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PubMedDate not supplied

Stability of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in fresh blood and plasma and postmortem blood samples.

The present study was designed to determine the stability of morphine and its glucuronides in spiked fresh blood and plasma from live individuals as well as in four authentic postmortem blood specimens for a time interval of up to six months. The samples were stored in glass vials at -20 degrees C, 4 degrees C, and 20 degrees C. Additionally, spiked samples were exposed to light through window glass and subjected to a forced-degradation study at 40 degrees C. Data were established using solid-phase extraction and high-performance liquid chromatography coupled to atmospheric pressure ionization mass spectrometry for isolation and quantitation, providing a sensitive and specific detection method for the parent drug in the presence of its glucuronide metabolites. Morphine and its glucuronide metabolites were found to be stable in both blood and plasma at 4 degrees C for the whole observation period. In postmortem blood the analytes were stable only when stored at -20 degrees C. The thermal decomposition of morphine and morphine-6-glucuronide in spiked blood and plasma could be interpreted using pseudo first-order kinetics. Photodegradation of morphine-3-glucuronide in plasma was consistent with a second-order reaction. In postmortem samples the degradation pattern differed completely from that observed in fresh blood and plasma. The elevated morphine levels observed were primarily due to postmortem hydrolysis of morphine glucuronides.

Drug Stability↗
PubMed1994

Comparative assessment of phenolphthalein and phenolphthalein glucuronide: is phenolphthalein glucuronide a better laxative?

BACKGROUND: Phenolphthalein is widely used as a safe and effective laxative. After oral administration, phenolphthalein is absorbed in the small bowel and is conjugated in the liver to phenolphthalein glucuronide which passes into the colon where it is deconjugated and the active compound, phenolphthalein, is released. Since phenolphthalein glucuronide does not undergo enterohepatic circulation it should theoretically have a more rapid onset of action and a lower threshold dose for laxation. The present study was designed to examine this issue. METHODS: Ten normal healthy subjects volunteered for the study. All subjects were administered placebo, phenolphthalein (at doses of 15, 30, 45, 60, 75 and 90 mg) or phenolphthalein glucuronide (at equivalent doses of 24, 48, 72, 96, 120 and 144 mg) in a random order. Stool weight, the frequency and consistency of stools, and the development of symptoms were recorded at 12-h intervals for 84 h. RESULTS: There was a significant increase in the mean stool weight obtained within the first 24 h of administration of a 30 mg dose of phenolphthalein and its glucuronide equivalent compared to the values obtained with placebo. A further increase in the dose did not improve the therapeutic response. There was no difference between phenolphthalein and phenolphthalein glucuronide with respect to the rapidity of action, the threshold dose, effectiveness of laxation, or the frequency of adverse effects. CONCLUSIONS: The therapeutic response and side effect profile of the different doses favoured 30 mg phenolphthalein as the optimum laxative dose. Although theoretically superior, phenolphthalein glucuronide was not found to be a more effective laxative compared to phenolphthalein in normal subjects.

Cathartics↗
PubMed2006

Quantitative prediction of in vivo inhibitory interactions involving glucuronidated drugs from in vitro data: the effect of fluconazole on zidovudine glucuronidation.

