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PubMed1992

[Pilot study of dose dependence in glucuronidation of morphine to morphine-3- and morphine-5-glucuronide].

In the capacity of an initial study both, the half-lives of morphine and its metabolites morphine-3-glucuronide and morphine-6-glucuronide as well as the ratio of concentrations in the development of time using two different dosages were determined and shown by comparison. A bolus of 10 mg (10 micrograms) tritium-marked morphine was administered intravenously. Subsequently the half-lives of morphine, morphine-3-glucuronide and morphine-6-glucuronide in serum, saliva and urine were determined. To achieve this, morphine and its glucuronides were separated via HPLC and then quantified by measuring the radioactivity. In addition to the short half-lives of morphine and morphine-glucuronides long half-lives were found in the range of 12.6 to 20 hours in serum and urine. There was no positive evidence for glucuronides in saliva. In urine the morphine/glucuronide ratio showed a linear resp. exponential development dependent of dose.

Adult↗
PubMedDate not supplied

N-glucuronidation reactions. II. Relative N-glucuronidation reactivity of methylbiphenyl tetrazole, methylbiphenyl triazole, and methylbiphenyl imidazole in rat, monkey, and human hepatic microsomes.

The relative intrinsic in vitro N-glucuronidation reactivity of three classes of heterocyclic compounds was compared using model compounds incubated with UDP-glucuronic acid-enriched liver microsomes from rats, monkeys, and humans. These compounds, all methylbiphenyl (MB) derivatives, represent three classes of N-containing heterocycles commonly used in the design of new drug entities [i.e MB-tetrazole, MB-triazole, (1,2,3- and 1,2,4-), and MB-imidazole (C2- and C4-substituted)]. The structures of all respective N-glucuronides generated from microsomal incubations were determined by Nuclear Overhauser Effect difference NMR spectroscopy. The chemical and enzymic stabilities of N-glucuronides were also studied. In general, relatively low reactivity was found at nitrogens located next to substituted carbons in heterocycles such as N3 in MB-C4-imidazole, N3 in MB-1,2,3-triazole, N2 (or N4) in MB-1,2,4-triazole, and N1 (or N4) in MB-tetrazole. MB-C2-imidazole, in which both nitrogens are in immediate neighboring positions of the substituted carbon, was unreactive toward N-glucuronidation. When the rate of N-glucuronidation was compared under optimal reaction conditions for each compound, most compounds showed higher reactivity with liver microsomes from monkeys than those from rats, except for N2-glucuronidation of MB-tetrazole and MB-1,2,3-triazole. However, the trend for the relative N-glucuronidation reactivity of these compounds by liver microsomes from humans is quite different from those by monkeys and rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Method for quantification of morphine and its 3- and 6- glucuronides, codeine, codeine glucuronide and 6-monoacetylmorphine in human blood by liquid chromatography-electrospray mass spectrometry for routine analysis in forensic toxicology.

Simultaneous determination of opiates and their glucuronides in body fluids has a great practical interest in the forensic assessment of heroin intoxication. A selective and sensitive method for quantification of morphine and its 3- and 6-glucuronides, codeine, codeine glucuronide and 6-monoacetylmorphine (6-MAM) based on liquid chromatography-electrospray ionisation mass spectrometry is described. The drugs were analysed in human autopsy whole blood after solid-phase extraction on a C8 cartridge. The separation was performed on an ODS column in acetonitrile (analysis time 15 min). For the quantitative analysis, deuterated analogues of each compound were used as internal standards. Selected-ion monitoring was applied where the molecular ion was chosen for quantification. The limits of quantification were 0.5 ng/ml for morphine and 6-MAM and 1 ng/ml for the 6-glucuronide of morphine, codeine-6-glucuronide and codeine and 5 ng/ml for the 3-glucuronide of morphine.

Calibration↗
PubMed2003

Glucuronidation of HMR1098 in human microsomes: evidence for the involvement of UGT1A1 in the formation of S-glucuronides.

HMR1098, a novel KATP-blocking agent, is metabolized to form an S-glucuronide in rat and dog bile. Synthesis of the S-glucuronide metabolite was studied in human liver and kidney microsomes. Recombinant UPD-glucuronosyltransferases (UGTs) were screened for activity, and kinetic analysis was performed to identify the isoform or isoforms responsible for the formation of this novel S-glucuronide in humans. S-Glucuronidation is relatively rare, but from this study it appears that S-glucuronides are not generated exclusively by a single UGT isoform. From the panel of recombinant isoforms used, both UGT1A1 and UGT1A9 catalyzed the glucuronidation of HMR1098. The Vmax values in both instances were similar, but the Km for UGT1A1 was substantially lower than that measured for UGT1A9, 82 microM compared with 233 microM, respectively. Liver and kidney microsomes displayed similar Km values, but the Vmax in kidney was more than 20-fold less than in liver microsomes, which is suggestive of a significant role for the bilirubin UGT in catalysis of HMR1098, although other UGTs may play a secondary role.

