Regio- and stereospecific N-glucuronidation of medetomidine: The differences between UDP glucuronosyltransferase (UGT) 1A4 and UGT2B10 account for the complex kinetics of human liver microsomes

Drug Metabolism and Disposition

Volumn 36, Issue 8, 2008, Pages 1529-1537

  Kaivosaari, Sanna ^a,b   Toivonen, Päivi ^a,b   Aitio, Olli ^c   Sipilä, Julius ^a,b   Koskinen, Mikko ^a   Salonen, Jarmo S ^a   Finel, Moshe ^b  

^a ORION CORPORATION   (Finland)

^b UNIVERSITY OF HELSINKI   (Finland)

^c UNIVERSITY OF HELSINKI   (Finland)

Author keywords

[No Author keywords available]

Indexed keywords

ALAMETHICIN; DEXMEDETOMIDINE; DEXMEDETOMIDINE DG1; DEXMEDETOMIDINE DG2; GLUCURONOSYLTRANSFERASE; GLUCURONOSYLTRANSFERASE 1A4; GLUCURONOSYLTRANSFERASE 2B10; LEVOMEDETOMIDINE; MEDETOMIDINE; MEDETOMIDINE DERIVATIVE;

ANIMAL CELL; ANIMAL TISSUE; ARTICLE; BINDING AFFINITY; BINDING KINETICS; CATALYSIS; CHEMICAL REACTION KINETICS; CHIRALITY; CONTROLLED STUDY; DOG; DRUG GLUCURONIDATION; DRUG PURIFICATION; ELUTION; ENANTIOMER; ENANTIOSELECTIVITY; ENZYME KINETICS; ENZYME SPECIFICITY; ENZYME SUBSTRATE COMPLEX; GUINEA PIG; HUMAN; HUMAN CELL; HUMAN TISSUE; LIQUID CHROMATOGRAPHY; LIVER METABOLISM; LIVER MICROSOME METABOLISM; MINIPIG; MONKEY; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTON NUCLEAR MAGNETIC RESONANCE; RABBIT; RACEMIC MIXTURE; RAT; STEREOSPECIFICITY;

ADRENERGIC ALPHA-AGONISTS; ANALGESICS, NON-NARCOTIC; CHROMATOGRAPHY, LIQUID; GLUCURONIDES; GLUCURONOSYLTRANSFERASE; HUMANS; ISOENZYMES; MAGNETIC RESONANCE SPECTROSCOPY; MASS SPECTROMETRY; MEDETOMIDINE; MICROSOMES, LIVER; RECOMBINANT PROTEINS; SPECTROPHOTOMETRY, ULTRAVIOLET;

EID: 47949097984     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.108.021709     Document Type: Article

References (33)

