![[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}
|
|
|
|
|
||
Vol. 28, Issue 10, 1176-1183, October 2000
Department of Pharmacology and Experimental Therapeutics, Tufts
University School of Medicine, and the Division of Clinical
Pharmacology, New England Medical Center, Boston, Massachusetts
The in vitro biotransformation of bupropion to hydroxybupropion was
studied in human liver microsomes and microsomes containing heterologously expressed human cytochromes P450 (CYP). The mean (±S.E.) Km in four human liver microsomes
was 89 (±14) µM. In microsomes containing cDNA-expressed CYPs,
hydroxybupropion formation was mediated only by CYP2B6 at 50 µM
bupropion (Km 85 µM). A CYP2B6 inhibitory
antibody produced more than 95% inhibition of bupropion hydroxylation
in four human livers. Bupropion hydroxylation activity at 250 µM was
highly correlated with S-mephenytoin
N-demethylation activity (yielding nirvanol), another
CYP2B6-mediated reaction, in a panel of 32 human livers
(r = 0.94). The CYP2B6 content of 12 human livers
highly correlated with bupropion hydroxylation activity
(r = 0.96). Thus bupropion hydroxylation is
mediated almost exclusively by CYP2B6 and can serve as an index
reaction reflecting activity of this isoform. IC50
values for inhibition of a CYP2D6 index reaction (dextromethorphan
O-demethylation) by bupropion and hydroxybupropion were
58 and 74 µM, respectively. This suggests a low inhibitory potency
versus CYP2D6, the clinical importance of which is not established.
Since bupropion is frequently coadministered with other
antidepressants, IC50 values (µM) for inhibition of
bupropion hydroxylation were determined as follows: paroxetine (1.6),
fluvoxamine (6.1), sertraline (3.2), desmethylsertraline (19.9),
fluoxetine (59.5), norfluoxetine (4.2), and nefazodone (25.4).
Bupropion hydroxylation was only weakly inhibited by venlafaxine, O-desmethylvenlafaxine, citalopram, and
desmethylcitalopram. The inhibition of bupropion hydroxylation in vitro
by a number of newer antidepressants suggests the potential for
clinical drug interactions.
This article has been cited by other articles:
|
|
 |
|
  A. J. Lau and T. K. H. Chang Inhibition of Human CYP2B6-Catalyzed Bupropion Hydroxylation by Ginkgo biloba Extract: Effect of Terpene Trilactones and Flavonols Drug Metab. Dispos., September 1, 2009; 37(9): 1931 - 1937. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. N. Bumpus and P. F. Hollenberg Investigation of the Mechanisms Underlying the Differential Effects of the K262R Mutation of P450 2B6 on Catalytic Activity Mol. Pharmacol., October 1, 2008; 74(4): 990 - 999. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Reese, R. M. Wurm, K. T. Muir, G. T. Generaux, L. St. John-Williams, and D. J. Mcconn An in Vitro Mechanistic Study to Elucidate the Desipramine/Bupropion Clinical Drug-Drug Interaction Drug Metab. Dispos., July 1, 2008; 36(7): 1198 - 1201. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Hofmann, J. K. Blievernicht, K. Klein, T. Saussele, E. Schaeffeler, M. Schwab, and U. M. Zanger Aberrant Splicing Caused by Single Nucleotide Polymorphism c.516G>T [Q172H], a Marker of CYP2B6*6, Is Responsible for Decreased Expression and Activity of CYP2B6 in Liver J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 284 - 292. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. D. Kharasch, D. Mitchell, and R. Coles Stereoselective Bupropion Hydroxylation as an In Vivo Phenotypic Probe for Cytochrome P4502B6 (CYP2B6) Activity J. Clin. Pharmacol., April 1, 2008; 48(4): 464 - 474. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. A. Farid, C. D. Payne, C. S. Ernest II, Y. G. Li, K. J. Winters, D. E. Salazar, and D. S. Small Prasugrel, a New Thienopyridine Antiplatelet Drug, Weakly Inhibits Cytochrome P450 2B6 in Humans J. Clin. Pharmacol., January 1, 2008; 48(1): 53 - 59. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Walsky and R. S. Obach A Comparison of 2-Phenyl-2-(1-piperidinyl)propane (PPP), 1,1',1''-Phosphinothioylidynetrisaziridine (ThioTEPA), Clopidogrel, and Ticlopidine as Selective Inactivators of Human Cytochrome P450 2B6 Drug Metab. Dispos., November 1, 2007; 35(11): 2053 - 2059. