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Biomedical subjects

J K Baker

Publications and source records attributed to J K Baker.

At least 37 records · Page 2Linked to original sources
PubMed1990

Structure elucidation and thermospray high-performance liquid chromatography/mass spectroscopy (HPLC/MS) of the microbial and mammalian metabolites of the antimalarial arteether.

Microbial metabolism studies of the antimalarial drug arteether (1) have shown that arteether is metabolized to six new metabolites in addition to those previously reported (3). Large-scale fermentations with Cunninghamella elegans (ATCC 9245) and Streptomyces lavendulae (L-105) have resulted in the characterization of these metabolites primarily by two-dimensional nuclear magnetic resonance (2D-NMR) methods as 9 beta-hydroxyarteether (2), a ring rearrangement metabolite (3), 3 alpha-hydroxy-11-epi-deoxydihydroartemisinin (4), 9 alpha-hydroxyarteether (5), 2 alpha-hydroxyarteether (6), and 14-hydroxyarteether (7). Thermospray mass spectroscopy/high-performance liquid chromatographic analyses have shown that four of these metabolites (2, 5, 6, 7) are also present in rat liver microsome preparations.

Animals↗
PubMed1989

Determination of baclofen and alpha-baclofen in rat liver homogenate and human urine using solid-phase extraction, o-phthalaldehyde-tert.-butyl thiol derivatization and high-performance liquid chromatography with amperometric detection.

Methods were developed for the determination of the zwitterionic compounds baclofen and alpha-baclofen in complex biological samples (rat liver homogenates and human urine) in concentration ranges that would be suitable for pharmacokinetic studies of these compounds. In the procedure, the biological samples along with an internal standard were selectively concentrated using C18 solid-phase extraction cartridges, evaporated, derivatized with o-phthalaldehyde and tert.-butyl thiol at room temperature for 2 min, then subjected to high-performance liquid chromatographic analysis. The reversed-phase (C18) chromatographic analysis with amperometric detection (glassy carbon electrode in oxidative mode, +0.6 V vs. Ag/AgCl) was found to be useful for the measurement of both baclofen and alpha-baclofen from 10 ng/ml to 10 micrograms/ml in these complex biological samples. The primary advantage of the method was that the derivatives formed using tert.-butyl thiol were markedly more stable than the previously reported derivatives prepared using mercaptoethanol.

Animals↗
PubMed1989

Thermospray mass spectroscopy/high performance liquid chromatographic identification of the metabolites formed from arteether using a rat liver microsome preparation.

Thermospray LC/MS methods with internal standardization were developed for the quantification of the antimalarial arteether and six of its metabolites at the 1-10 micrograms/ml level in liver microsome preparations without the use of solvent extraction. The thermospray mass spectra of arteether and most of its metabolites exhibited strong [M + NH4]+ and [M - OR]+ peaks arising from the molecular ion adduct and the loss of the alkoxy or hydroxy group of the side chain. In addition to the six metabolites for which authentic reference standards were available, three additional metabolites were detected. The major metabolites of arteether were found to be dihydroartemisinin, deoxydihydroartemisinin, 3-hydroxydeoxydihydroartemisinin, two isomers of hydroxyarteether, and 3-hydroxydeoxyarteether. Deoxyartheether was not found at significant concentrations in the microsome preparation.

Animals↗
PubMed1989

Metabolism of 3-(p-chlorophenyl)pyrrolidine. Structural effects in conversion of a prototype gamma-aminobutyric acid prodrug to lactam and gamma-aminobutyric acid type metabolites.

By use of rat liver or brain homogenate supernatants containing microsomes and/or mitochondria, it was found that the prototype GABAergic prodrug [3-(p-chlorophenyl)pyrrolidine (1)] underwent a series of alpha-oxidation transformations to a pair of amino acid metabolites and a pair of lactam metabolites [4-amino-3-(p-chlorophenyl)butanoic acid, baclofen (5); 4-amino-2-(p-chlorophenyl)butanoic acid (10); 4-(chlorophenyl)pyrrolidin-2-one and 3-(p-chlorophenyl)pyrrolidine-2-one (11)]. With the liver homogenates, the formation of the lactam metabolites was approximately 2 orders of magnitude greater than that of the amino acid metabolites, while with the brain homogenates, the amino acid and lactam pathways were of similar magnitude. For either tissue, for both the lactam and the amino acid series, attack at the less sterically hindered 5-position of the pyrrolidine ring was greater than the attack at the 2-position (5 greater than 10 and 6 greater than 11) with the exception of the liver homogenate mitochondrial fraction (6 less than 11). The parenteral administration of the prodrug 1 was found to give detectable brain levels of 5 as well as activity in an isoniazid-induced (GABA-inhibited) convulsion model.

