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Biomedical subjects

A J Hutt

Publications and source records attributed to A J Hutt.

15 recordsLinked to original sources
PubMed1990

Interindividual variability in the enantiomeric disposition of ibuprofen following the oral administration of the racemic drug to healthy volunteers.

The plasma disposition of the enantiomers of ibuprofen has been investigated following the oral administration of the racemic drug (400 mg) to 24 healthy male volunteers. The plasma elimination of (R)-ibuprofen was found to be more rapid than that of the S-enantiomer [plasma half-life: (R) 2.03 h; (S) 3.05 h; 2P less than 0.001], resulting in a progressive enrichment in the plasma content of this isomer, some 64% of the total area under the plasma concentration time curves (AUC) being due to the pharmacologically active enantiomer. The influence of dose on the pharmacokinetic characteristics of the enantiomers of ibuprofen, over the range 200-800 mg, was investigated in three subjects. Examination of dose-normalized AUC values and oral clearance indicate the dose dependence of (R)-ibuprofen disposition.

Administration, Oral↗
PubMed1988

The metabolic chiral inversion and dispositional enantioselectivity of the 2-arylpropionic acids and their biological consequences.

The 2-arylpropionic acids are currently an important group of non-steroidal anti-inflammatory agents. They contain a chiral centre, and in vitro studies on inhibition of prostaglandin synthesis show that their activity resides almost exclusively in the S(+)-isomers. However, this stereoselectivity of action is not manifest in vivo, due to the thus-far-unique unidirectional metabolic inversion of the chiral centre from the inactive R(-)-isomers to the S(+)-antipodes. Available evidence strongly suggests that this reaction proceeds via the formation of the acyl CoA thioesters of the 2-arylpropionates, but the participation of enzyme(s) in the inversion process remains uncertain. Although the chiral inversion is seemingly a general feature of the fate of 2-arylpropionates, there do occur important combinations of acid and species where the reaction is not extant. The stereochemistry of the chiral centre of these acids also influences other aspects of their disposition, including the oxidative metabolism of the aryl/arylakyl moiety, glucuronidation of the -COOH group and plasma protein binding, and the importance of certain of these becomes more evident when renal function is impaired. The biological consequences of the metabolic chiral inversion and enantioselective disposition of the 2-arylpropionates have been summarized in terms of their implications for the development and use of safer and more effective drugs of this class.

Animals↗
PubMed1988

Metabolism of chlorpromazine and promazine in vitro: isolation and characterization of N-oxidation products.

1. The syntheses of the secondary hydroxylamines of nor1chlorpromazine and nor1promazine via their corresponding primary hydroxylamines and oximes are described. 2. The N-oxidation products are unstable to analysis by g.l.c. without prior derivatization; the decomposition products and the structures of the trimethylsilyl (TMS) and trifluoroacetyl (TFA) derivatives were characterized by g.l.c.-mass spectrometry. 3. Chlorpromazine, promazine and their demethylated products were shown to undergo metabolic N- and alpha-C-oxidation, to yield hydroxylamines and carboxylic acids, on incubation with fortified 9000 g liver homogenates of male New Zealand white rabbits. 4. A condensation product, an artifact formed by reaction of the metabolically derived primary hydroxylamines with acetaldehyde, an impurity in the extraction solvent, diethyl ether, was identified. 5. N-hydroxynor1- and N-hydroxynor2chlorpromazine undergo metabolic reduction to the parent amines, and the secondary hydroxylamine undergoes N-demethylation to yield the corresponding primary hydroxylamine.

Animals↗
PubMed1987

Determination of the enantiomeric composition of ibuprofen in human plasma by high-performance liquid chromatography.

A normal-phase high-performance liquid chromatographic method, using a hexane-ethyl acetate solvent system, for the determination of the enantiomeric composition of ibuprofen in human plasma is described. The method is based on the resolution of the diastereoisomeric amides formed on reaction of the ibuprofen enantiomers with S-1-(naphthen-1-yl)ethylamine using p-chlorophenoxy-acetic acid as internal standard. The application of the method for the determination of the enantiomeric composition of ibuprofen in human plasma following the repeated oral administration of the drug to two volunteers is reported. The plasma concentrations of the S-(+) enantiomer were always greater than that of the R-(-), the ratio of the areas under the enantiomer plasma concentration-time curves (S/R) being 1.8 and 1.6.

Chromatography, High Pressure Liquid↗
PubMed1987

Metabolism of estragole in rat and mouse and influence of dose size on excretion of the proximate carcinogen 1'-hydroxyestragole.

