Cytochrome P450 (CYP3A4, CYP2A6, CYP2C19, CYP2D6)의 약물대사에 대한 bupropion의 영향 = Effects of bupropion on oxidation metabolism catalyzed by human cytochrome P450 isoenzymes (CYP3A4, CYP2A6, CYP2C19 and CYP2D6)

다국어 초록 (Multilingual Abstract)

Background: Bupropion is an antidepressant and a non-nicotine aid used in smoking cessation. It blocks the neuronal uptake of serotonin and norepinephrine and inhibits the neuronal reuptake of dopamine. Although several in vitro study demonstrated that CYP2D6 activity was inhibited by
bupropion, there is no in vitro study that directly reports the inhibitory effects of bupropion on human major CYP isoforms. In the present study, we investigated the inhibitory effects and mechanism-based inactivation potencies of bupropion for human CYP2C19, CYP2D6, CYP2A6 and CYP3A4 activities.
Methods: In vitro study was performed using microsomes from baculovirus-infected insect cells expressing specific human CYP isoforms. The specific activities for human CYP isoforms included in this study were S-mephenytoin 4'-hydroxylation (CYP2C19), bufuralol 1'-hydroxylation (CYP2D6),
testosterone 6-hydroxylation (CYP3A4), and coumarin 7-hydroxylation (CYP2A6).
Results: Bupropion competitively inhibited S-mephenytoin 4'-hydroxylase (Ki = 1.631±0.544 μM) and bufuralol 1'-hydroxylase (Ki = 1.017±0.284 μM). The IC50 values for inhibition of CYP2C19 (coumarin, 1 μM) and CYP2D6 (bufuralol, 1 μM) index reaction by bupropion were 3.36 μM and 6.45 μM,
respectively. CYP3A4 and CYP2A6 activities were not significantly inhibited by bupropion. Furthermore, bupropion did not reveal a mechanism-based inactivation of CYP2C19 and CYP2D6. It was clearly shown that CYP2C19 and CYP2D6 were not inactivated by bupropion in a time and concentration
dependent manner.
Conclusions: Bupropion showed inhibitory effects on CYP2C19 and CYP2D6 activities. These results suggest that bupropion would affect the pharmacokinetics of clinically used drugs that are metabolized by CYP2C19 and CYP2D6.

다국어 초록 (Multilingual Abstract)

Background: Bupropion is an antidepressant and a non-nicotine aid used in smoking cessation. It blocks the neuronal uptake of serotonin and norepinephrine and inhibits the neuronal reuptake of dopamine. Although several in vitro study demonstrated that CYP2D6 activity was inhibited by
bupropion, there is no in vitro study that directly reports the inhibitory effects of bupropion on human major CYP isoforms. In the present study, we investigated the inhibitory effects and mechanism-based inactivation potencies of bupropion for human CYP2C19, CYP2D6, CYP2A6 and CYP3A4 activities.
Methods: In vitro study was performed using microsomes from baculovirus-infected insect cells expressing specific human CYP isoforms. The specific activities for human CYP isoforms included in this study were S-mephenytoin 4'-hydroxylation (CYP2C19), bufuralol 1'-hydroxylation (CYP2D6),
testosterone 6-hydroxylation (CYP3A4), and coumarin 7-hydroxylation (CYP2A6).
Results: Bupropion competitively inhibited S-mephenytoin 4'-hydroxylase (Ki = 1.631±0.544 μM) and bufuralol 1'-hydroxylase (Ki = 1.017±0.284 μM). The IC50 values for inhibition of CYP2C19 (coumarin, 1 μM) and CYP2D6 (bufuralol, 1 μM) index reaction by bupropion were 3.36 μM and 6.45 μM,
respectively. CYP3A4 and CYP2A6 activities were not significantly inhibited by bupropion. Furthermore, bupropion did not reveal a mechanism-based inactivation of CYP2C19 and CYP2D6. It was clearly shown that CYP2C19 and CYP2D6 were not inactivated by bupropion in a time and concentration
dependent manner.
Conclusions: Bupropion showed inhibitory effects on CYP2C19 and CYP2D6 activities. These results suggest that bupropion would affect the pharmacokinetics of clinically used drugs that are metabolized by CYP2C19 and CYP2D6.

