Passage of allophanoyl-gamma-lactones through the kidney

SummaryIn order to establish if allophanoyl-γlactones (B compounds) can pass through the kidney or if only the corresponding 6-hydroxybarbiturates (A compounds), formed by intramolecular alcoholysis, are able to do so, nine experiments were performed to study the urinary excretion of four different allophanoylγ-lactones B after administration to dogs. Excreted compounds were extracted, identified and quantised. From the amounts of unmodified administered lactones that were recovered, it is concluded that B compounds can pass through the kidney before isomerisation into the corresponding barbiturates A.

Correlation between lipophilicity and reactivity under biomimetic conditions of β-hydroxybarbiturates

Abstract The effects of lipophilicity are studied on a chemical equilibrium between β-hydroxybarbiturates and corresponding allophanoyl γ-lactones under biomimetic conditions, in order to show that this physicochemical parameter is not only active in vivo on drug disposition, but also on the kinetics of chemical reactions.