Glucuronidation of the second-generation antipsychotic clozapine and its active metabolite N-desmethylclozapine. Potential importance of the UGT1A1 A(TA)7TAA and UGT1A4 L48V polymorphisms

Pharmacogenetics and Genomics

Volumn 22, Issue 8, 2012, Pages 561-576

  Erickson Ridout, Kathryn K ^a   Sun, Dongxiao ^a   Lazarus, Philip ^a,b  

^a PENN STATE COLLEGE OF MEDICINE   (United States)

^b PENN STATE CANCER INSTITUTE   (United States)

Author keywords

clozapine; drug metabolism; N desmethylclozapine; UGT1A1; UGT1A4; uridine diphosphate glucuronosyltransferases; variant alleles

Indexed keywords

CLOZAPINE; GLUCURONOSYLTRANSFERASE 1A1; GLUCURONOSYLTRANSFERASE 1A10; GLUCURONOSYLTRANSFERASE 1A3; GLUCURONOSYLTRANSFERASE 1A4; GLUCURONOSYLTRANSFERASE 1A6; GLUCURONOSYLTRANSFERASE 1A7; GLUCURONOSYLTRANSFERASE 1A9; GLUCURONOSYLTRANSFERASE 2B7; NORCLOZAPINE;

ARTICLE; CONTROLLED STUDY; DRUG GLUCURONIDATION; DRUG MECHANISM; ENZYME ACTIVITY; GENETIC VARIABILITY; HUMAN; HUMAN CELL; HUMAN TISSUE; LIVER MICROSOME; MISSENSE MUTATION; PHARMACOGENETICS; PRIORITY JOURNAL; PROTEIN EXPRESSION; SINGLE NUCLEOTIDE POLYMORPHISM;

EID: 85027939338     PISSN: 17446872     EISSN: 17446880     Source Type: Journal    
DOI: 10.1097/FPC.0b013e328354026b     Document Type: Article

References (60)