AIMS: Using the fluconazole-zidovudine (AZT) interaction as a model, to determine whether inhibition of UDP-glucuronosyltransferase (UGT) catalysed drug metabolism in vivo could be predicted quantitatively from in vitro kinetic data generated in the presence and absence bovine serum albumin (BSA). METHODS: Kinetic constants for AZT glucuronidation were generated using human liver microsomes (HLM) and recombinant UGT2B7, the principal enzyme responsible for AZT glucuronidation, as the enzyme sources with and without fluconazole. K(i) values were used to estimate the decrease in AZT clearance in vivo. RESULTS: Addition of BSA (2%) to incubations decreased the K(m) values for AZT glucuronidation by 85-90% for the HLM (923 +/- 357 to 91 +/- 9 microm) and UGT2B7 (478-70 microm) catalysed reactions, with little effect on V(max). Fluconazole, which was shown to be a selective inhibitor of UGT2B7, competitively inhibited AZT glucuronidation by HLM and UGT2B7. Like the K(m), BSA caused an 87% reduction in the K(i) for fluconazole inhibition of AZT glucuronidation by HLM (1133 +/- 403 to 145 +/- 36 microm) and UGT2B7 (529 to 73 microm). K(i) values determined for fluconazole using HLM and UGT2B7 in the presence (but not absence) of BSA predicted an interaction in vivo. The predicted magnitude of the interaction ranged from 41% to 217% of the reported AUC increase in patients, depending on the value of the in vivo fluconazole concentration employed in calculations. CONCLUSIONS: K(i) values determined under certain experimental conditions may quantitatively predict inhibition of UGT catalysed drug glucuronidation in vivo.

Alamethicin↗
PubMed2000

Determination of nicotine N-1-glucuronide, a quaternary N-glucuronide conjugate, in human biological samples.

[Methyl-d3]-N-1-beta-D-glucopyranosyl-(+/-)-nicotinium inner salt ((+/-)-[methyl-d3]nicotine N-1-glucuronide) was synthesized from (+/-)-[methyl-d3]nicotine via reaction with methyl-2,3,4-tri-O-acetyl-1-bromodeoxy-alpha-D-glucopyranouronate, followed by deprotection with 1 M aqueous NaOH and purification by preparative TLC. Nicotine N-glucuronide was identified and determined directly in smokers' urine. A solid phase extraction method was used to partially isolate the material from urine. Subsequent determination was by thermospray-LC/MS using the synthetic d3-labeled nicotine N-glucuronide as internal standard. The identified urinary component had the same retention time as a synthetic standard and gave the same mass spectrum. The thermospray mass spectrum was characterized from the protonated molecular ion (m/z 339) and the protonated aglycone ion (m/z 163). Quantitative results from this direct method were compared with those from an indirect method, which calculated the nicotine glucuronide in the biological sample from the amount of nicotine released following treatment of the sample with the deconjugating enzyme, beta-glucuronidase. On average, the concentration of nicotine N-glucuronide determined by the direct method was 34% greater than that determined by the indirect method. Concentrations of nicotine N-glucuronide in urine ranged from 2.2 to 7.6 nmol/ml with a limit of detection of 1.3 nmol/ml.

Adult↗
PubMed1980

The effect of conception on the concentration of urinary oestrone-3-glucuronide, LH/hCG and pregnanediol-3 alpha-glucuronide.

The concentrations of oestrone-3-glucuronide, LH/hCG and pregnanediol-3 alpha-glucuronide have been measured in daily samples of early morning urine from 6 women throughout the normal ovarian cycle and from 5 subjects, who conceived during the period of study. In addition, the ratio of oestrone to pregnanediol glucuronide was calculate as an additional index of ovarian function. The results showed that the ratio during the follicular phase of the cycle was similar in both groups of women. Moreover, there was no significant difference between the groups in either the duration or intensity of the LH peak. Seven days later, however, the women who conceived excreted significantly higher amounts of oestrone-3-glucuronide (P less than 0.05) and 12 days after the LH peak the values for pregnanediol-3 alpha-glucuronide and LH/hCG were also elevated (P less than 0.05). A defined increment, in the concentration of hCH (3 times the mean basal level) occurred 11 to 15 days after the peak of LH and appeared 3 to 5 days after the increased excretion of the steroid glucuronides.

Adult↗
PubMedDate not supplied

Chemopreventive activity of a C-glucuronide analog of N-(4-hydroxyphenyl) retinamide-O-glucuronide against mammary tumor development and growth.

