-
The Journal of Pediatrics Jul 2015To determine the balance of metabolism of free bisphenol A (BPA) to the inactive conjugate, BPA glucuronide (BPAG), in neonates.
OBJECTIVE
To determine the balance of metabolism of free bisphenol A (BPA) to the inactive conjugate, BPA glucuronide (BPAG), in neonates.
STUDY DESIGN
Free BPA and BPAG concentrations were measured in 78 urine samples collected between December 2012 and August 2013 from a cohort of 44 healthy full term (≥ 37 weeks' gestation) neonates at 2 intervals (3-6 days and 7-27 days of age). A questionnaire was administered at the time of sample collection. Neonates recruited into the study were born in an urban, tertiary care hospital.
RESULTS
Only BPAG was detected in the urine samples; concentrations ranged from <0.1 μg/L to 11.21 μg/L (median: 0.27 μg/L). Free BPA concentrations were below the limit of quantification of 0.1 μg/L. Age, but not sex or type of diet, was significantly associated with urinary BPAG concentration (P = .002).
CONCLUSIONS
Our results illustrate widespread BPA exposure in healthy full-term neonates and efficient conjugation of BPA to its readily excretable and biologically inactive form (BPAG) as early as 3 days of age. Factors other than type of diet may be important contributors to BPA exposure in neonates.
Topics: Age Factors; Benzhydryl Compounds; Breast Feeding; Female; Glucuronides; Humans; Infant Formula; Infant, Newborn; Male; Phenols; Sex Factors
PubMed: 25921439
DOI: 10.1016/j.jpeds.2015.03.036 -
Drug Discovery Today Sep 2020Acyl glucuronidation is a common metabolic fate for acidic drugs and their metabolites and, because these metabolites are reactive, they have been linked to adverse drug... (Review)
Review
Acyl glucuronidation is a common metabolic fate for acidic drugs and their metabolites and, because these metabolites are reactive, they have been linked to adverse drug reactions (ADRs) and drug withdrawals. However, alternative routes of metabolism leading to reactive metabolites (e.g., oxidations and acyl-CoA thioesters) mean that unambiguous proof that acyl glucuronides are toxic is lacking. Here, we review the synthesis and reactivity of these metabolites, and describe the use of molecular modelling and in vitro and in vivo reactivity assessment of acyl glucuronide reactivity. Based on the emerging structure-dependent differences in reactivity and protein adduction methods for risk assessment for acyl glucuronide-forming acid drugs or drug candidates in drug discovery/development are suggested.
Topics: Acylation; Animals; Glucuronides; Humans
PubMed: 32681884
DOI: 10.1016/j.drudis.2020.07.009 -
Journal of Analytical Toxicology Oct 2020Total urinary 11-nor-9-carboxy-tetrahydrocannabinol (THCCOOH) concentrations are generally reported following cannabis administration. Few data are available for...
Total urinary 11-nor-9-carboxy-tetrahydrocannabinol (THCCOOH) concentrations are generally reported following cannabis administration. Few data are available for glucuronide and minor cannabinoid metabolite concentrations. All urine specimens from 11 frequent and 9 occasional cannabis users were analyzed for 11 cannabinoids for ~85 h by liquid chromatography with tandem mass spectrometry following controlled smoked, vaporized or oral 50.6 mg Δ9-tetrahydrocannabinol (THC) in a randomized, placebo-controlled, within-subject dosing design. No cannabidiol, cannabinol, cannabigerol, tetrahydrocannabivarin (THCV), THC, 11-OH-THC and Δ9-tetrahydrocannabinolic acid were detected in urine. Median THCCOOH-glucuronide maximum concentrations (Cmax) following smoked, vaporized and oral routes were 68.0, 26.7 and 360 μg/L for occasional and 378, 248 and 485 μg/L for frequent users, respectively. Median time to specific gravity-normalized Cmax (Tmax) was 5.1-7.9 h for all routes and all users. Median Cmax for THCCOOH, THC-glucuronide and 11-nor-9-carboxy-Δ9-THCV (THCVCOOH) were <7.5% of THCCOOH-glucuronide Cmax concentrations. Only THC-glucuronide mean Tmax differed between routes and groups, and was often present only in occasional users' first urine void. Multiple THCCOOH-glucuronide and THCCOOH peaks were observed. We also evaluated these urinary data with published models for determining recency of cannabis use. These urinary cannabinoid marker concentrations from occasional and frequent cannabis users following three routes of administration provide a scientific database to assess single urine concentrations in cannabis monitoring programs. New target analytes (CBD, CBN, CBG, THCV and phase II metabolites) were not found in urine. The results are important to officials in drug treatment, workplace and criminal justice drug monitoring programs, as well as policy makers with responsibility for cannabis regulations.