참고문헌 (Reference)

1 Nakajima M, "Yamazaki H, Yokoi T. Isoform selective inhibition and inactivation of human cytochrome P450s by methylenedioxyphenyl compounds" 29 : 1191-1202, 1999

2 de Morais SM, "The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans" 269 : 15419-15422, 1994

3 Lynch T, "The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects" 76 : 391-396, 2007

4 Madeira M, "The effect of cimetidine on dextromethorphan O-demethylase activity of human liver microsomes and recombinant CYP2D6" 32 : 460-467, 2004

5 Caraballo RS, "Racial and ethnic differences in serum cotinine levels of cigarette smokers" 280 : 135-139, 1998

6 Cryan JF, "Non-nicotinic neuropharmacological strategies for nicotine dependence: beyond bupropion" 8 : 1025-1034, 2003

7 Kwon JT, "Nicotine metabolism and CYP2A6 allele frequencies in Koreans" 11 : 317-323, 2001

8 Kagimoto M, "Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes" 265 : 17209-17214, 1990

9 von Moltke LL, "Metabolism of drugs by cytochrome P450 3A isoforms. Implications for drug interactions in psychopharmacology" 29 : 33-44, 1995

10 Shimada T, "Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians" 270 : 414-423, 1994

11 Nakajima M, "Inhibitory effects of azelastine and its metabolites on drug oxidation catalyzed by human cytochrome P-450 enzyme" 27 : 792-797, 1999

12 Emoto C, "In vitro inhibitory effect of 1- aminobenzotriazole on drug oxidations catalyzed by human cytochrome P450 enzymes: a comparison with SKF-525A and ketoconazole" 18 : 287-295, 2003

13 Ko JW, "In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6" 49 : 343-351, 2000

14 Westlind-Johnsson A, "Identification and characterization of CYP3 A4*20, a novel rare CYP3A4 allele without functional activity" 79 : 339-349, 2006

15 Ingelman-Sundberg M, "Home page of the human cytochrome P450(CYP) allele nomenclature committee"

16 Dahl ML, "Genetically variable metabolism of antidepressants and neuroleptic drugs in man" 3 : 61-70, 1993

17 Furuta T, "Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pyroli infection and peptic ulcer" 129 : 1027-1030, 1998

18 Ioannides C, "Cytochromes P450 metabolic and toxicological aspects" CRC press 29-35, 1996

19 Nakajima M, "Comprehensive evaluation of variability in nicotine metabolism and CYP2A6 polymorphic alleles in four ethnic populations" 80 : 282-297, 2006

20 Nebert DW, "Clinical importance of the cytochrome P450" 360 : 1155-1162, 2002

21 Buchert E, "Clinical implications of variable antiarrhythmic drug metabolism" 2 : 2-11, 1992

22 Guzey C, "Change from the CYP2D6 extensive metabolizer to the poor metabolizer phenotype during treatment with bupropion" 24 : 436-437, 2002

23 Hoover CA, "Cardiac arrest associated with combination cisapride and itraconazole therapy" 1 : 255-258, 1996

24 Roh HK, "CYP2C19 genotype and phenotype determined by omeprazole in a Korean population" 6 : 547-551, 1996

25 Hesse LM, "CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants" 28 : 1176-1183, 2000

26 Ereshefsky L, "Antidepressant drug interactions and the cytochrome P450 system. The role of cytochrome P450 2D6" 29 : 10-19, 1995

27 Ohyama K, "A significant role of human cytochrome P450 2C8 in amiodarone N-diethylation: approach to predict the contribution with relative activity factor" 28 : 1303-1310, 2000

28 Nunoya KI, "A new CYP2A6 gene deletion responsible for the In vivo polymorphic metabolism of (+)- cis-3,5-dimethyl-2-(3-pyridyl) thiazolidin-4- one hydrochloride in humans" 289 : 437-442, 1999

29 Hurt RD, "A comparison of sustained-release bupropion and placebo for smoking cessation" 337 : 1195-1202, 1997