Animals↗
PubMed2006

Analysis of lorazepam and its 30-glucuronide in human urine by capillary electrophoresis: evidence for the formation of two distinct diastereoisomeric glucuronides.

Lorazepam (LOR) is a 3-hydroxy-1,4-benzodiazepine that is chiral and undergoes enantiomerization at room temperature. In humans, about 75% of the administered dose of LOR is excreted in the urine as its 30-glucuronide. CE-MS with negative ESI was used to confirm the presence of LOR-30-glucuronide in urines that stemmed from a healthy individual who ingested 1 or 2 mg LOR, whereas free LOR could be detected in extracts prepared from enzymatically hydrolyzed urines. As the 30-glucuronidation reaction occurs at the chiral center of the molecule, two diastereoisomers can theoretically be formed, molecules that can no longer interconvert. The stereoselective formation of LOR glucuronides in humans and in vitro was investigated. MEKC analysis of extracts of the nonhydrolyzed urines suggested the presence of the two different LOR glucuronides in the urine. The formation of the same two diastereoisomers was also observed in vitro employing incubations of LOR with human liver microsomes in the presence of uridine 5'-diphospho-glucuronic acid as coenzyme. The absence of other coenzymes excluded the formation of phase I or other phase II metabolites of LOR. Both results revealed a stereoselectivity, one diastereoisomer being formed in a higher amount than the other. After enzymatic hydrolysis using beta-glucuronidase, these peaks could not be detected any more. Instead, LOR was monitored. Analysis of the extracts prepared from enzymatically hydrolyzed urines by MEKC in the presence of 2-hydroxypropyl-beta-CD revealed the enantiomerization process of LOR (observation of two peaks of equal magnitude connected with a plateau zone). The data presented provide for the first time the evidence of the stereoselectivity of the LOR glucuronidation in humans.

Electrophoresis, Capillary↗
PubMed1986

Study of fluorescein glucuronide. II. A comparative ocular kinetic study of fluorescein and fluorescein glucuronide.

Comparative studies of fluorescein and fluorescein glucuronide were carried out. Binding to human serum protein was studied using an Amicon MPS-3 ultrafiltration unit; it averaged 63% for fluorescein glucuronide and 85% for fluorescein. Intracameral penetration of both compounds was studied in the human eye, and the concentration changes of both compounds in the plasma ultrafiltrate and in the anterior chamber were analyzed, based on Davson's equation. The coefficient of entry into the anterior chamber (ki) was 0.018 +/- 0.007 h-1 (mean +/- SD, n = 10) for fluorescein glucuronide and 0.054 +/- 0.033 h-1 for fluorescein, and the former was significantly lower than the latter (P less than 0.005). The rate of loss from the vitreous (kv) was studied by injecting each compound into the vitreous of the pigmented rabbit and following the fluorescein intensity changes in it. It was 0.042 +/- 0.008 h-1 (mean +/- SD, n = 8) for fluorescein glucuronide and 0.17 +/- 0.01 h-1 for fluorescein, and the former was significantly smaller than the latter (P less than 0.001). Intraperitoneal injection of probenecid significantly decreased the kv of fluorescein but had little effection that of fluorescein glucuronide. It was suggested that fluorescein glucuronide is lost from the vitreous mainly by a passive mechanism.

Adult↗
PubMed1986

Stereoselective formation of fenoterol-para-glucuronide and fenoterol-meta-glucuronide in rat hepatocytes and enterocytes.

The glucuronidation of fenoterol (Berotec, Partusisten) in isolated rat hepatocytes and enterocytes was investigated. Two different glucuronides, fenoterol para-glucuronide and fenoterol meta-glucuronide, were formed in proportions, that were constant over the concentration range investigated (0-1 mM). The fraction of para-glucuronide formed was 0.40 +/- 0.01 for hepatocytes and 0.54 +/- 0.01 for enterocytes. Fenoterol consists of a racemic mixture of SS'(+)fenoterol and RR'(-)fenoterol. The maximum glucuronidation rate of the (-)enantiomer (Vmax = 3.6 +/- 0.3 nmol/min/mg in hepatic microsomes and 3.4 +/- 0.1 nmol/min/mg in intestinal microsomes) is significantly lower than the same values of the (+)isomer (Vmax = 6.7 +/- 0.8 nmol/min/mg in hepatic microsomes and 5.8 +/- 0.4 nmol/min/mg in intestinal microsomes). Kmapp-values for the (-)enantiomer were lower than for the (+)enantiomer. Similar, but less pronounced, differences in Vmax were observed in isolated cells: Vmax = 148 +/- 13 and 372 +/- 50 pmol/min/mg [(-)fenoterol in hepatocytes and enterocytes], Vmax = 173 +/- 12 and 444 +/- 57 pmol/min/mg [(+)fenoterol in hepatocytes and enterocytes]. Calculation of intrinsic metabolic clearance (Clint = Vmax/Kmapp) from the cellular data suggests that the (+)enantiomer may be more efficiently eliminated by liver metabolism in vivo than the (-)enantiomer. This can result in stereoselective first-pass metabolism of the fenoterol enantiomers.

