Glucuronides

Publication Title: 
Drug Metabolism and Disposition: The Biological Fate of Chemicals

beta-Artemether (AM), the O-methyl ether prodrug of dihydroartemisinin (DHA), is an endoperoxide antimalarial. The biliary metabolites of AM in adult male Wistar rats were characterized with particular reference to potential antimalarial compounds and stable derivatives of free radical intermediates. [13-(14)C]-AM (35 micromol kg(-1), i.v.) was administered to anesthetized rats. Within 0 to 3 h, 38.6 +/- 4.8% (mean +/- S.D., n = 6) of the radiolabel was recovered in bile; the 0- to 5-h recovery was 42.3 +/- 4.3%.

Author(s): 
Maggs, J. L.
Bishop, L. P.
Edwards, G.
O'Neill, P. M.
Ward, S. A.
Winstanley, P. A.
Park, B. K.
Publication Title: 
Drug Metabolism and Disposition: The Biological Fate of Chemicals

The aim of this study was to elucidate the metabolic pathways for dihydroartemisinin (DHA), the active metabolite of the artemisinin derivative artesunate (ARTS). Urine was collected from 17 Vietnamese adults with falciparum malaria who had received 120 mg of ARTS i.v., and metabolites were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Human liver microsomes were incubated with [12-(3)H]DHA and cofactors for either glucuronidation or cytochrome P450-catalyzed oxidation. Human liver cytosol was incubated with cofactor for sulfation.

Author(s): 
Ilett, Kenneth F.
Ethell, Brian T.
Maggs, James L.
Davis, Timothy M. E.
Batty, Kevin T.
Burchell, Brian
Binh, Tran Quang
Thu, Le Thi Anh
Hung, Nguyen Canh
Pirmohamed, Munir
Park, B. Kevin
Edwards, Geoffrey
Publication Title: 
Molecules (Basel, Switzerland)

Gossypol, the polyphenolic constituent isolated from cottonseeds, has been used as a male antifertility drug for a long time, and has been demonstrated to exhibit excellent anti-tumor activity towards multiple cancer types. The toxic effects of gossypol limit its clinical utilization, and enzyme inhibition is an important facet of this. In the present study, in vitro human liver microsomal incubation system supplemented with UDPGA was used to investigate the inhibition of gossypol towards UGT1A1, 1A9 and 2B7-mediated metabolism of xenobiotics and endogenous substances.

Author(s): 
Zhang, Yong-sheng
Yuan, Jun
Fang, Zhong-Ze
Tu, Yan-yang
Hu, Cui-Min
Li, Gan
Wang, Liang
Deng, Jian-Ping
Yao, Jia-Jiu
Li, Hai-Rong
Publication Title: 
Xenobiotica; the Fate of Foreign Compounds in Biological Systems

Andrographolide is a major labdane diterpenoid of the traditional Chinese and Ayurvedic medicine. Andrographis paniculate (Burm) Nees, is used in clinical situations in China mainly to treat fever, cold, and inflammation. In our previous study, fifteen metabolites of andrographolide were identified in human urine. However, there are still two other unknown metabolites. The aim of this study was to elucidate the structures of these two metabolites. 3.

Author(s): 
Qiu, Feng
Cui, Liang
Chen, Lixia
Sun, Jiawen
Yao, Xinsheng
Publication Title: 
Drug Metabolism and Disposition: The Biological Fate of Chemicals

UDP-glucuronosyltransferase 2B7 (UGT2B7) is involved in the glucuronidation of a wide array of clinically important drugs and endogenous compounds in humans. The aim of this study was to identify an isoform-selective probe substrate that could be used to investigate genetic and environmental influences on glucuronidation mediated by UGT2B7. Three potential probe substrates [3'-azido-3'-deoxythymidine (AZT), morphine, and codeine], were evaluated using recombinant UGTs and human liver microsomes (HLMs; n = 54).

Author(s): 
Court, Michael H.
Krishnaswamy, Soundarajan
Hao, Qin
Duan, Su X.
Patten, Christopher J.
von Moltke, Lisa L.
Greenblatt, David J.
Publication Title: 
The Journal of Pharmacology and Experimental Therapeutics

Oxazepam is a commonly used 1,4-benzodiazepine anxiolytic drug that is polymorphically metabolized in humans. However, the molecular basis for this phenomenon is currently unknown. We have previously shown that S-oxazepam glucuronide, the major oxazepam metabolite, is selectively formed by UDP-glucuronosyltransferase (UGT) 2B15, whereas the minor R-oxazepam glucuronide is produced by multiple UGTs other than UGT2B15. Phenotype-genotype studies were conducted using microsomes and DNA prepared from the same set of 54 human livers.

Author(s): 
Court, Michael H.
Hao, Qin
Krishnaswamy, Soundararajan
Bekaii-Saab, Tanios
Al-Rohaimi, Abdul
von Moltke, Lisa L.
Greenblatt, David J.
Publication Title: 
The Journal of Pharmacology and Experimental Therapeutics

The objective of this study was to use recombinant enzymes and human liver microsomes (HLMs) to comprehensively evaluate the functional impact of the three most common nonsynonymous polymorphisms (S7A, T181A, and R184S) identified in the human UDP glucuronosyltransferase (UGT) 1A6 gene. In addition to the known allozymes, other possible amino acid variants were expressed in human embryonic kidney (HEK)293 cells to enable structure-function analysis.

Author(s): 
Krishnaswamy, Soundararajan
Hao, Qin
Al-Rohaimi, Abdul
Hesse, Leah M.
von Moltke, Lisa L.
Greenblatt, David J.
Court, Michael H.
Publication Title: 
The Journal of Pharmacology and Experimental Therapeutics

UDP glucuronosyltransferase (UGT) 1A6 is a major isoform in human liver that glucuronidates numerous drugs, toxins, and endogenous substrates with high interindividual variability. The molecular basis for this variability remains unknown, although it likely involves genetic and environmental factors. Phenotype-genotype studies were conducted using a well characterized human liver bank (n = 54) and serotonin glucuronidation as a UGT1A6-specific phenotype marker.

Author(s): 
Krishnaswamy, Soundararajan
Hao, Qin
Al-Rohaimi, Abdul
Hesse, Leah M.
von Moltke, Lisa L.
Greenblatt, David J.
Court, Michael H.
Publication Title: 
Pharmaceutical Research

PURPOSE: The absorption potential and metabolism of 8-prenylnaringenin (8-PN) from hops (Humulus lupulus L.) were investigated. 8-PN is a potent estrogen with the potential to be used for the relief of menopausal symptoms in women. METHODS: Monolayers of the human intestinal epithelial cancer cell line Caco-2 and human hepatocytes were incubated with 8-PN to model its intestinal absorption and hepatic metabolism, respectively.

Author(s): 
Nikolic, Dejan
Li, Yongmei
Chadwick, Lucas R.
van Breemen, Richard B.
Publication Title: 
The Journal of Nutrition

Ellagitannins (ETs) from pomegranate juice (PJ) are reported to have numerous biological properties, but their absorption and metabolism in humans are poorly understood. To investigate the pharmacokinetics of pomegranate ETs, 18 healthy volunteers were given 180 mL of PJ concentrate, and blood samples were obtained for 6 h afterwards. Twenty-four-hour urine collections were obtained on the day before (-1), the day of (0), and the day after (+1) the study.

Author(s): 
Seeram, Navindra P.
Henning, Susanne M.
Zhang, Yanjun
Suchard, Marc
Li, Zhaoping
Heber, David

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