Loading Pathway...
Error: Pathway image not found.
Hide
Pathway Description
Imipramine
Homo sapiens
Drug Metabolism Pathway
Created: 2013-09-11
Last Updated: 2026-05-25
Imipramine is a tricyclic antidepressant that exerts its therapeutic effects by inhibiting norepinephrine and serotonin reuptake in the brain. It does so by competing for the same binding site as norepinephrine on the sodium-dependent noradraneline transporter (SLC6A2) and by competing with serotonin for binding to the sodium-dependent serotonin transporter (SLC6A4). This increases the concentrations of both norepinephrine and serotonin in their respective synapses and reverses the state of low concentrations of both neurotransmitters found in depression. Higher concentrations of norepinephrine and serotonin have also been shown to have long-term neuromodulatory effects. Binding of these neurotransmitters to their respective receptors activate adenylate cyclase, which produces cAMP. cAMP activates protein kinase A which activates cAMP-responsive binding protein 1 (CREB-1). CREB-1 enters the nucleus and affects transcription of brain-derived neurotrophic factor (BDNF). BDNF subsequently stimulates neurogenesis, which may contribute to the long-term reversal of depression. Imipramine is metabolized in the liver mostly through N-demethylation by CYP2C19 into desipramine. Desipramine is an active metabolite and also has similar actions to imipramine on norepinephrine and serotonin reuptake.
References
Imipramine References
Shelton RC: The dual-action hypothesis: does pharmacology matter? J Clin Psychiatry. 2004;65 Suppl 17:5-10.
Pubmed: 15600376
Tofranil. (2009). e-CPS (online version of Compendium of Pharmaceuticals and Specialties). Retrieved December 23, 2009.
Pacholczyk T, Blakely RD, Amara SG: Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature. 1991 Mar 28;350(6316):350-4. doi: 10.1038/350350a0.
Pubmed: 2008212
Porzgen P, Bonisch H, Bruss M: Molecular cloning and organization of the coding region of the human norepinephrine transporter gene. Biochem Biophys Res Commun. 1995 Oct 24;215(3):1145-50. doi: 10.1006/bbrc.1995.2582.
Pubmed: 7488042
Porzgen P, Bonisch H, Hammermann R, Bruss M: The human noradrenaline transporter gene contains multiple polyadenylation sites and two alternatively spliced C-terminal exons. Biochim Biophys Acta. 1998 Jul 9;1398(3):365-70. doi: 10.1016/s0167-4781(98)00072-4.
Pubmed: 9655936
Lesch KP, Wolozin BL, Estler HC, Murphy DL, Riederer P: Isolation of a cDNA encoding the human brain serotonin transporter. J Neural Transm Gen Sect. 1993;91(1):67-72.
Pubmed: 8452685
Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, Ganapathy V, Blakely RD: Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2542-6. doi: 10.1073/pnas.90.6.2542.
Pubmed: 7681602
Lesch KP, Wolozin BL, Murphy DL, Reiderer P: Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter. J Neurochem. 1993 Jun;60(6):2319-22. doi: 10.1111/j.1471-4159.1993.tb03522.x.
Pubmed: 7684072
Kimura S, Umeno M, Skoda RC, Meyer UA, Gonzalez FJ: The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am J Hum Genet. 1989 Dec;45(6):889-904.
Pubmed: 2574001
Gaedigk A, Bhathena A, Ndjountche L, Pearce RE, Abdel-Rahman SM, Alander SW, Bradford LD, Rogan PK, Leeder JS: Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans. Pharmacogenomics J. 2005;5(3):173-82. doi: 10.1038/sj.tpj.6500305.
Pubmed: 15768052
Sridar C, Snider NT, Hollenberg PF: Anandamide oxidation by wild-type and polymorphically expressed CYP2B6 and CYP2D6. Drug Metab Dispos. 2011 May;39(5):782-8. doi: 10.1124/dmd.110.036707. Epub 2011 Feb 2.
Pubmed: 21289075
Miyazawa M, Shindo M, Shimada T: Metabolism of (+)- and (-)-limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes. Drug Metab Dispos. 2002 May;30(5):602-7. doi: 10.1124/dmd.30.5.602.
Pubmed: 11950794
Ibeanu GC, Goldstein JA, Meyer U, Benhamou S, Bouchardy C, Dayer P, Ghanayem BI, Blaisdell J: Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin. J Pharmacol Exp Ther. 1998 Sep;286(3):1490-5.
Pubmed: 9732415
Ibeanu GC, Blaisdell J, Ghanayem BI, Beyeler C, Benhamou S, Bouchardy C, Wilkinson GR, Dayer P, Daly AK, Goldstein JA: An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians. Pharmacogenetics. 1998 Apr;8(2):129-35.
Pubmed: 10022751
Ikeya K, Jaiswal AK, Owens RA, Jones JE, Nebert DW, Kimura S: Human CYP1A2: sequence, gene structure, comparison with the mouse and rat orthologous gene, and differences in liver 1A2 mRNA expression. Mol Endocrinol. 1989 Sep;3(9):1399-408. doi: 10.1210/mend-3-9-1399.
Pubmed: 2575218
Jaiswal AK, Nebert DW, Gonzalez FJ: Human P3(450): cDNA and complete amino acid sequence. Nucleic Acids Res. 1986 Aug 26;14(16):6773-4. doi: 10.1093/nar/14.16.6773.
Pubmed: 3755823
Quattrochi LC, Pendurthi UR, Okino ST, Potenza C, Tukey RH: Human cytochrome P-450 4 mRNA and gene: part of a multigene family that contains Alu sequences in its mRNA. Proc Natl Acad Sci U S A. 1986 Sep;83(18):6731-5. doi: 10.1073/pnas.83.18.6731.
Pubmed: 3462722
Hsieh KP, Lin YY, Cheng CL, Lai ML, Lin MS, Siest JP, Huang JD: Novel mutations of CYP3A4 in Chinese. Drug Metab Dispos. 2001 Mar;29(3):268-73.
Pubmed: 11181494
Molowa DT, Schuetz EG, Wrighton SA, Watkins PB, Kremers P, Mendez-Picon G, Parker GA, Guzelian PS: Complete cDNA sequence of a cytochrome P-450 inducible by glucocorticoids in human liver. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5311-5. doi: 10.1073/pnas.83.14.5311.
Pubmed: 3460094
Gonzalez FJ, Schmid BJ, Umeno M, Mcbride OW, Hardwick JP, Meyer UA, Gelboin HV, Idle JR: Human P450PCN1: sequence, chromosome localization, and direct evidence through cDNA expression that P450PCN1 is nifedipine oxidase. DNA. 1988 Mar;7(2):79-86. doi: 10.1089/dna.1988.7.79.
Pubmed: 3267210
Highlighted elements will appear in red.
Highlight Compounds
Highlight Proteins
Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.
Visualize Compound Data
Visualize Protein Data
Downloads
Settings