Amino Acids↗
PubMed1988

Differential metabolism of the enantiomers of primaquine.

When racemic primaquine was administered to rats, the majority of the residual primaquine excreted in urine was found to be the (+)-isomer. Using a liver microsome preparation, there was no selectivity in the metabolism of the (+)- and (-)-isomers; however, a liver fraction containing mitochondria and microsomes did show selectivity. In the latter preparation, there was a marked preference for the conversion of (-)-primaquine to (-)-carboxy-primaquine.

Animals↗
PubMed1987

Photooxidation products of primaquine. Structure, antimalarial activity and hemolytic effects.

Photooxidation of primaquine (1) and 5-hydroxyprimaquine (5) afforded a blue dye for which o-quinone structure 4 was elaborated. Similar oxidation of N-ethoxyacetylprimaquine (10) afforded o-quinone 11. Tissue schizontocidal activity of 4 and 11, and bisquinolylmethine 3 prepared earlier, showed that none of them had noteworthy antimalarial activity, but all three produced methemoglobin.

Animals↗
PubMed1986

Role of N-methyltransferases in the neurotoxicity associated with the metabolites of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and other 4-substituted pyridines present in the environment.

Amine N-methyltransferases in the brains of humans, monkeys, mice, rabbits and rats, as well as two homogeneous enzymes isolated from rabbit liver, are capable of N-methylating 4-phenyl-1,2,3,6-tetrahydropyridine to 1-methyl-4-phenyltetrahydropyridine (MPTP), and 4-phenylpyridine to 1-methyl-4-phenylpyridinium ion (MPP+). The product in each instance is a neurotoxin. The suggestion is offered that the known long half-life of methylpyridinium compounds in brain may be due to limitations in transport of such charged metabolites out of this tissue and to metabolic recycling of the desmethyl species by amine N-methyltransferases. The methylation of pyridines to quaternary amines is suggested as a means by which lipophilic compounds, having gained entrance to the cell, are converted to charged species that efflux much less readily.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Microbial metabolism of bornaprine, 3-(diethylamino)propyl 2-phenylbicyclo[2.2.1]heptane-2-carboxylate.

Metabolism studies of the anticholinergic drug, bornaprine [3-(diethylamino)propyl 2-phenylbicyclo[2.2.1]heptane-2-carboxylate, an epimeric mixture], in rats, dogs, and humans have been conducted previously, but the identities of the metabolites were not established. Using an in vitro microbial system to study the metabolism of bornaprine resulted in the isolation of four metabolites whose structures were rigorously established using spectroscopic techniques, especially 13C NMR. The four metabolites found were hydroxylated at C-5 or C-6 in the bicyclic ring.

Antiparkinson Agents↗
PubMed1986

Novel sulfur-containing microbial metabolite of primaquine.

Microbial metabolism studies of the antimalarial drug primaquine, using Streptomyces roseochromogenus (ATCC 13400) have produced an N-acetylated metabolite and a methylene-linked dimeric product, both of which have been previously reported, and a novel sulfur-containing microbial metabolite. The structure of the metabolite as a sulfur-linked dimer was proposed on the basis of spectral and chemical data. The molecular formula C34H44N6O4S was established from field-desorption mass spectroscopy and analytical data. The 1H- and 13C-nuclear magnetic resonance spectral data firmly established that the novel metabolite was a symmetrically substituted dimer of primaquine N-acetate with a sulfur atom linking the two units at C-5. The metabolite has been shown to be a mixture of stereoisomers which can equilibrate in solution. This observation was confirmed by microbial synthesis of the metabolite from optically active primaquine.

Chemical Phenomena↗
PubMed1985

Metabolism of phencyclidine. The role of the carbinolamine intermediate in the formation of lactam and amino acid metabolites of nitrogen heterocycles.

The transformation of phencyclidine in a mouse liver microsome preparation to several oxidative metabolites was studied. With use of GLC and HPLC methods with internal standards, phencyclidine and six metabolites were quantitated and the amino acid 12, resulting from the alpha-oxidation of the piperidine ring, was produced in 10-50 times greater amounts than the other metabolites. While most piperidines and pyrrolidines produce an amino acid and a corresponding lactam, it was found that phencyclidine was not converted to the lactam 11.

Amino Acids↗
PubMed1985

A simple colorimetric method for the determination of primaquine metabolites in urine.