The long term chemopreventive effects of the N-(4-hydroxyphenyl) retinamide-O-glucuronide (4-HPROG), and its stable C-linked benzyl glucuronide analog, retinamidobenzyl glucuronide (4-HPRCG) on the growth and development of 7,12-dimethylbenz[a]anthracene-induced mammary tumors were compared. The retinamidobenzyl glucuronide is stable toward acid hydrolysis and resists the actions of beta-glucuronidase. The results indicate that the C-linked glucuronide analog, 4-HPRCG has a greater chemopreventive potency than an equimolar concentration of 4-HPROG. Tumor latency was 15% longer in rats fed 2 mmol/kg diet of 4-HPRCG as compared to 4-HPROG. At 80 days post DMBA-intubation, tumor incidence was 57% and 27% in the 4-HPROG and 4-HPRCG treated rats, respectively. Tumor multiplicity was also markedly decreased in the 4-HPRCG treated rats. At 80 days post DMBA intubation the control rats had an average of 1.43 tumors/rat compared to 0.71 and 0.36 tumors/rat in the 4-HPROG and 4-HPRCG respectively. The higher potency and low toxicity of 4-HPRCG suggest that this stable analog may have an in vivo chemopreventive advantage over its analog, 4-HPROG. The results also demonstrated that these glucuronide analogs do not bind effectively in vitro either to the nuclear retinoid receptors or to the cellular retinoid binding proteins. Regardless of the mode of action of these retinoids, they are clearly effective chemopreventive agents.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Glucuronidation of labetalol at the two hydroxy positions by bovine liver microsomes. Isolation, purification, and structure elucidation of the glucuronides of labetalol.

Glucuronidation is known to be a major metabolic pathway for labetalol. As the drug contains a phenolic and an alcoholic hydroxy group, in principle two regio isomeric glucuronides can be formed. By incubating the substrate labetalol with bovine liver microsomes, in the presence of the co-substrate UDP-glucuronic acid, both hydroxy positions were glucuronidated. The different glucuronides were isolated from the incubation mixture using Bond-Elut extraction cartridges and separated by means of high performance liquid chromatography. The formation of glucuronides was confirmed by performing reference incubations using radiolabeled UDP-glucuronic acid. Structure elucidation of the various glucuronides was done by nuclear magnetic resonance, ultraviolet spectroscopy, and mass spectrometry.

Animals↗
PubMed1986

Glucuronides of monohydroxylated bile acids: specificity of microsomal glucuronyltransferase for the glucuronidation site, C-3 configuration, and side chain length.

The ability of rat liver microsomes to catalyze UDP-glucuronic acid-dependent glucuronidation of monohydroxy-bile acids was examined. The following bile acids were used as substrates, each as the 3 alpha and 3 beta epimer: 3-hydroxy-5 beta-cholanoic acid (C24), 3-hydroxy-5 beta-norcholanoic acid (C23), 3-hydroxy-5 beta-bisnorcholanoic acid (C22), 3-hydroxy-5 beta-pregnan-21-oic acid (C21), and 3-hydroxy-5 beta-androstane-17 beta-carboxylic acid (C20). The corresponding glucuronides were chemically synthesized to serve as standards and were characterized by thin-layer and gas-liquid chromatography as well as by nuclear magnetic resonance. Enzymatic glucuronidation reactions were optimized with respect to pH for each product formed and the kinetic parameters for each reaction were measured. Analytical techniques necessary to separate products from unreacted substrates and to identify them included thin-layer chromatography, gas-liquid chromatography, and nuclear magnetic resonance. It was found that the 3 alpha epimers of the five bile acids listed above enzymatically formed 3-O-glucuronides, C24 being the best substrate, followed by C21 and C20; C22 and C23 gave rise to only small amounts of this product. The 3 beta epimers of all bile acids tested were poorer substrates, although by a factor that varied widely. In addition to the expected hydroxyl-linked glucuronide, three of the 3 alpha-bile acids (C23, C22, and C20) and at least one 3 beta-bile acid (C20), gave rise to a novel metabolite in which the 1-OH of glucuronic acid was esterified with the steroidal carboxyl group (carboxyl-linked glucuronide).

