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At least 19 recordsLinked to original sources

PubMed1990

Validity testing of commercial urine cocaine metabolite assays: IV. Evaluation of the EMIT d.a.u. cocaine metabolite assay in a quantitative mode for detection of cocaine metabolite.

The EMIT d.a.u. cocaine metabolite assay (EMIT dau) was evaluated in a quantitative mode for analysis of clinical specimens obtained after controlled cocaine administration to human subjects. The quantitative results showed high concordance with those of gas chromatography/mass spectrometry (GC/MS) assays of the same specimens for benzoylecgonine, and no false positive or false negative results were obtained. The evaluation also included analysis of standardized solutions containing benzoylecgonine, cocaine, and other cocaine metabolites and isomers. The EMIT dau antibody demonstrated high selectivity for benzoylecgonine. The precision was somewhat less than that reported earlier for other commercial cocaine metabolite immunoassays. Quantitation of initial screening results from EMIT dau testing can serve as a useful guide for confirmation by GC/MS in forensic science urine testing.

Cocaine↗

PubMed1991

Investigations on the metabolic pathways of cyclosporine: I. Excretion of cyclosporine and its metabolites in human bile--isolation of 12 new cyclosporine metabolites.

1. Cyclosporine metabolites of known and unknown structures were isolated, by semi-preparative h.p.l.c., from human bile from the T-tube of liver-grafted patients, who received cyclosporine treatment. Their structures were elucidated by FAB mass spectrometry and 1H-n.m.r. spectroscopy. 2. Twelve of the cyclosporine metabolites, with known chemical structures, were isolated and identified using authentic standard material. 3. Four isolated fractions contained tri-hydroxylated metabolites; two fractions contained di-hydroxylated, demethylated metabolites; one fraction contained a tri-hydroxylated, demethylated metabolite; and one fraction a mono-hydroxylated, demethylated metabolite. The exact metabolism sites were partially defined. 4. Two carboxylated cyclosporine metabolites, of which one was hydroxylated in an unknown position, were isolated. 5. One new metabolite proved to be a glucuronylated phase II metabolite. Deglucuronylation of this metabolite by beta-glururonidase yielded metabolite AM1c. The proposed structure was AM1c-Glc; is a proposed extension of the Hawk's Cay nomenclature of the cyclosporine metabolites for glucuronylated metabolites. 6. One of the unknown metabolites was hydroxylated in two positions of amino acid 1. The proposed nomenclature was 'AM11d', where '1d' indicates hydroxylation at the delta C of amino acid 1. 7. A metabolite with an aldehyde functional group at amino acid 1, which had two isomeric forms, was isolated. I.r.-spectroscopy indicated that isomerism may be caused by conjugation of the aldehyde group with the double bond between C6 and C7 of amino acid 1.

Aldehydes↗

PubMed1992

Polar metabolites of dihydrotachysterol3 in the rat. Comparison with in vitro metabolites of 1 alpha,25-dihydroxydihydrotachysterol3.