1. FDA. Electronic Orange Book. Silver Spring, MD: U.S. Department of Health & Human Services; 2009. Available at: http://www.accessdata.fda.gov/ scripts/cder/ob/default.cfm [Accessed 6 October 2009].
2. Swartz MS, Perkins KO, Stroup TS, Davis SM, Capuano G, Rosenheck RA, et al. Effects of antipsychotic medications on psychosocial functioning in patients with chronic schizophrenia: findings from the NIMH CATIE study. Am J Psychiatry 2007; 164:428-436. (Pubitemid 46513156)
3. Swartz MS, Stroup TS, McEvoy JP, Davis SM, Rosenheck RA, Keefe RSE, et al. What CATIE found: results from the schizophrenia trial. Psychiatr Serv 2008; 59:500-506.
4. American Psychiatric Association. Practice guidelines for the treatment of patients with schizophrenia 2004. Available at: http://psychiatryonline.org/ content.aspx?bookid =28§ionid = 1665359#45892 [Accessed 10 January 2011].
5. Gothelf DFB, Falk B, Singer P, Kairi M, Phillip M, Zigel L, et al. Weight gain associated with increased food intake and low habitual activity levels in male adolescent schizophrenic inpatients treated with olanzapine. Am J Psychiatry 2002; 159:1055-1057. (Pubitemid 34586957)
6. Kinon BJBB, Gilmore JA, Tollefson GD. Longterm olanzapine treatment: weight change and weight-related health factors in schizophrenia. J Clin Psychiatry 2001; 62:92-100. (Pubitemid 32199865)
7. Wirshing DAWW, Kysar L, Berisford MA, Goldstein D, Pashdag J, et al. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry 1999; 60:358-363. (Pubitemid 29289721)
8. Parsons B, Allison DB, Loebel A, Williams K, Giller E, Romano S, et al. Weight effects associated with antipsychotics: a comprehensive database analysis. Schizophr Res 2009; 110:103-110.
9. Rosenheck RA, Davis S, Covell N, Essock S, Swartz M, Stroup S, et al. Does switching to a new antipsychotic improve outcomes? Data from the CATIE Trial. Schizophr Res 2009; 107:22-29.
10. Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Duggan L, et al. Olanzapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 2010; 3:CD006654.
11. Monteleone P, Martiadis V, Maj M. Management of schizophrenia with obesity, metabolic, and endocrinological disorders. Psychiatr Clin North Am 2009; 32:775-794.
12. Laurent S, Boutouyrie P. Arterial stiffness and stroke in hypertension: therapeutic implications for stroke prevention. CNS Drugs 2005; 19:1-11. (Pubitemid 40165153)
13. Asenjo Lobos C, Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, et al. Clozapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 2010; 10:CD006633.
14. Rostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J Clin Psychopharmacol 2004; 24:70-78. (Pubitemid 38134168)
15. Spina E, Avenoso A, Facciolà G, Scordo MG, Ancione M, Madia AG, et al. Relationship between plasma concentrations of clozapine and norclozapine and therapeutic response in patients with schizophrenia resistant to conventional neuroleptics. Psychopharmacology 2000; 148:83-89. (Pubitemid 30062476)
16. Raedler TJ, Hinkelmann K,Wiedemann K. Variability of the in vivo metabolism of clozapine. Clin Neuropharmacol 2008; 31:347-352.
17. Hiemke C, Dragicevic A, Grü nder G, Hä tter S, Sachse J, Vernaleken I, et al. Therapeutic monitoring of new antipsychotic drugs. Ther Drug Monit 2004; 26:156-160. (Pubitemid 38501210)
18. Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999; 286:487-491.
19. Chen G, Giambrone NE, Dluzen DF, Muscat JE, Berg A, Gallagher CJ, et al. Glucuronidation genotypes and nicotine metabolic phenotypes: importance of functional UGT2B10 and UGT2B17 polymorphisms. Cancer Res 2010; 70:7543-7552.
20. Dain JG, Nicoletti J, Ballard F. Biotransformation of clozapine in humans. Drug Metab Dispos 1997; 25:603-609. (Pubitemid 27213102)
21. Schaber G,Wiatr G,Wachsmuth H, Dachtler M, Albert K, Gaertner I, et al. Isolation and identification of clozapine metabolites in patient urine. Drug Metabol Dispos 2001; 29:923-931. (Pubitemid 32488652)
22. Erickson-Ridout KK, Zhu J, Lazarus P. Olanzapine metabolism and the significance of UGT1A448V and UGT2B1067Y variants. Pharmacogenet Genomics 2011; 21:539-551.
23. Andersson ML, Bjorkhem-Bergman L, Lindh JD. Possible drug-drug interaction between quetiapine and lamotrigine-evidence from a Swedish TDM database. Br J Clin Pharmacol 2011; 72:153-156.