Topics: Administration, Oral; Adult; Cannabidiol; Cannabinoids; Cannabinol; Cannabis; Glucuronides; Humans; Marijuana Smoking; Smoke; Substance Abuse Detection
PubMed: 32369162
DOI: 10.1093/jat/bkaa046 -
Drug Metabolism Reviews May 2017Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances. Although it is usually the... (Review)
Review
Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances. Although it is usually the secondary metabolic pathway for a compound preceded by phase I hydroxylation, glucuronidation alone could serve as the dominant metabolic pathway for many compounds, including some with high aqueous solubility. Glucuronidation involves the metabolism of parent compound by UDP-glucuronosyltransferases (UGTs) into hydrophilic and negatively charged glucuronides that cannot exit the cell without the aid of efflux transporters. Therefore, elimination of parent compound via glucuronidation in a metabolic active cell is controlled by two driving forces: the formation of glucuronides by UGT enzymes and the (polarized) excretion of these glucuronides by efflux transporters located on the cell surfaces in various drug disposition organs. Contrary to the common assumption that the glucuronides reaching the systemic circulation were destined for urinary excretion, recent evidences suggest that hepatocytes are capable of highly efficient biliary clearance of the gut-generated glucuronides. Furthermore, the biliary- and enteric-eliminated glucuronides participate into recycling schemes involving intestinal microbes, which often prolong their local and systemic exposure, albeit at low systemic concentrations. Taken together, these recent research advances indicate that although UGT determines the rate and extent of glucuronide generation, the efflux and uptake transporters determine the distribution of these glucuronides into blood and then to various organs for elimination. Recycling schemes impact the apparent plasma half-life of parent compounds and their glucuronides that reach intestinal lumen, in addition to prolonging their gut and colon exposure.
Topics: Animals; Glucuronides; Glucuronosyltransferase; Hepatocytes; Humans; Pharmacokinetics
PubMed: 28266877
DOI: 10.1080/03602532.2017.1293682 -
Scientific Reports Jul 2022We have studied the physiological effects and health functions of luteolin, especially focusing on its absorption and metabolism. Recent studies have reported the...
We have studied the physiological effects and health functions of luteolin, especially focusing on its absorption and metabolism. Recent studies have reported the advantages of microemulsion to improve the bioavailability of poorly water-soluble compounds, including luteolin. In the present study, we aimed to evaluate the absorption and metabolic profile of luteolin delivered in microemulsion system via oral intake. First, we prepared water-dispersed luteolin (WD-L) using a microemulsion-based delivery system and confirmed that WD-L has superior water dispersibility compared to free luteolin (CO-L) based on their particle size distributions. Following administration of WD-L and CO-L to rats, we detected high level of luteolin-3'-O-β-glucuronide and lower levels of luteolin, luteolin-4'-O-β-glucuronide, and luteolin-7-O-β-glucuronide in plasma from both CO-L and WD-L groups, indicating that the metabolic profile of luteolin was similar for both groups. On top of that, we found a 2.2-fold increase in the plasma area under the curve (AUC) of luteolin-3'-O-β-glucuronide (main luteolin metabolite) in WD-L group (vs. CO-L). Altogether, our results suggested that delivering luteolin by microemulsion system improve its oral bioavailability without affecting its metabolite profile. This evidence thereby provides a solid basis for future application of microemulsion system for optimal delivery of luteolin.