The metabolism of 25-hydroxydihydrotachysterol3 (25-OH-DHT3) to more polar metabolites was investigated in vivo in the rat and compared with the in vitro metabolism of 1 alpha,25-dihydroxy-DHT3 (1 alpha,25-(OH)2DHT3) in the osteosarcoma cell line UMR 106. Rats were given 2 mg of DHT3 in divided doses at 0 and 6 hr. Plasma was collected 24 hr after the initial dose, extracted, separated, and polar metabolites purified by HPLC. A number of polar metabolites were formed in vivo with mass spectrometric characteristics which suggested that they were derived from a previously isolated metabolite of 25-OH-DHT3, T3/H. Of these, four were isolated and identified as 24-oxo-T3/H, 24-hydroxy-T3/H, 26-hydroxy-T3/H and the 26,23-lactone of T3/H. In view of the identification of T3/H as a mixture of 1 alpha- and 1 beta-hydroxylated 25-OH-DHT3, osteosarcoma cells (UMR 106) were incubated with chemically synthesized 1 alpha,25-(OH)2DHT3 in an attempt to determine from which component of the T3/H mixture these metabolites were derived. Again, more polar metabolites were formed and five of these were isolated by lipid extraction, purified by HPLC and identified as 24-oxo-1 alpha,25-(OH)2DHT3, 1 alpha,23,25-(OH)3DHT3, 24-oxo-1 alpha,23,25-(OH)3DHT3, 1 alpha,24,25-(OH)3DHT3 and 1 alpha,25,26-(OH)3DHT3. Three of the in vitro metabolites were similar to those found in rat plasma but only two of these metabolites were available in sufficient amounts to allow comparison. The chromatographic characteristics, using HPLC and gas chromatography, of these two pairs of metabolites (24-oxo and 24-hydroxy) were examined and it was demonstrated that they were not the same. It is therefore suggested that the polar metabolites formed in vivo are in fact metabolites of the T3/Hb component (1 beta,25-(OH)2DHT3) rather than the T3/Ha component (1 alpha,25-(OH)2DHT3). Supporting evidence for this suggestion was obtained when a small quantity of 1 beta,25-(OH)2DHT3, obtained from chemically synthesized 1 beta-OH-DHT3 by incubation with Hep 3B cells, was further incubated in the osteosarcoma UMR 106 system. Preliminary studies indicated that the putative 24-oxo and 24-hydroxy metabolites formed from 1 beta,25-(OH)2DHT3 had chromatographic and mass spectral properties almost indistinguishable from those of corresponding metabolites of T3/H formed in vivo. All the metabolites formed in vivo and in vitro are components of two metabolic pathways described previously for 25-hydroxyvitamin D3 and also for 25-OH-DHT3.

Animals↗

PubMed1988

Metabolite formation pharmacokinetics: rate and extent of metabolite formation determined by deconvolution.

A two-step analytic procedure to determine the rate and extent of metabolite production following administration of the parent compound is described. The procedure provides the rate and extent of metabolite production as a function of time by application of the general model independent approach of deconvolution. The metabolite unit impulse response function is obtained by implicit deconvolution of the metabolite data with a truncated constant-rate metabolite input function. Then the obtained unit impulse response function is used in an analytic deconvolution with metabolite data following administration of the parent compound to obtain the rate and extent of metabolite production. The input function is also deconvolved with metabolite data to obtain the unit impulse response function appropriate for prediction of metabolite levels given a selected input of parent compound. The expected profile following administration of the consecutive infusions of parent drug is shown for both parent and metabolite. The rationale for selection of deconvolution methods is discussed. The approach is applied to data for procainamide and N-acetylprocainamide from three human subjects. The results indicate that from 27 to 39% of the procainamide was converted to N-acetylprocainamide in these subjects.

Acecainide↗

PubMedDate not supplied

Valproate metabolites in serum and urine during antiepileptic therapy in children with infantile spasms: abnormal metabolite pattern associated with reversible hepatotoxicity.

The purpose of this study was to identify abnormal metabolite patterns of valproate (VPA) as possible early indicators of VPA-induced liver toxicity. In a prospective study, we determined serum and urine levels of VPA metabolites by gas chromatography-mass spectrometry (GC-MS) during the course of therapy in 25 children treated for infantile spasms with high VPA doses (less than or equal to 100 mg/kg body weight/day). Most patients had similar metabolite profiles: The main metabolites in serum were the beta-oxidation products (2-en-VPA and 3-keto-VPA) and the major diunsaturated metabolite 2,3'-dien-VPA. Glucuronide conjugates and the oxidation products represent the most abundant metabolites in urine. Other metabolites, including the potential hepatotoxin 4-en-VPA, were detected only in low concentrations. Two children had transiently aberrant metabolite profiles, indicating altered beta-oxidation, (levels of 2-en-VPA, 2,3'-dien-VPA, and 3-en-VPA were markedly increased) in connection with hepatomegaly and increased liver enzyme activities at a time when both had febrile infections and were receiving dexamethasone comedication. At no time were increased levels of 4-en-VPA or its derivatives detected. Establishing the VPA metabolite profile may aid in evaluation of patients who show signs and symptoms of liver dysfunction during VPA therapy. The present study shows that initial stages of hepatotoxicity reactions to VPA may be accompanied by characteristic changes in VPA metabolism; early detection of such abnormal metabolite patterns might decrease the risk of severe hepatic injury.