24. Van de Wetering-Krebbers SF, Jacobs PL, Kemperman GJ, Spaans E, Peeters PA, Delbressine LP, et al. Metabolism and excretion of asenapine in healthy male subjects. Drug Metabol Dispos 2011; 39:580-590.
25. Breyer-Pfaff U, Wachsmuth H. Tertiary N-glucuronides of clozapine and its metabolite desmethylclozapine in patient urine. Drug Metabol Dispos 2001; 29:1343-1348. (Pubitemid 32896585)
26. Mori A, Maruo Y, Iwai M, Sato H, Takeuchi Y. UDP-Glucuronosyltransferase 1A4 polymorphisms in a Japanese population and kinetics of clozapine glucuronidation. Drug Metabol Dispos 2005; 33:672-675. (Pubitemid 40593882)
27. Wiener D, Doerge DR, Fang JL, Upadhyaya P, Lazarus P. Characterization of N-glucuronidation of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanol (NNAL) in human liver: importance of UDPglucuronosyltransferase 1A4. Drug Metabol Dispos 2004; 32:72-79. (Pubitemid 38112538)
28. Sun D, Chen G, Dellinger RW, Sharma AK, Lazarus P. Characterization of 17-dihydroexemestane glucuronidation: potential role of the UGT2B17 deletion in exemestane pharmacogenetics. Pharmacogenet Genomics 2010; 20:575-585.
29. Coughtrie MW, Burchell B, Bend JR. A general assay for UDPglucuronosyltransferase activity using polar amino-cyano stationary phase HPLC and UDP[U-14C]glucuronic acid. Anal Biochem 1986; 159:198-205. (Pubitemid 17228246)
30. Chen G, Dellinger RW, Gallagher CJ, Sun D, Lazarus P. Identification of a prevalent functional missense polymorphism in the UGT2B10 gene and its association with UGT2B10 inactivation against tobacco-specific nitrosamines. Pharmacogenet Genomics 2008; 18:181-191. (Pubitemid 351323232)
31. Chen G, Dellinger RW, Sun D, Spratt TE, Lazarus P. Glucuronidation of tobacco-specific nitrosamines by UGT2B10. Drug Metabol Dispos 2008; 36:824-830. (Pubitemid 351574879)
32. Ren Q, Murphy SE, Zheng Z, Lazarus P. O-Glucuronidation of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by human UDP-glucuronosyltransferases 2B7 and 1A9. Drug Metabol Dispos 2000; 28:1352-1360.
33. Dellinger RW, Fang JL, Chen G,Weinberg R, Lazarus P. Importance of UDPglucuronosyltransferase 1A10 (UGT1A10) in the detoxification of polycyclic aromatic hydrocarbons: decreased glucuronidative activity of the UGT1A10 139Lys isoform. Drug Metabol Dispos 2006; 34:943-949. (Pubitemid 43763749)
34. Sun D, Chen G, Dellinger RW, Duncan K, Fang JL, Lazarus P. Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants. Breast Cancer Res 2006; 8:R50.
35. Lazarus P, Blevins Primeau AS, Zheng Y, Sun D. Potential role of UGT pharmacogenetics in cancer treatment and prevention: focus on tamoxifen. Ann N Y Acad Sci 2009; 1155:99-111.
36. Blevins-Primeau AS, Sun D, Chen G, Sharma AK, Gallagher CJ, Amin S, et al. Functional significance of UDP-glucuronosyltransferase variants in the metabolism of active tamoxifen metabolites. Cancer Res 2009; 69:1892-1900.
37. Fang JL, Lazarus P. Correlation between the UDP-glucuronosyltransferase (UGT1A1) TATAA box polymorphism and carcinogen detoxification phenotype: significantly decreased glucuronidating activity against benzo(a)pyrene-7,8- dihydrodiol(-) in liver microsomes from subjects with the UGT1A1*28 variant. Cancer Epidemiol Biomarkers Prev 2004; 13:102-109. (Pubitemid 38116627)
38. Gallagher CJ, Muscat JE, Hicks AN, Zheng Y, Dyer A-M, Chase GA, et al. The UDP-glucuronosyltransferase 2B17 gene deletion polymorphism: sexspecific association with urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol glucuronidation phenotype and risk for lung cancer. Cancer Epidemiol Biomarkers Prev 2007; 16:823-828. (Pubitemid 46650589)
39. Uchaipichat V, Mackenzie PI, Elliot DJ, Miners JO. Selectivity of substrate (trifluoperazine) and inhibitor (amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone) "probes" for human UDP-glucuronosyltransferases. Drug Metabol Dispos 2006; 34:449-456.
40. Miners JO, Bowalgaha K, Elliot DJ, Baranczewski P, Knights KM. Characterization of niflumic acid as a selective inhibitor of human liver microsomal UDP-glucuronosyltransferase 1A9: application to the reaction phenotyping of acetaminophen glucuronidation. Drug Metabol Dispos 2011; 39:644-652.
