Inhibitory Effects of Tricyclic Antidepressants (TCAs) on Human Cytochrome P450 Enzymes in Vitro: Mechanism of Drug Interaction between TCAs and Phenytoin

doi:10.1124/dmd.30.10.1102

QUICK SEARCH:

[advanced]

	Author:		Keyword(s):
Year:		Vol:		Page:

This Article

	Full Text
	Full Text (PDF)
	Submit a response
	Alert me when this article is cited
	Alert me when eLetters are posted
	Alert me if a correction is posted

Services

	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new issues of the journal
	Download to citation manager

Citing Articles

	Citing Articles via HighWire
	Citing Articles via Google Scholar

Google Scholar

	Articles by Shin, J.-G.
	Articles by Flockhart, D. A.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Shin, J.-G.
	Articles by Flockhart, D. A.

Vol. 30, Issue 10, 1102-1107, October 2002

Inhibitory Effects of Tricyclic Antidepressants (TCAs) on Human Cytochrome P450 Enzymes in Vitro: Mechanism of Drug Interaction between TCAs and Phenytoin

Jae-Gook Shin, Ji-Young Park, Min-Jung Kim, Ji-Hong Shon, Young-Ran Yoon, In-June Cha, Sang-Seop Lee, Se-Wook Oh, Sang-Woo Kim, and David A. Flockhart

Department of Pharmacology, Inje University College of Medicine and Clinical Pharmacology Center, Busan Paik Hospital (J.-G.S., J.-Y.P., M.-J.K., J.-H.S., Y.-R.Y., I.-J.C., S.-S.L); Department of Pediatrics, Seoul Paik Hospital (S.-W.O.) and Sanggye Paik Hospital (S.-W.K.), Busan, Seoul, Korea; and Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis (D.A.F.)

The ability of tricyclic antidepressants (TCAs) to inhibit phenytoin p-hydroxylation was evaluated in vitro by incubationstudies of human liver microsomes and cDNA-expressed cytochromeP450s (P450s). The TCAs tested were amitriptyline, imipramine,nortriptyline, and desipramine. Amitriptyline and imipramine stronglyand competitively inhibited phenytoin p-hydroxylation in microsomalincubations (estimated K_i values of 5.2 and 15.5 µM, respectively).In contrast, nortriptyline and desipramine produced only weakinhibition. In the incubation study using cDNA-expressed P450s,both CYP2C9 and CYP2C19 catalyzed phenytoin p-hydroxylation, whereasTCAs inhibited only the CYP2C19 pathway. All of the TCAs testedinhibited CYP2D6-catalyzed dextromethorphan-O-demethylation competitively,with estimated K_i values of 31.0, 28.6, 7.9, and 12.5 µM, respectively.The tertiary amine TCAs, amitriptyline and imipramine, also inhibitedCYP2C19-catalyzed S-mephenytoin 4'-hydroxylation (estimated K_iof 37.7 and 56.8 µM, respectively). The secondary amine TCAs,nortriptyline and desipramine, however, showed minimal inhibitionof CYP2C19 (estimated IC₅₀ of 600 and 685 µM, respectively). Noneof the TCAs tested produced remarkable inhibition of any otherP450 isoforms. These results suggest that TCAs inhibit both CYP2D6and CYP2C19 and that the interaction between TCAs and phenytoininvolves inhibition of CYP2C19-catalyzed phenytoin p-hydroxylation.

This article has been cited by other articles:

S. K. Bae, S. Cao, K.-A. Seo, H. Kim, M.-J. Kim, J.-H. Shon, K.-H. Liu, H.-H. Zhou, and J.-G. Shin
Cytochrome P450 2B6 Catalyzes the Formation of Pharmacologically Active Sibutramine (N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine) Metabolites in Human Liver Microsomes
Drug Metab. Dispos., August 1, 2008; 36(8): 1679 - 1688.
[Abstract] [Full Text] [PDF]

A. Di Marco, A. Cellucci, A. Chaudhary, M. Fonsi, and R. Laufer
High-Throughput Radiometric CYP2C19 Inhibition Assay Using Tritiated (S)-Mephenytoin
Drug Metab. Dispos., October 1, 2007; 35(10): 1737 - 1743.
[Abstract] [Full Text] [PDF]

Y.-J. Yoon, K.-B. Kim, H. Kim, K.-A. Seo, H.-S. Kim, I.-J. Cha, E.-Y. Kim, K.-H. Liu, and J.-G. Shin
Characterization of Benidipine and Its Enantiomers' Metabolism by Human Liver Cytochrome P450 Enzymes
Drug Metab. Dispos., September 1, 2007; 35(9): 1518 - 1524.
[Abstract] [Full Text] [PDF]

H. Shen, M. M. He, H. Liu, S. A. Wrighton, L. Wang, B. Guo, and C. Li
Comparative Metabolic Capabilities and Inhibitory Profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17
Drug Metab. Dispos., August 1, 2007; 35(8): 1292 - 1300.
[Abstract] [Full Text] [PDF]