Chemical and Drug Induced Liver Injury↗

PubMed1991

Identification of cannabichromene metabolites by mass spectrometry: identification of eight new dihydroxy metabolites in the rabbit.

Metabolites of cannabichromene (CBC) produced by hepatic microsomal incubates from rabbits and mice were examined by gas chromatography/mass spectrometry (GC/MS) as trimethylsilyl (TMS) and (2H9)TMS derivatives. Most metabolites were hydroxylated compounds whose mass spectra gave very little information on metabolite structure as fragmentation was dominated by formation of the substituted chromenyl ion. This prevented charge localization and diagnostic fragmentation at the site of metabolic attack. This paper describes the identification of these metabolites by GC/MS techniques using both deuterium-exchange reactions and hydrogenation of the metabolites to tetrahydro derivatives; the latter method was used to suppress chromenyl ion formation and to enhance the relative abundance of diagnostic fragment ions. Twenty-one metabolites were identified. Metabolites were found hydroxylated in all positions of both aliphatic chains, with additional compounds formed by epoxidation and reduction of the aliphatic double bond in the methylpentenyl chain. Dihydroxy metabolites were hydoxylated in both the pentyl and methylpentenyl chains in positions common to those hydroxylated in the monohydroxy metabolites.

Animals↗

PubMed2026

Trichoderma specialized metabolites in biocontrol: gene-metabolite links, ecological functions, and translational bottlenecks.

Trichoderma spp. produce a diverse repertoire of metabolites with specific activities that contribute to biocontrol through direct antagonism, ecological signalling, and modulation of plant responses. However, current knowledge remains uneven: many metabolites are chemically described, whereas fewer are supported by robust gene-metabolite associations, experimentally validated ecological functions, and realistic translational evidence. Progress in this field will depend less on expanding compound catalogues than on integrating mechanistic, ecological, and translational evidence. This review examines the specialized metabolism of Trichoderma with emphasis on biosynthetic gene clusters, regulatory networks, ecological roles, and biosafety constraints relevant to biocontrol. Major metabolite classes, including polyketides, terpenoids, peptaibols, siderophores, diketopiperazines, and volatile organic compounds, are discussed together with representative case studies for which genetic and functional evidence is available. We further propose a translational framework to distinguish metabolites with mainly descriptive support from those approaching application readiness, based on four criteria: gene-level validation, demonstrated ecological role, manageable biosafety profile, and feasible delivery/stability. This perspective helps explain why metabolite inventories continue to expand faster than field translation. Recent advances in genomics, transcriptomics, metabolomics, genome editing, and formulation science are reshaping how Trichoderma metabolites are prioritized for future development.

Biosafety↗

PubMed1991

Metabolism of metandienone in man: identification and synthesis of conjugated excreted urinary metabolites, determination of excretion rates and gas chromatographic-mass spectrometric identification of bis-hydroxylated metabolites.

