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M Ulgen

Publications and source records attributed to M Ulgen.

46 records · Page 3Linked to original sources
PubMedDate not supplied

In vitro microsomal [correction of mircosomal] metabolism of N-benzyl and N-benzoylnornicotine derivates by rat.

The in vitro hepatic microsomal metabolism of N-1'-benzylnornicotine, N-l'-(p-chlorobenzyl)nornicotine, N-1'-benzoylnornicotine and N-1'-(p-chlorobenzoyl) nornicotine was studied using hepatic washed rat microsomal preparations fortified with NADPH. Substrates and their potential metabolites were synthesized, characterised by spectral methods, and separated using a reverse phase HPLC system consisted of a C18 column and a mobile phase composition of acetonitrile: phosphate buffer. Substrates and their potential metabolites were extracted from biological systems with dichloromethane. Metabolites detected were compared with retention times and uv spectra of authentic standards. Metabolic experiments indicated that oxidative dealkylation leading to the formation of nornicotine and the corresponding aldehydes was a major route of metabolism for N-alkylnornicotine substrates. In addition, N-1'-(p-chlorobenzyl)nornicotine produced the corresponding lactam and amide metabolites. N-Acylnornicotines were hydrolysed to nornicotine.

Animals↗
PubMedDate not supplied

In vitro metabolic N- and C-oxidation of phenanthridine.

The in vitro microsomal metabolism of phenanthridine has been studied to establish as to whether phenanthridine produces the corresponding N-oxide and lactam as metabolites and the mechanism involved. We now report our preliminary findings using rat hepatic microsomal preparations (control and induced with phenobarbitone) fortified with NADPH. The potential metabolite, phenanthridine-N-oxide, was prepared by m-CPBA oxidation of substrate; the lactam was commercially available. The substrate and metabolites were extracted and analysed by HPLC and TLC. Five metabolites, i.e. the corresponding N-oxide, lactam and three other products, were detected. Both N-oxide and lactam metabolites showed identical chromatographic behaviour and UV spectrum--using a multi-array UV detector linked to a HPLC system--as the authentic compounds. The uncharacterised metabolites are proposed to be phenolic because of their chromatographic behaviour and response to detection reagents. The amount of N-oxide and lactam formed was significantly increased when phenobarbitone induced rat microsomes were used as enzyme source. The results indicate that these latter metabolites are probably formed by a phenobarbitone inducible CYP450 isozyme. It may be that the lactam was produced via the N-oxide and experiments are under way to investigate the proposed pathway.

Animals↗
PubMedDate not supplied

In vitro microsomal metabolism of nuclear chloro substituted secondary amines and imines.

The metabolism of N-(4-chlorobenzyl)-4-chloroaniline (CBCA), N-(4-chlorobenzyl)-4-chlorobenzylamine (CBCBA), and N-(4-chlorobenzylidene)-4-chlorobenzylamine (CBDCBA) were studied in vitro using rat liver microsomal preparations. The secondary amines produced the corresponding N-oxidation products (hydroxylamines and nitrones) and dealkylation products (4-chlorobenzaldehyde and primary amines). Both secondary amines failed to produce the corresponding amides, whilst the parent imine was detected as a metabonate. CBDCBA, the intermediate imine of CBCBA metabolism, was also incubated under similar conditions. However, no oxaziridine was detected.

Amines↗
PubMedDate not supplied

The in vitro metabolism of norcotinine and related biotransformation products by microsomal preparations.