A simple method of screening large numbers of urine samples for the presence of primaquine metabolites has been developed using a commercially available diazonium salt reagent and an extraction cartridge. The extraction requires only 1.0 ml of urine and is selective for acidic or neutral primaquine metabolites. With primaquine-dosed rats, primaquine metabolites could be detected 36 hours after administration of the drug. The sensitivity of the method was found to be approximately 400 mug/l.

Animals↗
PubMed1984

Metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mouse liver preparations.

Using a mouse liver microsomal preparation, it was found that the heterocyclic ring system of MPTP underwent an initial alpha-oxidation to give chemically reactive metabolites that may be associated with the induction of Parkinsonism by MPTP. Subsequent oxidative metabolic transformations of these intermediates were found to give a lactam metabolite and a pyridone metabolite that potentially may interact with the neurotransmitter system.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1984

Excretion, distribution, and metabolism of primaquine in rats.

The metabolism of the 8-aminoquinoline antimalarial drug, primaquine (I) was studied using rats. The drug was administered intravenously, intraperitoneally, and orally, and blood samples were collected at various time intervals. Primaquine was metabolized by oxidative deamination to give 8-(3-carboxy-l- methylpropylamino )-6- methoxyquinoline (III). The plasma levels of both primaquine and its metabolite were determined by HPLC. The tissue distributions of radioactive primaquine after intravenous, intraperitoneal, and oral administrations were also determined. Significant concentrations of radioactivity were found in the lungs, adrenal glands, and liver. In addition, a significant portion of the dose was found to be excreted in the feces within 24 h after administration of the drug by either of the three routes.

Administration, Oral↗
PubMed1983

Demethylation of imipramine by enteric bacteria.

The ability of a number of aerobic and anaerobic bacteria to N-demethylate imipramine (I) to desipramine (II) has been investigated. Of the bacteria investigated, almost half were known inhabitants of the human GI tract. More than half of the enteric bacteria studied were capable of N-demethylating imipramine (I) to desipramine (II) to some extent in at least one medium. It was found that the medium in which the organism was grown had a significant effect on the N-demethylase activity observed.

Bacteria, Aerobic↗
PubMed1982

High-performance liquid chromatographic analysis of the metabolism of primaquine and the identification of a new mammalian metabolite.

Using rats that had been dosed with 20 mg/kg of primaquine diphosphate (11.4 mg/kg free base), it was found that the drug underwent a metabolic oxidative deamination to give 8-(3-carboxy-1-methylpropylamino)-6-methoxyquinoline. The presence of this new mammalian metabolite was verified using high-performance liquid chromatographic, gas chromatographic, and mass spectral methods. A quantitative high-performance liquid chromatographic method for the determination of primaquine and the carboxylic acid metabolite in plasma using only 50 microliters of whole blood from the rat was developed and the method could be used to detect levels as low as 0.05 microgram/ml of the metabolite. Following intravenous administration of the drug, it was found that the plasma levels of primaquine fell very rapidly and after 30 min, the levels of the metabolite were much higher than those of primaquine.

Animals↗
PubMed1982

Effects of propranolol and a number of its analogues on sodium channels.

To assess the relative contributions that the sodium channel blocking activity of propranolol may play in a variety of its therapeutic applications, its effects were examined in vitro with a sodium channel specific 22Na+ uptake system, using rat brain membranes. Propranolol inhibited 22Na+ uptake in the rat brain membrane preparation by acting as a competitive inhibitor of the binding of the sodium channel opening agent veratridine, with an IC50 for this action of 6.5 microM. This is approximately one order of magnitude higher in concentration than that necessary for expression of the beta-adrenergic antagonism of propranolol. The binding of propranolol and its action to block sodium channels were demonstrably different from those of the neurotoxins tetrodotoxin and saxitoxin. Propranolol had effects on sodium channels that are similar, although not identical to those of the local anesthetics procaine and lidocaine. The concentrations of propranolol and a number of its analogues which produced 50% inhibition of 22Na+ uptake (IC50 values ranging from 4 to greater than 100 microM) were similar to the concentrations of these same analogues which were required to produce negative inotropic and antiarrythmic effects (ED40) on isolated rabbit atria [D. O. Rauls and J. K. Baker, J. med. Chem, 22, 81 (1979)]. These effects showed correlations of 0.945 and 0.936, respectively, with the 22Na+ uptake inhibition. It is concluded from this information that a substantial proportion of the negative inotropic and antiarrythmic effects of propranolol is due to its action on sodium channels.

Animals↗