After oral administration of metandienone (17 alpha-methyl-androsta-1,4-dien-17 beta-ol-3-one) to male volunteers conjugated metabolites are isolated from urine via XAD-2-adsorption, enzymatic hydrolysis and preparative high-performance liquid chromatography (HPLC). Four conjugated metabolites are identified by gas chromatography-mass spectrometry (GC/MS) with electron impact (EI)-ionization after derivatization with N-methyl-N-trimethyl-silyl-trifluoroacetamide/trimethylsilyl-imidazole (MSTFA/TMS-Imi) and comparison with synthesized reference compounds: 17 alpha-methyl-5 beta-androst-1-en-17 beta-ol-3-one (II), 17 alpha-methyl-5 beta-androst-1-ene-3 alpha,17 beta-diol (III), 17 beta-methyl-5 beta-androst-1-ene-3 alpha,17 alpha-diol (IV) and 17 alpha-methyl-5 beta-androstane-3 alpha,17 beta-diol (V). After administration of 40 mg of metandienone four bis-hydroxy-metabolites--6 beta,12-dihydroxy-metandienone (IX), 6 beta,16 beta-dihydroxy-metandienone (X), 6 beta,16 alpha-dihydroxy-metandienone (XI) and 6 beta,16 beta-dihydroxy-17-epimetandienone (XII)--were detected in the unconjugated fraction. The metabolites III, IV and V are excreted in a comparable amount to the unconjugated excreted metabolites 17-epimetandienone (VI), 6 beta-hydroxy-metandienone (VII) and 6 beta-hydroxy-17-epimetandienone (VIII). Whereas the unconjugated excreted metabolites show maximum excretion rates between 4 and 12 h after administration the conjugated metabolites III, IV and V are excreted with maximum rates between 12 and 34 h.

Administration, Oral↗

PubMed1991

Ciclosporin metabolite pattern in blood and urine of liver graft recipients. I. Association of ciclosporin metabolites with nephrotoxicity.

Blood ciclosporin (Cs) metabolite pattern in 58 liver grafted patients was routinely monitored by HPLC from the first Cs dose after transplantation until discharge from hospital. Eighteen patients with normal kidney function were allocated to Group I and 14 patients in Group II suffered Cs nephrotoxicity during their clinical course. There were no significant differences between both groups in blood Cs level, kidney function before transplantation, liver function or co-administration of other potentially nephrotoxic drugs. A correlation matrix involving both groups showed a significant correlation between the blood concentration of metabolite M1c9 and serum creatinine and urea, and an inverse correlation with creatinine clearance. During a nephrotoxic episode the blood concentrations of metabolites M1c9 and M1A were significantly elevated in patients in Group II. Analysis of the time course revealed significantly higher blood levels of M19 and M1c9 in Group II patients compared with those in Group I for the first 10 days after transplantation. Serum creatinine and urea concentrations remained significantly elevated, the creatinine clearance being significantly reduced throughout the period of observation. The elevated blood concentrations of ciclosporin metabolites M1c9 and M19 during nephrotoxic episodes suggest that these metabolites are associated with ciclosporin nephrotoxicity. It could not be decided if the elevated metabolite concentrations were the result of and/or the reason for impaired kidney function.

Adult↗

PubMed1991

The pharmacokinetics of antipyrine and three of its metabolites in the rabbit: intravenous administration of pure metabolites.

Antipyrine (AP) is a commonly used probe of oxidative metabolism. Indirect evidence demonstrates formation rate limited disposition of its metabolites. Kinetic studies using antipyrine and its major metabolites 3-hydroxymethylantipyrine (HMA), norantipyrine (NORA), and 4-hydroxyantipyrine (OHA) were completed to investigate the metabolic fate of preformed antipyrine metabolite and to demonstrate directly formation rate-limited metabolite disposition in vivo. Bolus injections of antipyrine and preformed metabolites (40-50 mg/kg) were administered to male, New Zealand white rabbits. Plasma and urine were analyzed using HPLC. These studies demonstrate that HMA, NORA, and OHA are formation rate limited in the rabbit. NORA appears to undergo further extensive oxidative and conjugative metabolism. Unknown additional peaks were detected in urine after NORA dosing but not after HMA or OHA administration. Mass spectroscopy of the unknown HPLC eluents identified potential structures of these NORA metabolites.

Animals↗

PubMed1992

Species differences in urinary butadiene metabolites; identification of 1,2-dihydroxy-4-(N-acetylcysteinyl)butane, a novel metabolite of butadiene.