K.-H. Liu, M.-G. Kim, D.-J. Lee, Y.-J. Yoon, M.-J. Kim, J.-H. Shon, C. S. Choi, Y. K. Choi, Z. Desta, and J.-G. Shin
Characterization of Ebastine, Hydroxyebastine, and Carebastine Metabolism by Human Liver Microsomes and Expressed Cytochrome P450 Enzymes: Major Roles for CYP2J2 and CYP3A
Drug Metab. Dispos., November 1, 2006; 34(11): 1793 - 1797.
[Abstract] [Full Text] [PDF]

C. Marcucci, N. B. Sandson, E. M. Thorn, and D. L. Bourke
Unrecognized drug-drug interactions: a cause of intraoperative cardiac arrest?
Anesth. Analg., May 1, 2006; 102(5): 1569 - 1572.
[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]

J.-Y. Park, K.-A. Kim, and S.-L. Kim
Chloramphenicol Is a Potent Inhibitor of Cytochrome P450 Isoforms CYP2C19 and CYP3A4 in Human Liver Microsomes
Antimicrob. Agents Chemother., November 1, 2003; 47(11): 3464 - 3469.
[Abstract] [Full Text] [PDF]

K.-A. Kim, M.-J. Kim, J.-Y. Park, J.-H. Shon, Y.-R. Yoon, S.-S. Lee, K.-H. Liu, J.-H. Chun, M.-H. Hyun, and J.-G. Shin
STEREOSELECTIVE METABOLISM OF LANSOPRAZOLE BY HUMAN LIVER CYTOCHROME P450 ENZYMES
Drug Metab. Dispos., October 1, 2003; 31(10): 1227 - 1234.
[Abstract] [Full Text] [PDF]

K.-A. Kim and J.-Y. Park
INHIBITORY EFFECT OF GLYBURIDE ON HUMAN CYTOCHROME P450 ISOFORMS IN HUMAN LIVER MICROSOMES
Drug Metab. Dispos., September 1, 2003; 31(9): 1090 - 1092.
[Abstract] [Full Text] [PDF]

				A. Di Marco, A. Cellucci, A. Chaudhary, M. Fonsi, and R. Laufer High-Throughput Radiometric CYP2C19 Inhibition Assay Using Tritiated (S)-Mephenytoin Drug Metab. Dispos., October 1, 2007; 35(10): 1737 - 1743. [Abstract] [Full Text] [PDF]

				Y.-J. Yoon, K.-B. Kim, H. Kim, K.-A. Seo, H.-S. Kim, I.-J. Cha, E.-Y. Kim, K.-H. Liu, and J.-G. Shin Characterization of Benidipine and Its Enantiomers' Metabolism by Human Liver Cytochrome P450 Enzymes Drug Metab. Dispos., September 1, 2007; 35(9): 1518 - 1524. [Abstract] [Full Text] [PDF]

				H. Shen, M. M. He, H. Liu, S. A. Wrighton, L. Wang, B. Guo, and C. Li Comparative Metabolic Capabilities and Inhibitory Profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17 Drug Metab. Dispos., August 1, 2007; 35(8): 1292 - 1300. [Abstract] [Full Text] [PDF]

				K.-H. Liu, M.-G. Kim, D.-J. Lee, Y.-J. Yoon, M.-J. Kim, J.-H. Shon, C. S. Choi, Y. K. Choi, Z. Desta, and J.-G. Shin Characterization of Ebastine, Hydroxyebastine, and Carebastine Metabolism by Human Liver Microsomes and Expressed Cytochrome P450 Enzymes: Major Roles for CYP2J2 and CYP3A Drug Metab. Dispos., November 1, 2006; 34(11): 1793 - 1797. [Abstract] [Full Text] [PDF]

				C. Marcucci, N. B. Sandson, E. M. Thorn, and D. L. Bourke Unrecognized drug-drug interactions: a cause of intraoperative cardiac arrest? Anesth. Analg., May 1, 2006; 102(5): 1569 - 1572. [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]

				J.-Y. Park, K.-A. Kim, and S.-L. Kim Chloramphenicol Is a Potent Inhibitor of Cytochrome P450 Isoforms CYP2C19 and CYP3A4 in Human Liver Microsomes Antimicrob. Agents Chemother., November 1, 2003; 47(11): 3464 - 3469. [Abstract] [Full Text] [PDF]

				K.-A. Kim, M.-J. Kim, J.-Y. Park, J.-H. Shon, Y.-R. Yoon, S.-S. Lee, K.-H. Liu, J.-H. Chun, M.-H. Hyun, and J.-G. Shin STEREOSELECTIVE METABOLISM OF LANSOPRAZOLE BY HUMAN LIVER CYTOCHROME P450 ENZYMES Drug Metab. Dispos., October 1, 2003; 31(10): 1227 - 1234. [Abstract] [Full Text] [PDF]

				K.-A. Kim and J.-Y. Park INHIBITORY EFFECT OF GLYBURIDE ON HUMAN CYTOCHROME P450 ISOFORMS IN HUMAN LIVER MICROSOMES Drug Metab. Dispos., September 1, 2003; 31(9): 1090 - 1092. [Abstract] [Full Text] [PDF]