Animals↗
PubMedDate not supplied

N-glucuronidation reactions. I. Tetrazole N-glucuronidation of selected angiotensin II receptor antagonists in hepatic microsomes from rats, dogs, monkeys, and humans.

In vitro conditions for the preparation of tetrazole N2-glucuronides using liver microsomes (enriched with UDP-glucuronic acid) from rats, dogs, monkeys, and humans have been developed and optimized. The structures of tetrazole N2-glucuronides of 3 biphenyl tetrazole-containing angiotensin II (AII) receptor antagonists MK-954 (I), L-158,338 (II), and L-158,809 (III), and a model compound methyl biphenyl tetrazole (IV) were determined either by NMR and mass spectrometry or by comparison of HPLC retention times with that from authentic compounds. The species difference as well as gender difference in the rate of the in vitro reaction were compared. The optimal pH for the reaction was determined to be 5.0 with liver microsomes from monkeys and humans, and 6.2 with those from rats and dogs. For the model compound IV, the rate of N2-glucuronidation by liver microsomes from rats, dogs, and monkeys was approximately 10-fold faster than that by humans. For the AII receptor antagonists I, II, and III, the rate of the same reaction by liver microsomes from dogs and monkeys was much faster than that by humans. The relative intrinsic rate of this reaction for these three substrates ranked similarly in rats and humans as II > III > I. With compound I, a biphenyl tetrazole-containing imidazole derivative that has potential sites for both O- (primary hydroxyl) and N2-(tetrazole) glucuronidation, both O- and tetrazole N2-glucuronides were formed by liver microsomes from rats and monkeys (at neutral pH), whereas N2-glucuronide was the only product from dogs and humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1976

Analysis of estrogen glucuronides. I--Characterization of estrogen glucuronides by gas chromatography mass spectrometry.

The mass spectral characterization of nine kinds of estrogen glucuronides was investigated. The glucuronides were analysed after conversion to n-propyl ester-O-TMS ether derivatives by gas chromatography mass spectrometry. The fragmentation of these derivatives is discussed using deuterium labels and TMS-d9 imidazole. A clear-cut difference was found between aliphatic and aromatic glucuronic acid conjugates. In particular the [M - 362]+- fragment ion was characteristic in the mass spectra of estrogen 3-glucuronides. On the other hand, four isomers of estriol and 16-epiestriol glucuronides containing an aliphatic acetal linkage were also characterized by the fragment ions of m/e value 204, 345, 415, and 431 and their relative intensities. Thus, all nine estrogen glucuronides were discriminated mass spectrometrically.

Chemical Phenomena↗
PubMed1977

Isolation and identification of morphine 3- and 6-glucuronides, morphine 3,6-diglucuronide, morphine 3-ethereal sulfate, normorphine, and normorphine 6-glucuronide as morphine metabolites in humans.

Morphine metabolites were isolated with column chromatography on a resin and neutral aluminum oxide and TLC from the urine of morphine-dependent subjects maintained on morphine sulfate at a dose of 240 mg/day. These metabolites were characterized as morphine 3-glucuronide, morphine 6-glucuronide, morphine 3,6-diglucuronide, morphine 3-ethereal sulfate, normorphine, normorphine 6-glucuronide, and, possibly, normorphine 3-glucuronide by free phenol and glucuronide tests, enzymatic hydrolysis, GLC, TLC, UV spectroscopy, and GLC--mass spectrometry.

Adult↗
PubMed1982

Preparation and antigenic properties of estriol 16-glucuronide- and estradiol 17-glucuronide-[C-6]-bovine serum albumin conjugates.