1. Ansah OB, Raekallio M, and Vainio O (2000) Correlation between serum concentrations following continuous intravenous infusion of dexmedetomidine or medetomidine in cats and their sedative and analgesic effects. J Vet Pharmacol Ther 23:1-8.
2. Bhana N, Goa KL, and McClellan KJ (2000) Dexmedetomidine. Drugs 59:263-268.
3. Borlak J, Gasparic A, Locher M, Schupke H, and Hermann R (2006) N-glucuronidation of the antiepileptic drug retigabine: results from studies with human volunteers, heterologously expressed human UGTs, human liver, kidney, and liver microsomal membranes of Crigler-Najjar type II. Metab Clin Exp 55:711-721.
4. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye-binding. Anal Biochem 72:248-254.
5. Breyer-Pfaff U, Mey U, Green MD, and Tephly TR (2000) Comparative N-glucuronidation kinetics of ketotifen and amitriptyline by expressed human UDP-glucuronosyltransferases and liver microsomes. Drug Metab Dispos 28:869-872.
6. Chen G, Blevins-Primeau AS, Dellinger RW, Muscat JE, and Lazarus P (2007) Glucuronidation of nicotine and cotinine by UGT2B10: loss of function by the UGT2B10 Codon 67 (Asp>Tyr) polymorphism. Cancer Res 67:9024-9029.
7. Cornish-Bowden A (1995) Fundamentals of Enzyme Kinetics, revised ed. Portland Press, London, UK.
8. Fisher MB, Campanale K, Ackermann BL, VandenBranden M, and Wrighton SA (2000) In vitro glucuronidation using human liver microsomes and the pore-forming peptide alamethicin. Drug Metab Dispos 28:560-566.
9. Girard H, Thibaudeau J, Court MH, Fortier LC, Villeneuve L, Caron P, Hao Q, von Moltke LL, Greenblatt DJ, and Guillemette C (2005) UGT1A1 polymorphisms are important determinants of dietary carcinogen detoxification in the liver. Hepatology 42:448-457.
10. Green MD and Tephly TR (1998) Glucuronidation of amine substrates by purified and expressed UDP-glucuronosyltransferase proteins. Drug Metab Dispos 26:860-867.
11. +-Glucuronidation, a common pathway in human metabolism of drugs with a tertiary amine group. Drug Metab Dispos 26:830-837.
12. Houston JB and Kenworthy KE (2000) In vitro-in vivo scaling of CYP kinetic data not consistent with the classical Michaelis-Menten model. Drug Metab Dispos 28:246-254.
13. Ji QC, Zhou JY, Gonzales RJ, Gage EM, and El-Shourbagy TA (2004) Simultaneous quantitation of dexmedetomidine and glucuronide metabolites (G-Dex-1 and G-Dex-2) in human plasma utilizing liquid chromatography with tandem mass spectrometric detection. Rapid Commun Mass Spectrom 18:1753-1760.
14. Kaivosaari S, Salonen JS, Mortensen J, and Taskinen J (2001) High-performance liquid chromatographic method combining radiochemical and ultraviolet detection for determination of low activities of uridine 5′-diphosphate-glucuronosyltransferase. Anal Biochem 292:178-187.
15. Kaivosaari S, Salonen JS, and Taskinen J (2002) N-glucuronidation of some 4-arylalkyl-1H-imidazoles by rat, dog, and human liver microsomes. Drug Metab Dispos 30:295-300.
16. Kaivosaari S, Toivonen P, Hesse LM, Koskinen M, Court MH, and Finel M (2007) Nicotine glucuronidation and the human UDP-glucuronosyltransferase UGT2B10. Mol Pharmacol 72:761-768.
17. Kaji H and Kume T (2005) Characterization of afloqualone N-glucuronidation: species differences and identification of human UDP-glucuronosyltransferase isoform (s). Drug Metab Dispos 33:60-67.
18. Kuehl GE and Murphy SE (2003) N-glucuronidation of nicotine and cotinine by human liver microsomes and heterologously expressed UDP-glucuronosyltransferases. Drug Metab Dispos 31:1361-1368.
19. Kurkela M, Garcia-Horsman JA, Luukkanen L, Morsky S, Taskinen J, Baumann M, Kostiainen R, Hirvonen J, and Finel M (2003) Expression and characterization of recombinant human UDP-glucuronosyltransferases (UGTs). UGT1A9 is more resistant to detergent inhibition than other UGTs and was purified as an active dimeric enzyme. J Biol Chem 278:3536-3544.
20. Kurkela M, Patana AS, Mackenzie PI, Court MH, Tate CG, Hirvonen J, Goldman A, and Finel M (2007) Interactions with other human UDP- glucuronosyltransferases attenuate the consequences of the Y485D mutation on the activity and substrate affinity of UGT1A6. Pharmacogenet Genomics 17:115-126.
21. Kuusela E, Raekallio M, Anttila M, Falck I, MölsäS, and Vainio O (2000) Clinical effects and pharmacokinetics of medetomidine and its enantiomers in dogs. J Vet Pharmacol Ther 23:15-20.
22. MacDonald E, Scheinin M, Scheinin H, and Virtanen R (1991) Comparison of the behavioral and neurochemical effects of the two optical enantiomers of medetomidine, a selective alpha-2-adrenoceptor agonist. J Pharmacol Exp Ther 259:848-854.
23. Mackenzie PI, Gregory PA, Gardner-Stephen DA, Lewinsky RH, Jorgensen BR, Nishiyama T, Xie W, and Radominska-Pandya A (2003) Regulation of UDP glucuronosyltransferase genes. Curr Drug Metab 4:249-257.
24. Mackenzie PI, Walter Bock K, Burchell B, Guillemette C, Ikushiro S, Iyanagi T, Miners JO, Owens IS, and Nebert DW (2005) Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily. Pharmacogenet Genomics 15:677-685.
25. Nakajima M, Tanaka E, Kobayashi T, Ohashi N, Kume T, and Yokoi T (2002) Imipramine N-glucuronidation in human liver microsomes: biphasic kinetics and characterization of UDP-glucuronosyltransferase isoforms. Drug Metab Dispos 30:636-642.
26. Omura K, Nakazawa T, Sato T, Iwanaga T, and Nagata O (2007) Characterization of Nglucuronidation of 4-(5-pyridin-4-yl-1H-[1,2, 4]triazol-3-yl) pyridine-2-carbonitrile (FYX-051): a new xanthine oxidoreductase inhibitor. Drug Metab Dispos 35:2143-2148.
27. Radominska-Pandya A, Czernik PJ, Little JM, Battaglia E, and Mackenzie PI (1999) Structural and functional studies of UDP-glucuronosyltransferases. Drug Metab Rev 31:817-899.
28. Rowland A, Elliot DJ, Williams JA, Mackenzie PI, Dickinson RG, and Miners JO (2006) In vitro characterization of lamotrigine N2-glucuronidation and the lamotrigine-valproic acid interaction. Drug Metab Dispos 34:1055-1062.
29. Savola JM and Virtanen R (1991) Central alpha 2-adrenoceptors are highly stereoselective for dexmedetomidine, the dextro enantiomer of medetomidine. Eur J Pharmacol 195:193-199.
30. Staines AG, Coughtrie MW, and Burchell B (2004) N-glucuronidation of carbamazepine in human tissues is mediated by UGT2B7. J Pharmacol Exp Ther 311:1131-1137.
31. Tukey RH and Strassburg CP (2000) Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 40:581-616.
32. Wells PG, Mackenzie PI, Chowdhury JR, Guillemette C, Gregory PA, Ishii Y, Hansen AJ, Kessler FK, Kim PM, Chowdhury NR, et al. (2004) Glucuronidation and the UDP-glucuronosyltransferases in health and disease. Drug Metab Dispos 32:281-290.
33. Zenser TV, Lakshmi VM, Hsu FF, and Davis BB (2002) Metabolism of N-acetylbenzidine and initiation of bladder cancer. Mutat Res 506-507:29-40.