Topics: Administration, Oral; Animals; Biological Availability; Emulsions; Glucuronides; Luteolin; Particle Size; Rats; Rats, Sprague-Dawley; Solubility; Water
PubMed: 35831358
DOI: 10.1038/s41598-022-16220-4 -
Clinical Pharmacology and Therapeutics Mar 2021The aim of this study was to investigate the sensitivity and specificity of endogenous glycochenodeoxycholate and glycodeoxycholate 3-O-glucuronides (GCDCA-3G and...
The aim of this study was to investigate the sensitivity and specificity of endogenous glycochenodeoxycholate and glycodeoxycholate 3-O-glucuronides (GCDCA-3G and GDCA-3G) as substrates for organic anion transporting polypeptide 1B1 (OATP1B1) in humans. We measured fasting levels of plasma GCDCA-3G and GDCA-3G using liquid chromatography-tandem mass spectrometry in 356 healthy volunteers. The mean plasma levels of both compounds were ~ 50% lower in women than in men (P = 2.25 × 10 and P = 4.73 × 10 ). In a microarray-based genome-wide association study, the SLCO1B1 rs4149056 (c.521T>C, p.Val174Ala) variation showed the strongest association with the plasma GCDCA-3G (P = 3.09 × 10 ) and GDCA-3G (P = 1.60 × 10 ) concentrations. The mean plasma concentration of GCDCA-3G was 9.2-fold (P = 8.77 × 10 ) and that of GDCA-3G was 6.4-fold (P = 2.45x10 ) higher in individuals with the SLCO1B1 c.521C/C genotype than in those with the c.521T/T genotype. No other variants showed independent genome-wide significant associations with GCDCA-3G or GDCA-3G. GCDCA-3G was highly efficacious in detecting the SLCO1B1 c.521C/C genotype with an area under the receiver operating characteristic curve of 0.996 (P < 0.0001). The sensitivity (98-99%) and specificity (100%) peaked at a cutoff value of 180 ng/mL for men and 90 ng/mL for women. In a haplotype-based analysis, SLCO1B1*5 and *15 were associated with reduced, and SLCO1B1*1B, *14, and *35 with increased OATP1B1 function. In vitro, both GCDCA-3G and GDCA-3G showed at least 6 times higher uptake by OATP1B1 than OATP1B3 or OATP2B1. These data indicate that the hepatic uptake of GCDCA-3G and GDCA-3G is predominantly mediated by OATP1B1. GCDCA-3G, in particular, is a highly sensitive and specific OATP1B1 biomarker in humans.
Topics: Adult; Biomarkers; Chromatography, Liquid; Female; Genome-Wide Association Study; Genotype; Glucuronides; Glycochenodeoxycholic Acid; HEK293 Cells; Healthy Volunteers; Humans; Liver; Liver-Specific Organic Anion Transporter 1; Male; Metabolic Detoxication, Phase II; Oligonucleotide Array Sequence Analysis; Pharmacogenomic Variants; Phenotype; Polymorphism, Single Nucleotide; Tandem Mass Spectrometry; Young Adult
PubMed: 32961594
DOI: 10.1002/cpt.2053 -
Journal of Agricultural and Food... Oct 2022Stilbene metabolites are attracting great interest because many of them exhibit similar or even stronger biological effects than their parent compounds. Furthermore, the...
Oxyresveratrol and Gnetol Glucuronide Metabolites: Chemical Production, Structural Identification, Metabolism by Human and Rat Liver Fractions, and Anti-inflammatory Properties.