The preparation and antigenic properties of estriol 16-glucuronide-bovine serum albumin (BSA) and estradiol 17-glucuronide-BSA conjugates in which the hapten molecule is linked to the carrier protein through an (O-carboxymethyl)oxime bridge at the C-6 position on the steroid nucleus, have been described. Antibodies raised against the two immunogens in the rabbit possessed excellent specificity to estriol 16-glucuronide and estradiol 17-glucuronide, respectively, exhibiting no significant cross-reactions with estrogen glucuronides having a substituent in ring A and no cross-reactivities with free estrogens, their sulfates and related steroids.

Antibodies↗
PubMed1996

Direct characterization of drug glucuronide isomers in human urine by HPLC-NMR spectroscopy: application to the positional isomers of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid glucuronide.

In this work, 400 and 600 MHz 1H HPLC-NMR spectroscopic methods were developed and applied to separate and identify the positional glucuronide isomers and anomers of the model nonsteroidal antiinflammatory drug, 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid, in whole human urine. The HPLC methods utilized either an isocratic system, comprising 30% acetonitrile in water at pH 2.5, or a gradient elution system increasing from 30% to 60% acetonitrile, in order to achieve improved separation of the 2-, 3-, and 4-O-acylglucuronide isomers from the faster eluting endogenous urinary metabolites. Directly coupled stop-flow 1H HPLC-NMR spectroscopic measurements were made at the retention times indicated by the UV-monitored chromatographic peaks. The glucuronide isomers were identified from the 1H NMR spectra on the basis of their chemical shifts and spin-spin coupling patterns. The elution order was 4-O-acyl-, 3-O-acyl-, and finally 2-O-acylglucuronide, with tR values of 10.04, 11.68, and 12.64 min, respectively. Although the alpha- and beta-anomers of each of the positional isomers could not be separated in these solvent systems, they could be identified in the individual 1H NMR spectra. This work shows for the first time that directly coupled HPLC-NMR spectroscopy can be used directly to isolate and characterize acyl-migrated isomers of drug glucuronides in whole urine. This approach will be of value in the study of glucuronide acyl migration reactions of nonsteroidal antiinflammatory drugs and other xenobiotic ester glucuronides in whole biofluids.

Acetates↗
PubMed1993

Comparison of plasma androgen glucuronide levels after percutaneous or peroral androgen treatment in men: evidence for important splanchnic contribution to plasma 17 beta-hydroxyandrogen glucuronides.

To investigate whether glucuronides of 17 beta-hydroxyandrogens are formed mainly in peripheral tissues or in splanchnic tissues, we compared androstanediol (AD) glucuronide (ADG) and dihydrotestosterone (DHT) glucuronide (DHTG) levels as well as the ratios of glucuronides over free steroids after transcutaneous DHT gel administration to levels and ratios found after oral administration of testosterone undecanoate. Whereas DHT and AD plasma levels were much higher after transcutaneous DHT gel administration, ADG and DHTG levels as well as glucuronide/free androgen ratios were an order of a magnitude higher after oral TU. This indicates that 17 beta-hydroxyandrogen glucuronides cannot be considered specific metabolites of androgen target tissues and are formed to a large extent in the splanchnic circulation.

Administration, Cutaneous↗
PubMedDate not supplied

Stereoselective formation of glucuronides in metabolism of hexobarbital enantiomers in vivo: isolation and quantitation of glucuronides in rabbit urine.

An improved column-chromatographic method was described for isolation and purification on preparative scale of a glucuronide from urine of rabbits administered (RS)-hexobarbital. The analytically pure preparation obtained was found to be a mixture of two glucuronides of diastereomeric 3'-hydroxyhexobarbitals. Rates of hydrolysis of the glucuronides were dependent on the enzyme preparations used as well as on the configuration of the substrate. For quantitative determination, the glucuronides were hydrolyzed completely by beta-glucuronidases from either Escherichia coli or abalone entrails under the conditions used. In vivo studies on the metabolism of (R)-(-)- and (S)-(+)-hexobarbital in the rabbit showed that the glucuronides excreted in 24-hr urine accounted for about 30% of the dose of each enantiomer, and that conjugation of the hydroxy isomers with glucuronic acid was so stereoselective that the isomers with S-configuration at the 3'-position were preferentially conjugated. There were almost no differences in the urinary metabolite profile between normal an PB-treated rabbits; however, a noticeable change was observed in recovery of unchanged (S)-hexobarbital after phenobarbital treatment.