1,3-Butadiene (BD) is used in the manufacture of styrene-BD and polybutadiene rubber. Differences seen in chronic toxicity studies in the susceptibility of B6C3F1 mice and Sprague-Dawley rats to BD raise the question of how to use the rodent toxicology data to predict the health risk of BD in humans. The purpose of this study was to determine if there are species differences in the metabolism of BD to urinary metabolites that might help to explain the differences in the toxicity of BD. The major urinary metabolites of BD in F344/N rats, Sprague-Dawley rats, B6C3F1 mice, Syrian hamsters, and cynomolgus monkeys were identified as 1,2-dihydroxy-4-(N-acetylcysteinyl)-butane (I) and the N-acetylcysteine conjugate of BD monoxide [1-hydroxy-2-(N-acetylcysteinyl)-3-butene] (II). These mercapturic acids are formed by addition of glutathione at either the double bond (I) or the epoxide (II) respectively. When exposed to approximately 8000 p.p.m. of BD for 2 h, the mice excreted 3-4 times as much metabolite II as I, the hamster and the rats produced approximately 1.5 times as much metabolite II as I, while the monkeys produced primarily metabolite I. The ratio of formation of metabolite I to the total formation of the two mercapturic acids correlated well with the known hepatic epoxide hydrolase activity in the different species. These data suggest that (i) the availability of the monoepoxide for conjugation with glutathione is highest in the mouse, followed by the hamster and the rat, and is lowest in the monkey; and (ii) the epoxide availability is inversely related to the hepatic activity of epoxide hydrolase, the enzyme that removes the epoxide by hydrolysis. The ratio of the two mercapturic acids in human urine following BD exposure may indicate the pathways of BD metabolism in humans and may aid in the determination of the most appropriate animal model for BD toxicity.

Acetylcysteine↗

PubMed1990

Michaelis-Menten metabolite formation kinetics: equations relating area under the curve and metabolite recovery to the administered dose.

A computational approach which concomitantly determines the capacity-limited rate constants of parent drug elimination and metabolite formation is presented. The approach applies both the presently derived total excretory recovery versus dose relationships of the metabolite and the AUC versus dose relationships of the parent drug to identify the parameters. Three parent drug elimination conditions were assessed: pooled first-order, pooled Michaelis-Menten, and parallel first-order and pooled Michaelis-Menten kinetics. Model and parameter identification criteria are discussed. Literature data for theophylline and two of its metabolites in rats were examined to reveal pooled Michaelis-Menten elimination kinetics of theophylline and capacity-limited formation of the metabolites. The proposed technique is useful for quantitating commonly obtained nonlinear drug disposition data such as AUC and amount of metabolites excreted.

Animals↗

PubMed1992

Biological profile of the metabolites and potential metabolites of the anticonvulsant remacemide.