The major metabolic pathways of estragole have been established in rats and mice, and in both species the relative importance of the different pathways has been shown to be dose related. At low doses, estragole mainly undergoes detoxication reactions, notably O-demethylation and side-chain cleavage, but as the dose is increased, the extent of O-demethylation falls and other pathways, notably l'-hydroxylation, come into prominence. The disproportionate relationship between dose size and the elimination of the proximate carcinogenic metabolite l'-hydroxyestragole may influence the relationship between dose size and tumour incidence. These findings may have important implications for the safety assessment of this food flavouring, since the dose levels used in carcinogenicity studies have been very much larger than the estimated human daily intake. Moreover the percentage of an administered dose of estragole eliminated as 1-hydroxyestragole glucuronide in human urine is much lower than that found with even the lowest doses examined in rats in this study.

Allylbenzene Derivatives↗
PubMed1987

The metabolic disposition of [methoxy-14C]-labelled trans-anethole, estragole and p-propylanisole in human volunteers.

1. The metabolic fates of the naturally occurring food flavours trans-anethole and estragole, and their synthetic congener p-propylanisole, have been investigated in human volunteers using the [methoxy-14C]-labelled compounds. The doses used were close to those encountered in the diet, 1 mg, 100 micrograms and 100 micrograms respectively. 2. In each case, the major routes of elimination of 14C were in the urine and in the expired air as 14CO2. 3. Urinary metabolites were separated by solvent extraction, t.l.c. and h.p.l.c., and characterized by comparison of chromatographic mobilities with standards and by radioisotope dilution. Nine 14C urinary metabolites were found after trans-anethole administration, four after p-propylanisole and five after estragole. All were products of side chain oxidations. 4. The principal metabolites of p-propylanisole were 4-methoxyhippuric acid (12%) and 1-(4'-methoxyphenyl)propan-1-ol (2%) and -2-ol (8%). 5. The major metabolite of trans-anethole was 4-methoxyhippuric acid (56% of dose), accompanied by much smaller amounts of the two isomers of 1-(4'-methoxyphenyl)propane-1,2-diol (together 3%). 6. After estragole administration, the two volunteers eliminated 0.2 and 0.4% of the dose respectively as 1'-hydroxyestragole. 7. The human metabolic data is discussed with reference to the comparative metabolic disposition of these compounds in the mouse and rat, species commonly used in their safety assessment.

Adult↗
PubMed1986

Application of a radial compression column to the high-performance liquid chromatographic separation of the enantiomers of some 2-arylpropionic acids as their diastereoisomeric s-(-)-1-(naphthen-1-yl)ethylamines.

The enantiomers of 2-phenylpropionic acid and four congeneric anti-inflammatory drugs were separated as their diastereoisomeric amides with S-(-)-1-(naphthen-1-yl)ethylamine by high-performance liquid chromatography using a silica-packed radial compression cartridge. The order of elution of the diastereoisomeric amides was always R, S or -, S before S,S or +,S. The conditions for the derivatization, using 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide as coupling agent, were optimized, and it was found that the addition of 1-hydroxybenzotriazole rendered the reaction quantitative. Good calibration curves were obtained for the quantitation and determination of the enantiomeric composition of 2-phenylpropionic acid in urine, and the application of the method to the study of the metabolism of this acid in vivo is described.

Amides↗
PubMed1986

The metabolism of aspirin in man: a population study.

The metabolism of a 900 mg oral dose of aspirin has been investigated in 129 healthy volunteers. For this purpose, the 0-12 h urine was collected and analysed for the following excretion products: salicylic acid, its acyl and phenolic glucuronides, salicyluric acid, its phenolic glucuronide and gentisic acid. The total excretion of salicylate and metabolites was normally distributed within the population group studied, showing a 2.5-fold variation: a mean of 68.1% of the dose was recovered in 12 h. The excretion of salicylic acid was found to be highly variable within the study panel (1.3-31% of dose in 12 h), and was related to both urine volume and pH. Salicyluric acid was the major metabolite in the majority of the volunteers and its excretion was normally distributed amongst the study panel. The elimination of this metabolite ranged from 19.8 to 65% of the dose and was related to the total recovery of salicylate. The excretion of the two salicyl glucuronides was highly variable, ranging from 0.8 to 42% of the dose. The elimination of the glucuronides was inversely related to that of salicyluric acid. Gentisic acid and salicyluric acid phenolic glucuronide were minor metabolites of salicylate, accounting for 1 and 3% of the dose, respectively. The recovery of gentisic acid was statistically significantly greater in female subjects than in males, whilst the opposite was found for salicyluric acid and total salicylate. However, these differences were small in magnitude.

Adult↗