Animals↗
PubMedDate not supplied

Glucuronidation as a transient intermediate metabolic step in the elimination of (-)-carbovir. Identification of (-)-carbovir-5'-O-glucuronide in rat bile.

Carbocyclic 2',3'-didehydo-2',3'-dideoxy-guanosine [(-)-CBV] is a potent and selective inhibitor of the human immunodeficiency virus. The formation of the (-)-CBV-5'-O-glucuronide has been reported to be species-specific and stereoselective with rats forming little of the metabolite after administration of (-)-CBV. A series of studies of (-)-CBV disposition in bile duct-cannulated rats and in the in situ perfused rat liver were conducted. Based on differential hydrolysis with beta-glucuronidase, UV, and tandem MS, the 5'-O-glucuronide was unequivocally identified as the major metabolite of (-)-CBV in rat bile. In the bile duct-cannulated rats receiving 14C-(-)-CBV, 15.8 +/- 4.8% of the radioactivity was recovered in bile after > or = 4 hr. The 5'-O-glucuronide accounted for 75% of the biliary radioactivity. In the in situ perfused rat liver, approximately 20.5% of the radioactivity appeared in the bile. Of this (-)-CBV-derived radioactivity, approximately 70% was due to the glucuronide, 13% to unchanged (-)-CBV, and 17% to an unidentified metabolite. These results suggested that biliary excretion was an important source of radioactivity in the feces. A plausible explanation for the lack of excretion of the conjugate in the feces of rats is intestinal degradation of the conjugate catalyzed by the gut microflora. This hypothesis was supported by the demonstration that rat cecal contents efficiently hydrolyzed (-)-CBV-5'-O-glucuronide in bile to (-)-CBV under anaerobic conditions.

Animals↗
PubMed1998

Olanzapine 10-N-glucuronide. A tertiary N-glucuronide unique to humans.

In humans, a major metabolite of the atypical antipsychotic olanzapine in the plasma and in the urine was found to be an N-glucuronide. Unexpectedly, the glucuronic acid moiety was linked through a nitrogen of the benzodiazepine nucleus of olanzapine by way of a secondary amine linkage, rather than through a nitrogen on the piperazine substituent of the nucleus, to give a quaternary ammonium glucuronide. Derivatization with phenylisothiocyanate to yield a thiourea adduct indicated that conjugation occurred via a secondary amine. Subsequently, mass spectrometry and nuclear magnetic resonance studies with the isolated metabolite and later with the synthesized metabolite indicated that the glucuronide was linked at the 10- position of olanzapine. This phase 2 metabolite was only detected in the plasma and urine of human subjects and not in mice, rats, or monkeys; a trace of this metabolite was detected in dog urine. The N-10 glucuronide was resistant to enzymatic and base hydrolysis but was cleaved under acidic conditions. Formation of an N-glucuronide metabolite directly with the benzodiazepine nucleus has not previously been reported.

Animals↗
PubMed2006

Scintigraphic imaging with a peptide glucuronide in rabbits: 99mTc- exorphin C glucuronide.

A peptide glucuronide (Exorphin C glucuronide) was labeled with 99mTc using glucoheptonate (GH) as a bifunctional chelating agent. Scintigraphic imaging was performed in male Albino rabbits. Exorphin C glucuronide showed rapid and efficient labeling with 99mTc using glucoheptonate as a bifunctional chelate. Results demonstrated that 99mTc-GEG may be a useful new type of glucuronide derivative of peptides for diagnosis of some cancer diseases.

Animals↗