Remacemide hydrochloride ((+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)- acetamide hydrochloride or FPL 1292AA) is a novel compound undergoing clinical trials for patients with generalized tonic/clonic and complex partial epilepsy. Remacemide exhibits efficacy against maximal electroconvulsive shock (MES) in rodents and seizures elicited by N-methyl-D,L-aspartate (NMDLA) in mice. Using rat synaptic membrane fractions, remacemide was shown to possess relatively weak noncompetitive binding to the ionic channel site of the NMDA (N-methyl-D-aspartic acid) receptor complex. With the hypothesis that activity against NMDLA-elicited seizures might be reflected by transformation to a more active metabolic species, the aim of the present study was to evaluate potential pharmacological effects of the 9 identified metabolites of remacemide which were all found in human and dog urine. Moreover, specific entities were recognized in plasma (including the rat's), as well as dog and rat cerebrospinal fluid. Five putative metabolites were also examined. A major route of metabolic transformation of remacemide in rats yields the formation of a pharmacologically active more potent desglycine derivative, namely FPL 12495 (+/-). Potency over the parent compound is revealed in the MES test in mice and rats, the NMDA-induced convulsions/mortality test in mice, and especially involving in vitro displacement of MK801 binding to the channel subsite of the NMDA receptor. The S isomer (FPL 12859) of this desglycinate is even more potent, while the R isomer is less potent than the corresponding racemate. Unlike the non-competitive NMDA antagonist, MK801, these desglycinates did not prevent kindled seizures. Three other identified metabolites show efficacy in the mouse and rat in vivo tests, namely the N-hydroxy-desglycinate (FPL 15053) and the p-hydroxy-desglycinates (FPL 14331 and FPL 14465). FPL 15053 exhibited modest activity in all tests. The only in vivo activity exhibited by the 2 p-hydroxy-desglycinates was evidenced in the MES test following i.p. and i.v. dosing. However, FPL 14331 was active in the MK801 binding assay. An oxoacetate metabolite, PFL 15455, failed to demonstrate any biological activity. Of potential metabolites tested 2 beta-hydroxy-desglycinates (FPL 14991 and FPL 14981) displayed modest activity in the MES test, however, only FPL 14981 prevented NMDLA-induced convulsions/mortality in mice and was 2-fold more active regarding MK801 binding. The hydroxy-methyl derivative of remacemide (FPL 13592) and its desglycinate (FPL 15112) prevented MES-induced convulsions only after i.v. administration; only the desglycine derivative displaced MK801 binding.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetamides↗

PubMed1990

Disposition of nicotine and eight metabolites in smokers and nonsmokers: identification in smokers of two metabolites that are longer lived than cotinine.

The disposition of a single intravenous dose of 14C-nicotine was investigated in six cigarette smokers and six nonsmokers. Plasma and urinary elimination of both nicotine and cotinine was faster in smokers than in nonsmokers. In the urine of both smokers and nonsmokers, we identified nicotine and eight metabolites, including two new metabolites: metabolite A (3-hydroxycotinine glucuronide) and metabolite G (demethylcotinine delta 2',3'-enamine). Metabolites A and G were of particular interest because, in smokers, they both persisted longer than cotinine. This property renders them more sensitive than cotinine as potential indicators of passive exposure to cigarette smoke.

Adult↗

PubMed1989

Effect of sulphasalazine and its active metabolite, 5-amino-salicylic acid, on toxic oxygen metabolite production by neutrophils.

The possibility that the mode of action of sulphasalazine and its active metabolite 5-amino-salicylic acid (5ASA) involves modification of toxic oxygen metabolite production by neutrophils has been investigated by measuring the effect of these drugs on luminol-dependent chemiluminescence, superoxide release and oxygen consumption by stimulated neutrophils in vitro. 5ASA, and to a lesser extent sulphasalazine, had profound inhibitory effects on the luminol dependent chemiluminescent response of neutrophils stimulated with formyl-methionyl-leucyl-phenylalanine (1 microM) + cytochalasin B (5 micrograms/ml). A concentration of 50 microM 5ASA or sulphasalazine produced 93.8 (2.3)% and 65.7 (3.7)% inhibition of control responses respectively. The concentration of 5ASA and sulphasalazine producing 50% inhibition of chemiluminescence were 3.6 (1.8) microM and 16.5 (6) microM respectively. Both drugs had little effect on the chemiluminescent response of neutrophils stimulated with phorbol myristate acetate (1 microgram/ml), producing only 11.4 (3.9)% and 34 (7)% inhibition respectively, at a concentration of 50 microM. Superoxide release from fMLP + CB stimulated neutrophils was also inhibited slightly by 5ASA (50 microM) by 35.6% and by sulphasalazine (50 microM) by 7.9%. Similarly, there was little inhibition in the rate of oxygen consumption by fMLP + CB stimulated neutrophils by either 5ASA or sulphasalazine at concentrations which produced near total abolition of luminol dependent chemiluminescence. These results show that sulphasalazine and 5ASA inhibit the reaction of toxic metabolites produced by stimulated neutrophils with luminol, without inhibition of the oxidase system producing these metabolites. The site of action of these drugs on neutrophils in vitro is thus extracellular, by scavenging a released metabolite, probably hypochlorite. This has important implications for their mode of action in vivo in inflammatory bowel disease.