Stilbene metabolites are attracting great interest because many of them exhibit similar or even stronger biological effects than their parent compounds. Furthermore, the metabolized forms are predominant in biological fluids; therefore, their study is highly relevant. After hemisynthesis production, isolation, and structural elucidation, three glucuronide metabolites for oxyresveratrol (ORV) were formed: -ORV-4'--glucuronide, -ORV-3--glucuronide, and -ORV-2'--glucuronide. In addition, two glucuronide metabolites were obtained for gnetol (GN): -GN-2'--glucuronide and -GN-3--glucuronide. When the metabolism of ORV and GN is studied by human and rat hepatic enzymes, four of the five hemisynthesized compounds were identified and quantified. Human enzymes glucuronidated preferably at the C-2' position, whereas rat enzymes do so at the C-3 position. In view of these kinetic findings, rat enzymes have a stronger metabolic capacity than human enzymes. Finally, ORV, GN, and their glucuronide metabolites (mainly at the C-3 position) decreased nitric oxide, reactive oxygen species, interleukin 1β, and tumor necrosis factor α production in lipopolysaccharide-stimulated macrophages.
Topics: Humans; Rats; Animals; Glucuronides; Interleukin-1beta; Reactive Oxygen Species; Lipopolysaccharides; Nitric Oxide; Tumor Necrosis Factor-alpha; Stilbenes; Anti-Inflammatory Agents; Liver
PubMed: 35195403
DOI: 10.1021/acs.jafc.1c07831 -
Anesthesiology Dec 2011The long-lasting high-affinity opioid buprenorphine has complex pharmacology, including ceiling effects with respect to analgesia and respiratory depression. Plasma...
BACKGROUND
The long-lasting high-affinity opioid buprenorphine has complex pharmacology, including ceiling effects with respect to analgesia and respiratory depression. Plasma concentrations of the major buprenorphine metabolites norbuprenorphine, buprenorphine-3-glucuronide, and norbuprenorphine-3-glucuronide approximate or exceed those of the parent drug. Buprenorphine glucuronide metabolites pharmacology is undefined. This investigation determined binding and pharmacologic activity of the two glucuronide metabolites, and in comparison with buprenorphine and norbuprenorphine.
METHODS
Competitive inhibition of radioligand binding to human μ, κ, and δ opioid and nociceptin receptors was used to determine glucuronide binding affinities for these receptors. Common opiate effects were assessed in vivo in SwissWebster mice. Antinociception was assessed using a tail-flick assay, respiratory effects were measured using unrestrained whole-body plethysmography, and sedation was assessed by inhibition of locomotion measured by open-field testing.
RESULTS
Buprenorphine-3-glucuronide had high affinity for human μ (Ki [inhibition constant] = 4.9 ± 2.7 pM), δ (Ki = 270 ± 0.4 nM), and nociceptin (Ki = 36 ± 0.3 μM) but not κ receptors. Norbuprenorphine-3-glucuronide had affinity for human κ (Ki = 300 ± 0.5 nM) and nociceptin (Ki = 18 ± 0.2 μM) but not μ or δ receptors. At the dose tested, buprenorphine-3-glucuronide had a small antinociceptive effect. Neither glucuronide had significant effects on respiratory rate, but norbuprenorphine-3-glucuronide decreased tidal volume. Norbuprenorphine-3-glucuronide also caused sedation.
CONCLUSIONS
Both glucuronide metabolites of buprenorphine are biologically active at doses relevant to metabolite exposures, which occur after buprenorphine. Activity of the glucuronides may contribute to the overall pharmacology of buprenorphine.
Topics: Analgesics, Opioid; Animals; Behavior, Animal; Buprenorphine; CHO Cells; Cells, Cultured; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Female; Glucuronides; Humans; Male; Mice; Motor Activity; Pain; Pain Measurement; Plethysmography, Whole Body; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Respiratory Insufficiency; Tidal Volume; Nociceptin Receptor
PubMed: 22037640
DOI: 10.1097/ALN.0b013e318238fea0 -
Biochemical Pharmacology May 2017Conjugation with glucuronic acid is a prevalent metabolic pathway of orally administrated curcumin, the bioactive diphenol of the spice turmeric. The major in vitro...