Animals↗
PubMed1991

Lack of carcinogenicity of 2-aminofluorene, its glucuronide and the glucuronide of N-hydroxy-2-acetylaminofluorene in heterotopic bladder of the rat.

The role of 2-aminofluorene and its N-glucuronide and the O-glucuronide of N-hydroxy-2-acetylaminofluorene in the bladder carcinogenesis by 2-aminofluorene were investigated. These compounds were injected into heterotopically transplanted bladders of male rats at a weekly dose of 1 mumol for 20 weeks. The experiment was terminated at the end of 50 weeks. The results showed that none of these compounds were carcinogenic in the heterotopically transplanted bladder. The O-glucuronide was not carcinogenic even when it was administered in a phosphate saline (pH 8.0), that favors the activation of this compound. The N-glucuronide of N-hydroxy-2-aminofluorene, a positive control, produced urothelial tumors. These results are consistent with the hypothesis that the N-glucuronides of hydroxylamines, but not the O-glucuronides of hydroxamic acids, are responsible for bladder carcinogenesis by arylamines.

Animals↗
PubMed1999

Immunoaffinity extraction of morphine, morphine-3-glucuronide and morphine-6-glucuronide from blood of heroin victims for simultaneous high-performance liquid chromatographic determination.

The development of an immunoaffinity-based extraction method for the determination of morphine and its glucuronides in human blood is described. For the preparation of an immunoadsorber, specific antisera (polyclonal, host: rabbit) against morphine, morphine-3-glucuronide and morphine-6-glucuronide were coupled to 1,1'-carbonyldiimidazole-activated tris-acrylgel and used for immunoaffinity extraction of morphine and its glucuronides from coronary blood. The resulting extracts were analysed by HPLC with native fluorescence detection. The mean recoveries from spiked blood samples were 71%, 76% and 88% for morphine, morphine-3-glucuronide and morphine-6-glucuronide, respectively. The limit of detection was 3 ng/g blood and the limit of quantitation was 10 ng/g blood for all three analytes. The results of the analysis of coronary blood samples from 23 fatalities due to heroin are presented.

Chromatography, Affinity↗
PubMed1997

Morphine-3-glucuronide prevents tolerance to morphine-6-glucuronide in mice.

Daily subcutaneous (s.c.) pretreatment with morphine-3-glucuronide (6 mg/kg) was found to reduce morphine-6-glucuronide (4 mg/kg s.c.)-induced antinociception, with no decrease in the effect over 5 days. Morphine-6-glucuronide administration (4 mg/kg s.c.) on Day 6, without morphine-3-glucorinide pretreatment, results in a significant increase in antinociception (from 24% on Day 5 to 70%; p< or =0.05). Morphine-3-glucuronide may prevent tolerance to morphine-6-glucuronide by reducing morphine-6-glucuronide-induced antinociception.

Journal Article↗
PubMed1991

Morphine 6-glucuronide and morphine 3-glucuronide as molecular chameleons with unexpected lipophilicity.

Morphine 6-glucuronide, but not morphine 3-glucuronide, is a highly potent opiate receptor agonist. In fact, there is converging evidence that much of the analgesic effect occurring after morphine treatment in humans is due to this metabolite rather than to the parent drug. Yet glucuronides as a rule are considered as highly polar metabolites unable to cross the blood-brain barrier and rapidly excreted by the urinary and/or biliary routes. Here, we report that morphine 6-glucuronide, and to a lesser extent morphine 3-glucuronide, are far more lipophilic than predicted, and in fact not much less lipophilic than morphine itself. Force-field and quantum mechanical calculations indicate that the two glucuronides can exist in conformational equilibrium between extended and folded forms. The extended conformers, because they efficiently expose their polar groups, must be highly hydrophilic forms predominating in polar media such as water; in contrast, the folded conformers mask part of their polar groups, thus being more lipophilic and likely to predominate in media of low polarity such as biological membranes.

Calorimetry↗