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Volotinen, M. Turpeinen, A. Tolonen, J. Uusitalo, J. Maenpaa, and O. Pelkonen Timolol Metabolism in Human Liver Microsomes Is Mediated Principally by CYP2D6 Drug Metab. Dispos., July 1, 2007; 35(7): 1135 - 1141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. B. Sandson, K. L. Cozza, S. C. Armstrong, G. Eckermann, B. A. Fischer, and B. Phillips Clozapine Case Series Psychosomatics, April 1, 2007; 48(2): 170 - 175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. O'Donnell, K. Grime, P. Courtney, D. Slee, and R. J. Riley The Development of a Cocktail CYP2B6, CYP2C8, and CYP3A5 Inhibition Assay and a Preliminary Assessment of Utility in a Drug Discovery Setting Drug Metab. Dispos., March 1, 2007; 35(3): 381 - 385. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Obach, R. L. Walsky, and K. Venkatakrishnan Mechanism-Based Inactivation of Human Cytochrome P450 Enzymes and the Prediction of Drug-Drug Interactions Drug Metab. Dispos., February 1, 2007; 35(2): 246 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Krishnan and S. Moncrief An Evaluation of the Cytochrome P450 Inhibition Potential of Lisdexamfetamine in Human Liver Microsomes Drug Metab. Dispos., January 1, 2007; 35(1): 180 - 184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Blievernicht, E. Schaeffeler, K. Klein, M. Eichelbaum, M. Schwab, and U. M. Zanger MALDI-TOF Mass Spectrometry for Multiplex Genotyping of CYP2B6 Single-Nucleotide Polymorphisms Clin. Chem., January 1, 2007; 53(1): 24 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Walsky, A. V. Astuccio, and R. S. Obach Evaluation of 227 Drugs for In Vitro Inhibition of Cytochrome P450 2B6. J. Clin. Pharmacol., December 1, 2006; 46(12): 1426 - 1438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. T. Casabar, A. D. Wallace, E. Hodgson, and R. L. Rose Metabolism of Endosulfan-{alpha} by Human Liver Microsomes and Its Utility as a Simultaneous in Vitro Probe for CYP2B6 and CYP3A4 Drug Metab. Dispos., October 1, 2006; 34(10): 1779 - 1785. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Gardiner and E. J. Begg Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice Pharmacol. Rev., September 1, 2006; 58(3): 521 - 590. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. N. Bumpus, U. M. Kent, and P. F. Hollenberg Metabolism of Efavirenz and 8-Hydroxyefavirenz by P450 2B6 Leads to Inactivation by Two Distinct Mechanisms J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 345 - 351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Hesse, D. J. Greenblatt, L. L. von Moltke, and M. H. Court Ritonavir has minimal impact on the pharmacokinetic disposition of a single dose of bupropion administered to human volunteers. J. Clin. Pharmacol., May 1, 2006; 46(5): 567 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Greenblatt, R. A. Leigh-Pemberton, and L. L. von Moltke In Vitro Interactions of Water-Soluble Garlic Components with Human Cytochromes P450 J. Nutr., March 1, 2006; 136(3): 806S - 809S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. B. Sandson, S. C. Armstrong, and K. L. Cozza An Overview of Psychotropic Drug-Drug Interactions Psychosomatics, October 1, 2005; 46(5): 464 - 494. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. N. Bumpus, C. Sridar, U. M. Kent, and P. F. Hollenberg THE NATURALLY OCCURRING CYTOCHROME P450 (P450) 2B6 K262R MUTANT OF P450 2B6 EXHIBITS ALTERATIONS IN SUBSTRATE METABOLISM AND INACTIVATION Drug Metab. Dispos., June 1, 2005; 33(6): 795 - 802. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Lang, K. Klein, T. Richter, A. Zibat, R. Kerb, M. Eichelbaum, M. Schwab, and U. M. Zanger Multiple Novel Nonsynonymous CYP2B6 Gene Polymorphisms in Caucasians: Demonstration of Phenotypic Null Alleles J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 34 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Harleton, M. Webster, N. N. Bumpus, U. M. Kent, J. M. Rae, and P. F. Hollenberg Metabolism of N,N',N''-Triethylenethiophosphoramide by CYP2B1 and CYP2B6 Results in the Inactivation of Both Isoforms by Two Distinct Mechanisms J. Pharmacol. Exp. Ther., September 1, 2004; 310(3): 1011 - 1019. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Jacob, E. C. Johnstone, M. J. Neville, and R. T. Walton Identification of CYP2B6 Sequence Variants by Use of Multiplex PCR with Allele-Specific Genotyping Clin. Chem., August 1, 2004; 50(8): 1372 - 1377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Turpeinen, R. Nieminen, T. Juntunen, P. Taavitsainen, H. Raunio, and O. Pelkonen SELECTIVE INHIBITION OF CYP2B6-CATALYZED BUPROPION HYDROXYLATION IN HUMAN LIVER MICROSOMES IN VITRO Drug Metab. Dispos., June 1, 2004; 32(6): 626 - 631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Walsky and R. S. Obach VALIDATED ASSAYS FOR HUMAN CYTOCHROME P450 ACTIVITIES Drug Metab. Dispos., June 1, 2004; 32(6): 647 - 660. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Faucette, H. Wang, G. A. Hamilton, S. L. Jolley, D. Gilbert, C. Lindley, B. Yan, M. Negishi, and E. L. LeCluyse REGULATION OF CYP2B6 IN PRIMARY HUMAN HEPATOCYTES BY PROTOTYPICAL INDUCERS Drug Metab. Dispos., March 1, 2004; 32(3): 348 - 358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Richter, T. E. Murdter, G. Heinkele, J. Pleiss, S. Tatzel, M. Schwab, M. Eichelbaum, and U. M. Zanger Potent Mechanism-Based Inhibition of Human CYP2B6 by Clopidogrel and Ticlopidine J. Pharmacol. Exp. Ther., January 1, 2004; 308(1): 189 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Lu, M. L. Schrag, D. E. Slaughter, C. E. Raab, M. Shou, and A. D. Rodrigues MECHANISM-BASED INHIBITION OF HUMAN LIVER MICROSOMAL CYTOCHROME P450 1A2 BY ZILEUTON, A 5-LIPOXYGENASE INHIBITOR Drug Metab. Dispos., November 1, 2003; 31(11): 1352 - 1360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Salonen, L. Nyman, A. R. Boobis, R. J. Edwards, P. Watts, B. G. Lake, R. J. Price, A. B. Renwick, M.-J. Gomez-Lechon, J. V. Castell, et al. COMPARATIVE STUDIES ON THE CYTOCHROME P450-ASSOCIATED METABOLISM AND INTERACTION POTENTIAL OF SELEGILINE BETWEEN HUMAN LIVER-DERIVED IN VITRO SYSTEMS Drug Metab. Dispos., September 1, 2003; 31(9): 1093 - 1102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wang, S. R. Faucette, D. Gilbert, S. L. Jolley, T. Sueyoshi, M. Negishi, and E. L. LeCluyse Glucocorticoid Receptor Enhancement of Pregnane X Receptor-Mediated CYP2B6 Regulation in Primary Human Hepatocytes Drug Metab. Dispos., May 1, 2003; 31(5): 620 - 630. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Wang, S. Faucette, T. Sueyoshi, R. Moore, S. Ferguson, M. Negishi, and E. L. LeCluyse A Novel Distal Enhancer Module Regulated by Pregnane X Receptor/Constitutive Androstane Receptor Is Essential for the Maximal Induction of CYP2B6 Gene Expression J. Biol. Chem., April 11, 2003; 278(16): 14146 - 14152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Walsky and R. S. Obach Verification of the Selectivity of (+)N-3-Benzylnirvanol as a CYP2C19 Inhibitor Drug Metab. Dispos., March 1, 2003; 31(3): 343 - 343. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ai-Leng, T. Lai-San, L. Kang-Hoe, and L. Gek-Kee Acute Liver Failure with Concurrent Bupropion and Carbimazole Therapy Ann. Pharmacother., February 1, 2003; 37(2): 220 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Botts and C. Alfaro Antidepressant Drug Interactions Journal of Pharmacy Practice, December 1, 2001; 14(6): 467 - 477. [Abstract] [PDF]
|
|
|
|
|
|
M. Hidestrand, M. Oscarson, J. S. Salonen, L. Nyman, O. Pelkonen, M. Turpeinen, and M. Ingelman-Sundberg CYP2B6 and CYP2C19 as the Major Enzymes Responsible for the Metabolism of Selegiline, a Drug Used in the Treatment of Parkinson's Disease, as Revealed from Experiments with Recombinant Enzymes Drug Metab. Dispos., November 1, 2001; 29(11): 1480 - 1484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Faucette, R. L. Hawke, S. S. Shord, E. L. Lecluyse, and C. M. Lindley Evaluation of the Contribution of Cytochrome P450 3A4 to Human Liver Microsomal Bupropion Hydroxylation Drug Metab. Dispos., August 1, 2001; 29(8): 1123 - 1129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Venkatakrishnan, L. L. von Moltke, M. H. Court, J. S. Harmatz, C. L. Crespi, and D. J. Greenblatt Comparison between Cytochrome P450 (CYP) Content and Relative Activity Approaches to Scaling from cDNA-Expressed CYPs to Human Liver Microsomes: Ratios of Accessory Proteins as Sources of Discrepancies between the Approaches Drug Metab. Dispos., April 13, 2001; 28(12): 1493 - 1504. [Abstract] [Full Text]
|
|
|
|
|
|
L. M. Hesse, L. L. von Moltke, R. I. Shader, and D. J. Greenblatt Ritonavir, Efavirenz, and Nelfinavir Inhibit CYP2B6 Activity in Vitro: Potential Drug Interactions with Bupropion Drug Metab. Dispos., February 1, 2001; 29(2): 100 - 102. [Abstract] [Full Text]
|
|
|
|
|
|
L. M. Hesse, K. Venkatakrishnan, L. L. von Moltke, R. I. Shader, and D. J. Greenblatt CYP3A4 Is the Major CYP Isoform Mediating the in Vitro Hydroxylation and Demethylation of Flunitrazepam Drug Metab. Dispos., February 1, 2001; 29(2): 133 - 140. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