Conjugation with glucuronic acid is a prevalent metabolic pathway of orally administrated curcumin, the bioactive diphenol of the spice turmeric. The major in vitro degradation reaction of curcumin is autoxidative transformation resulting in oxygenation and cyclization of the heptadienedione chain to form cyclopentadione derivatives. Here we show that curcumin-glucuronide is much more stable than curcumin, degrading about two orders of magnitude slower. Horseradish peroxidase-catalyzed oxidation of curcumin-glucuronide occurred at about 80% of the rate with curcumin, achieving efficient transformation. Using LC-MS and NMR analyses the major products of oxidative transformation were identified as glucuronidated bicyclopentadione diastereomers. Cleavage into vanillin-glucuronide accounted for about 10% of the products. Myeloperoxidase and lactoperoxidase oxidized curcumin-glucuronide whereas tyrosinase and xanthine oxidase were not active. Phorbol ester-activated primary human leukocytes showed increased oxidative transformation of curcumin-glucuronide which was inhibited by the peroxidase inhibitor sodium azide. These studies provide evidence that the glucuronide of curcumin is not an inert product and may undergo further enzymatic and non-enzymatic metabolism. Oxidative transformation by leukocyte myeloperoxidase may represent a novel metabolic pathway of curcumin and its glucuronide conjugate.
Topics: Cells, Cultured; Chromatography, High Pressure Liquid; Curcumin; Glucuronides; Humans; Mass Spectrometry; Oxidation-Reduction; Peroxidases; Proton Magnetic Resonance Spectroscopy
PubMed: 28274615
DOI: 10.1016/j.bcp.2017.03.002 -
Clinical Chemistry Jul 2013Blood and plasma cannabinoid stability is important for test interpretation and is best studied in authentic rather than fortified samples.
BACKGROUND
Blood and plasma cannabinoid stability is important for test interpretation and is best studied in authentic rather than fortified samples.
METHODS
Low and high blood and plasma pools were created for each of 10 participants after they smoked a cannabis cigarette. The stabilities of Δ(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol (CBD), cannabinol (CBN), THC-glucuronide, and THCCOOH-glucuronide were determined after 1 week at room temperature; 1, 2, 4, 12, and 26 (±2) weeks at 4 °C; and 1, 2, 4, 12, 26 (±2), and 52 (±4) weeks at -20 °C. Stability was assessed by Friedman test.
RESULTS
Numbers of THC-glucuronide and CBD-positive blood samples were insufficient to assess stability. In blood, 11-OH-THC and CBN were stable for 1 week at room temperature, whereas THC and THCCOOH-glucuronide decreased and THCCOOH increased. In blood, THC, THCCOOH-glucuronide, THCCOOH, 11-OH-THC, and CBN were stable for 12, 4, 4, 12, and 26 weeks, respectively, at 4 °C and 12, 12, 26, 26, and 52 weeks at -20 °C. In plasma, THC-glucuronide, THC, CBN, and CBD were stable for 1 week at room temperature, whereas THCCOOH-glucuronide and 11-OH-THC decreased and THCCOOH increased. In plasma, THC-glucuronide, THC, THCCOOH-glucuronide, THCCOOH, 11-OH-THC, CBN, and CBD were stable for 26, 26, 2, 2, 26, 12, and 26 weeks, respectively, at 4 °C and 52, 52, 26, 26, 52, 52, and 52 weeks, respectively, at -20 °C.
CONCLUSIONS
Blood and plasma samples should be stored at -20 °C for no more than 3 and 6 months, respectively, to assure accurate cannabinoid quantitative results.
Topics: Blood Specimen Collection; Cannabidiol; Cannabinoids; Cannabinol; Dronabinol; Drug Stability; Female; Glucuronides; Humans; Male; Marijuana Smoking; Plasma; Substance Abuse Detection
PubMed: 23519966
DOI: 10.1373/clinchem.2012.201467