![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Department of Pharmacology (C.D.K., G.R.R., M.D.G., T.R.T.),
University of Iowa; and
Department of Clinical Pharmacology (P.I.M.),
Flinders Medical Center
Opioids are important drugs used as analgesics, antitussives,
antidiarrheals, and in the therapy of myocardial infarctions, and as
antagonists of opioid intoxication. The glucuronidation of these
compounds, catalyzed by UDP-glucuronosyltransferases (UGTs), is well
known to be a primary step in their metabolism to hydrophilic products
and in their ultimate excretion. The present study was designed to
compare the reactivity and relative glucuronidation efficiencies of
opioid agonists, antagonists, and partial agonists with two rat UGT
isoforms; UGT1.1, which is generally considered the "bilirubin
UGT," and UGT2B1, which has previously been shown to catalyze the
glucuronidation of testosterone, chloramphenicol, and (
)-morphine.
Rat UGT2B1, stably expressed in HK293 cells, exhibited high
glucuronidation rates and catalytic efficiencies for many opioids,
although values for ()-morphine and nalorphine were the highest. In
contrast, these compounds were very poor substrates for expressed rat
UGT1.1. Comparably high glucuronidation rates and efficiencies were
found for buprenorphine and diprenorphine with both UGT isoforms. These
results suggest that opioids with morphinan-based chemical structures
similar to ()-morphine interact with UGTs differently than those with
oripavine-based chemical structures similar to buprenorphine. To
investigate the contribution of rat UGT1.1 and UGT2B1 in the overall
rate of glucuronidation of buprenorphine in the rat liver, hepatic
microsomes from Gunn rats (where UGT1.1 activity is absent) and Wistar
rats (where UGT1.1 activity is present) were studied. Buprenorphine
glucuronidation activity in Gunn rat liver microsomes exhibit ~25%
of rates observed in Wistar rat liver microsomes, whereas
()-morphine, naloxone, and naltrexone glucuronidation rates were not
significantly different in microsomal preparations from Gunn and Wistar
rats. These data suggest that UGT2B1 is the major hepatic enzyme
involved in the glucuronidation of ()-morphine and naloxone in livers
from untreated rats, whereas buprenorphine glucuronidation is
preferentially catalyzed by rat UGT1.1.
This article has been cited by other articles:
|
|
 |
|
  L. Xu, D. M. Krenitsky, A. M. Seacat, J. L. Butenhoff, T. R. Tephly, and M. W. Anders N-GLUCURONIDATION OF PERFLUOROOCTANESULFONAMIDE BY HUMAN, RAT, DOG, AND MONKEY LIVER MICROSOMES AND BY EXPRESSED RAT AND HUMAN UDP-GLUCURONOSYLTRANSFERASES Drug Metab. Dispos., August 1, 2006; 34(8): 1406 - 1410. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Doherty, K. Poon, C. Tsang, and K. S. Pang Transport Is Not Rate-Limiting in Morphine Glucuronidation in the Single-Pass Perfused Rat Liver Preparation J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 890 - 900. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Yu, J. K. Ritter, R. J. Krieg, B. Rege, T. H. Karnes, and M. A. Sarkar EFFECT OF CHRONIC RENAL INSUFFICIENCY ON HEPATIC AND RENAL UDP-GLUCURONYLTRANSFERASES IN RATS Drug Metab. Dispos., April 1, 2006; 34(4): 621 - 627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kaji and T. Kume REGIOSELECTIVE GLUCURONIDATION OF DENOPAMINE: MARKED SPECIES DIFFERENCES AND IDENTIFICATION OF HUMAN UDP-GLUCURONOSYLTRANSFERASE ISOFORM Drug Metab. Dispos., March 1, 2005; 33(3): 403 - 412. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Wiener, D. R. Doerge, J.-L. Fang, P. Upadhyaya, and P. Lazarus CHARACTERIZATION OF N-GLUCURONIDATION OF THE LUNG CARCINOGEN 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANOL (NNAL) IN HUMAN LIVER: IMPORTANCE OF UDP-GLUCURONOSYLTRANSFERASE 1A4 Drug Metab. Dispos., January 1, 2004; 32(1): 72 - 79. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Nagar, R. P. Remmel, R. P. Hebbel, and C. L. Zimmerman METABOLISM OF OPIOIDS IS ALTERED IN LIVER MICROSOMES OF SICKLE CELL TRANSGENIC MICE Drug Metab. Dispos., January 1, 2004; 32(1): 98 - 104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-L. Fang, F. A. Beland, D. R. Doerge, D. Wiener, C. Guillemette, M. M. Marques, and P. Lazarus Characterization of Benzo(a)pyrene-trans-7,8-dihydrodiol Glucuronidation by Human Tissue Microsomes and Overexpressed UDP-glucuronosyltransferase Enzymes Cancer Res., April 1, 2002; 62(7): 1978 - 1986. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. King, W. Tang, J. Ngui, T. Tephly, and M. Braun Characterization of Rat and Human UDP-Glucuronosyltransferases Responsible for the in Vitro Glucuronidation of Diclofenac Toxicol. Sci., May 1, 2001; 61(1): 49 - 53. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Innocenti, L. Iyer, J. Ramírez, M. D. Green, and M. J. Ratain Epirubicin Glucuronidation Is Catalyzed by Human UDP-Glucuronosyltransferase 2B7 Drug Metab. Dispos., April 13, 2001; 29(5): 686 - 692. [Abstract] [Full Text]
|
|
|
|
|
|
Q. Ren, S. E. Murphy, Z. Zheng, and P. Lazarus O-Glucuronidation of the Lung Carcinogen 4-(methylnitrosamino)-1- (3-Pyridyl)-1-Butanol (nnal) by Human Udp-Glucuronosyltransferases 2b7 and 1a9 Drug Metab. Dispos., November 1, 2000; 28(11): 1352 - 1360. [Abstract] [Full Text]
|
|
|
|
|
|
Q. Ren, S. E. Murphy, A. J. Dannenberg, J. Y. Park, T. R. Tephly, and P. Lazarus Glucuronidation of the Lung Carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by Rat UDP-Glucuronosyltransferase 2B1 Drug Metab. Dispos., September 1, 1999; 27(9): 1010 - 1016. [Abstract] [Full Text]
|
|
|
|
|
|
M. D. Green and T. R. Tephly Glucuronidation of Amine Substrates by Purified and Expressed UDP-Glucuronosyltransferase Proteins Drug Metab. Dispos., September 1, 1998; 26(9): 860 - 867. [Abstract] [Full Text]
|
|
|
|
|
|
B. L. Coffman, C. D. King, G. R. Rios, and T. R. Tephly The Glucuronidation of Opioids, Other Xenobiotics, and Androgens by Human UGT2B7Y(268) and UGT2B7H(268) Drug Metab. Dispos., January 1, 1998; 26(1): 73 - 77. [Abstract] [Full Text]
|
|
|
|
|
|
M. D. Green, G. Bélanger, D. W. Hum, A. Bélanger, and T. R. Tephly Glucuronidation of Opioids, Carboxylic Acid-Containing Drugs, and Hydroxylated Xenobiotics Catalyzed by Expressed Monkey UDP-Glucuronosyltransferase 2B9 Protein Drug Metab. Dispos., December 1, 1997; 25(12): 1389 - 1394. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