Since norcotinine and 4-(3-pyridyl)-4-oxobutyramide (POBAM) are probable metabolites of nicotine and cotinine, it was of interest to investigate the further in vitro metabolism of these compounds. We now report our preliminary findings using rat microsomal preparations (induced and/or non-induced with phenobarbitone) fortified with NADPH. Following norcotinine metabolism, two compounds, i.e. the corresponding ketoamide (POBAM) and another product, were detected. The latter metabolite has an identical HPLC retention time as that of nicotinamide. Both metabolites showed identical UV spectra when compared to authentic compounds using a multi-array UV detector linked to a HPLC system. The structures of these metabolites were also confirmed by mass spectral analyses. The amount of POBAM was significantly increased when phenobarbitone induced rat microsomes was used. It indicates that the ketoamide is formed via a phenobarbitone inducible isozyme of CYP450. Following the metabolism of POBAM, two compounds, i.e. the corresponding acid (POBA) and an unidentified product, were detected. The uncharacterised compound had an identical HPLC retention time as nicotinamide. Both metabolites gave a UV spectrum identical to the authentic compounds. The detection of nicotinamide in incubates of norcotinine and POBAM suggests that it is released from NADP(H) by a stimulatory effect on glycohydrolase by the substrates. Further studies on the enzymology of these processes are in progress.

Animals↗
PubMedDate not supplied

Metabolism of (-)-(S)-nicotine by guinea pig and rat brain: identification of cotinine.

Since the brain is the major site of pharmacological activity of nicotine, it was of interest to investigate the metabolism of nicotine by this organ. We now report our findings using guinea pig and rat brain as the enzyme source. Whole brains were removed and washed with isotonic KCl, blotted dry and cut into small pieces. The tissue was weighed and homogenized in pH 7.4 Tris-KCl buffer, 2 ml/g tissue. Incubations were carried out using 0.5 ml of brain homogenate and 0.1-1 mumol of nicotine at 37 degrees C. The reactions were terminated by freezing at -80 degrees C. The samples were extracted and analyzed by capillary GC with nitrogen-phosphorus detection. Cotinine was detected as the major metabolite and its identity confirmed by GC-MS. Cotinine formation may contribute to the detoxication pathway of nicotine and may be important in controlling nicotine levels in the brain. Furthermore, the conversion of nicotine to cotinine involves the intermediacy of nicotine-delta [1'(5')]-iminium ion, which is an alkylating agent. This finding supports the concept that reactive intermediates may play a role in the pharmacology and toxicology of nicotine.

Animals↗
PubMedDate not supplied

Metabolic and chemical studies on N-(4-chlorobenzyl)-N'-benzoylhydrazine.

The in vitro hepatic microsomal metabolism of N-(4-chlorobenzyl)-N'-benzoylhydrazine (CBBAH), a model compound representing N-alkyl substituted hydrazides, was studied using hepatic washed rat microsomal preparations fortified with NADPH to identify the possible N-oxidative, N-dealkylated and hydrolytic metabolites. CBBAH and its potential metabolites were prepared, characterized using spectroscopic techniques and then separated using a reversed phase HPLC system with UV detection at 254 nm. CBBAH was chemically converted to the corresponding hydrazone by m-chloroperbenzoic acid (m-CPBA) oxidation. CBBAH was incubated with rat microsomal preparations in the presence of NADPH, extracted into dichloromethane and evaporated finally under nitrogen. The TLC and HPLC results from the metabolic experiments showed that CBBAH produced the corresponding hydrolytic and N-dealkylated metabolites together with the corresponding hydrazone.

Animals↗
PubMedDate not supplied

Evaluation of some arylhydrazones of p-aminobenzoic acid hydrazide as antimicrobial agents and their in vitro hepatic microsomal metabolism.

Benzoic acid p-amino-[(substituted phenyl/pyridyl) methylene] hydrazide derivatives were synthesised by interaction of p-aminobenzoic acid hydrazide with various aromatic aldehydes. The structures of the compounds were elucidated by use of their UV, IR, 1H-NMR and mass spectral data. These compounds were also evaluated for antimicrobial activity. The in vitro hepatic microsomal metabolism of benzoic acid p-amino-[(4-fluorophenyl)methylene]hydrazide (2d), a selected prototype from these compounds was also carried out.

Animals↗