41. Devane CL, Markowitz JS. Antipsychotics. In: Levy RH, Thummel K, TragerW, et al., editors. Metabolic drug interactions. Philadelphia: LippincottWilliams & Wilkins. 2000. pp. 245-259.
42. Green MD, King CD, Mojarrabi B, Mackenzie PI, Tephly TR. Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDPglucuronosyltransferase 1A3. Drug Metabol Dispos 1998; 26:507-512. (Pubitemid 28498354)
43. Green MD, Tephly TR. Glucuronidation of amines and hydroxylated xenobiotics and endobiotics catalyzed by expressed human UGT1.4 protein. Drug Metabol Dispos 1996; 24:356-363. (Pubitemid 26089830)
44. Luo H, McKay G, Midha KK. Identification of clozapine N(+)-glucuronide in the urine of patients treated with clozapine using electrospray mass spectrometry. Biol Mass Spectrom 1994; 23:147-148.
45. Ehmer U, Vogel A, Schü tte JK, Krone B, Manns MP, Strassburg CP. Variation of hepatic glucuronidation: novel functional polymorphisms of the UDPglucuronosyltransferase UGT1A4. Hepatology 2004; 39:970-977. (Pubitemid 38428936)
46. Wiener D, Fang JL, Dossett N, Lazarus P. Correlation between UDPglucuronosyltransferase genotypes and 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone glucuronidation phenotype in human liver microsomes. Cancer Res 2004; 64:1190-1196. (Pubitemid 38176928)
47. Saeki M, Saito Y, Jinno H, Sai K, Hachisuka A, Kaniwa N, et al. Genetic variations and haplotypes of UGT1A4 in a Japanese population. Drug Metab Pharmacokinet 2005; 20:144-151.
48. Gulcebi MI, Ozkaynakci A, Goren MZ, Aker RG, Ozkara C, Onat FY. The relationship between UGT1A4 polymorphism and serum concentration of lamotrigine in patients with epilepsy. Epilepsy Res 2011; 95:1-8.
49. Izukawa T, Nakajima M, Fujiwara R, Yamanaka H, Fukami T, Takamiya M, et al. Quantitative analysis of UDP-glucuronosyltransferase (UGT) 1A and UGT2B expression levels in human livers. Drug Metabol Dispos 2009; 37:1759-1768.
50. Ohno S, Nakajin S. Determination of mRNA expression of human UDPglucuronosyltransferases and application for localization in various human tissues by real-time reverse transcriptase-polymerase chain reaction. Drug Metabol Dispos 2009; 37:32-40.
51. Guillemette C. Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J 2003; 3:136-158. (Pubitemid 36850156)
52. Ghotbi R, Mannheimer B, Aklillu E, Suda A, Bertilsson L, Eliasson E, et al. Carriers of the UGT1A4 142T G gene variant are predisposed to reduced olanzapine exposure-an impact similar to male gender or smoking in schizophrenic patients. Eur J Clin Pharmacol 2010; 66:465-474.
53. Mori A, Maruo Y, Iwai M, Sato H, Takeuchi Y. UDP-glucuronosyltransferase 1A4 polymorphisms in a Japanese population and kinetics of clozapine glucuronidation. Drug Metab Dispos 2005; 33:672-675. (Pubitemid 40593882)
54. Li Z, Huang M, Ichikawa J, Dai J, Meltzer HY. N-desmethylclozapine, a major metabolite of clozapine, increases cortical acetylcholine and dopamine release in vivo via stimulation of M1 muscarinic receptors. Neuropsychopharmacology 2005; 30:1986-1995. (Pubitemid 43093499)
55. Lameh J, Burstein ES, Taylor E,Weiner DM, Vanover KE, Bonhaus DW. Pharmacology of N-desmethylclozapine. Pharmacol Ther 2007; 115:223-231. (Pubitemid 47042913)
56. Sur C, Mallorga PJ, Wittmann M, Jacobson MA, Pascarella D, Williams JB, et al. N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity. Proc Natl Acad Sci USA 2003; 100:13674-13679. (Pubitemid 37444798)
57. Couchman L, Morgan PE, Spencer EP, Flanagan RJ. Plasma clozapine, norclozapine, and the clozapine: norclozapine ratio in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 1993-2007. Ther Drug Monit 2010; 32:438-447.
58. Williams DP, Pirmohamed M, Naisbitt DJ, Uetrecht JP, Park BK. Induction of metabolism-dependent and-independent neutrophil apoptosis by clozapine. Mol Pharmacol 2000; 58:207-216. (Pubitemid 30452544)
59. Williams DP, Pirmohamed M, Naisbitt DJ, Maggs JL, Park BK. Neutrophil cytotoxicity of the chemically reactive metabolite(s) of clozapine: possible role in agranulocytosis. J Pharmacol Exp Ther 1997; 283:1375-1382. (Pubitemid 28016513)
60. Maggs JL,Williams D, Pirmohamed M, Park BK. The metabolic formation of reactive intermediates from clozapine, a drug associated with agranulocytosis in man. J Pharmacol Exp Ther 1995; 275:1463-1475.