Aminosalicylic Acids↗

PubMed2026

Genetic and metabolite diversity of Sundaland Heptapleurum (Araliaceae) insight into evolutionary and specialized metabolite.

BACKGROUND: The genus Heptapleurum Gaertn (previously treated as Schefflera J.R.Forst. & G.Forst.) within the Araliaceae family is recognized for its significant medicinal value and complex taxonomy. However, an integrated understanding of its evolutionary and metabolite diversity remains unexplored, especially in the Sundaland region (i.e., Java and Sumatra). Here, we integrate genomics and metabolomics to unravel the evolutionary relationships and metabolite diversity of 10 Heptapleurum species from Sundaland. RESULTS: We assembled 10 new complete plastid genomes (plastomes) and 45S nuclear ribosomal DNA (nrDNA) sequences, identifying significant variation and potential key molecular markers. Metabolomics identified 152 metabolites, mainly phenolics and terpenoids. Metabolite profiles of H. rhynchocarpum and H. capituliferum were more correlated with phylogeny than with geography; these two species were separate from the main Heptapleurum clade. Four species, H. farinosum, H. longifolium, H. rigidum, and H. fastigiatum, have almost identical plastomes and 45S nrDNA structures, suggesting they may represent closely related species with different phenotypes, as evidenced by distinctive metabolite compositions. CONCLUSIONS: Crucially, there is an incongruence between the genetic and chemical phylogenies, underscoring that while chemotaxonomy reflects functional diversity, genetic data remains the definitive standard for evolutionary inference, with the potential for reclassifying H. rhynchocarpum and H. capituliferum. This study provides a foundation for future taxonomic revisions, conservation, and drug discovery of Heptapleurum.

Phylogeny↗

PubMedDate not supplied

Synthesis of 10,11-dihydroxydihydroquinidine N-oxide, a new metabolite of quinidine. Preparation and 1H-nmr spectroscopy of the metabolites of quinine and quinidine and conformational analysis via 2D COSY nmr spectroscopy.

The first synthesis of 10,11-dihydroxydihydroquinidine N-oxide [7b], a recently isolated metabolite of quinidine, was accomplished in three steps from 1b. The related congener 7a in the quinine series was also prepared, as well as two other analogues 3a and 4a. In addition, the previously reported human metabolites 2a, 5a, and 6a of quinine [1a] and those 2b, 3b, 4b, 5b, and 6b of quinidine [1b] were synthesized. The chemical shift and coupling constants for all of the metabolites of quinine and quinidine were assigned via 2D COSY 1H-nmr spectroscopy. Moreover, the conformations of these metabolites in solution were found to parallel those of the parent alkaloids, quinine [1a] and quinidine [1b], respectively.

Molecular Conformation↗

PubMed1991

A preliminary study to evaluate an in vitro assay for determining patient whole blood immunosuppressive cyclosporine A and metabolite activity: comparison with cytosolic binding assays using cyclophilin or a 50-kilodalton binding protein, and the Abbott TDx cyclosporine A parent, and parent and metabolites assays.

Thirty-five allograft recipients undergoing cyclosporine A (CsA) therapy were randomly selected to evaluate a "novel" in vitro assay that determines CsA and metabolite immunosuppressive activity in whole blood. The assay uses a third party mixed lymphocyte culture (MLC) system to which patient whole blood extracts containing CsA and metabolites are added. The ability of the extracted CsA and metabolites to inhibit proliferation in this system is proportional to the immune suppressive activity in whole blood. Comparison of the MLC suppression assay against Abbott TDx parent, TDx parent and metabolites, and radioreceptor assays utilizing cyclophilin or a 50-kDa binding protein isolated from JURKAT cytosol gave the following correlation coefficients: r = 0.612, r = 0.672, r = 0.362, and r = 0.775, respectively.

Amino Acid Isomerases↗