Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDIOW1URPS)
  Drug Name Thiethylperazine Drug Info Fluoxetine Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Antiemetics Antidepressants
  Structure

 Mechanism of Thiethylperazine-Fluoxetine Interaction (Severity Level: Moderate)
     CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Thiethylperazine Fluoxetine
      Mechanism 1 CYP450 2D6 substrate CYP450 2D6 inhibitor
      Key Mechanism Factor 1
Factor Name Cytochrome P450 2D6
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Structure Sequence
MGLEALVPLAVIVAIFLLLVDLMHRRQRWAARYPPGPLPLPGLGNLLHVDFQNTPYCFDQLRRRFGDVFSLQLAWTPVVVLNGLAAVREALVTHGEDTADRPPVPITQILGFGPRSQGVFLARYGPAWREQRRFSVSTLRNLGLGKKSLEQWVTEEAACLCAAFANHSGRPFRPNGLLDKAVSNVIASLTCGRRFEYDDPRFLRLLDLAQEGLKEESGFLREVLNAVPVLLHIPALAGKVLRFQKAFLTQLDELLTEHRMTWDPAQPPRDLTEAFLAEMEKAKGNPESSFNDENLRIVVADLFSAGMVTTSTTLAWGLLLMILHPDVQRRVQQEIDDVIGQVRRPEMGDQAHMPYTTAVIHEVQRFGDIVPLGVTHMTSRDIEVQGFRIPKGTTLITNLSSVLKDEAVWEKPFRFHPEHFLDAQGHFVKPEAFLPFSAGRRACLGEPLARMELFLFFTSLLQHFSFSVPTGQPRPSHHGVFAFLVSPSPYELCAVPR
Gene Name CYP2D6
Uniprot ID CP2D6_HUMAN
KEGG Pathway hsa:1565
Protein Family Cytochrome P450 family
Protein Function
A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
    Click to Show/Hide
      Mechanism Description
  • Decreased metabolism of Thiethylperazine caused by Fluoxetine mediated inhibition of CYP450 enzyme
     Additive antidopaminergic effects Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Thiethylperazine Fluoxetine
      Mechanism 2 Extrapyramidal effects Extrapyramidal effects
      Key Mechanism Factor 2
Factor Name Antidopaminergic effects
Factor Description Antidopamines are medications that inhibit or block the neurotransmitter activity of dopamine or related substances. Dopamine deficiency is associated with Parkinson's disease, restless legs syndrome and depression, and low dopamine levels can make you feel tired, moody, unmotivated and many other symptoms.
      Mechanism Description
  • Additive antidopaminergic effects by the combination of Thiethylperazine and Fluoxetine 

Recommended Action
      Management Caution is recommended if fluoxetine is prescribed with phenothiazines or other neuroleptic agents that are thought to be metabolized by CYP450 2D6. Plasma neuroleptic levels and pharmacologic effects should be closely monitored and the dosage(s) adjusted accordingly, particularly following initiation or discontinuation of fluoxetine in patients who are stabilized on their neuroleptic regimen. Patients should be advised to contact their physician if they develop extrapyramidal symptoms such as tremor, shuffling gait, drooling, a mask-like face, tongue stiffness, muscle spasms or rigidity, and involuntary movements. Due to the long half-life of fluoxetine and norfluoxetine, the risk of an interaction may exist for an extended period (up to several weeks) after discontinuation of fluoxetine.

References
1 Avenoso A, Spina E, Campo G, Facciola G, Ferlito M, Zuccaro P, Perucca E, Caputi AP "Interaction between fluoxetine and haloperidol: Pharmacokinetic and clinical implications." Pharmacol Res 35 (1997): 335-9. [PMID: 9264051]
2 Baldessarini RJ, Marsh E "Fluoxetine and side effects." Arch Gen Psychiatry 47 (1990): 191-2. [PMID: 2105706]
3 Bork JA, Rogers T, Wedlund PJ, deLeon J "A pilot study on risperidone metabolism: The role of cytochromes P450 2D6 and 3A." J Clin Psychiatry 60 (1999): 469-76. [PMID: 10453802]
4 Ciraulo DA, Shader RI "Fluoxetine drug-drug interactions: I. Antidepressants and antipsychotics." J Clin Psychopharmacol 10 (1990): 48-50. [PMID: 1968472]
5 Dsouza DC, Bennett A, Abidargham A, Krystal JH "Precipitation of a psychoneuromotor syndrome by fluoxetine in a haloperidol-treated schizophrenic patient." J Clin Psychopharmacol 14 (1994): 361-3. [PMID: 7806697]
6 Fluoxetine and extrapyramidal side effects. Am J Psychiatry 146 (1989): 1352-3. [PMID: 2604792]
7 Goff DC, Midha KK, Brotman AW, Waites M, Baldessarini RJ "Elevation of plasma concentrations of haloperidol after the addition of fluoxetine." Am J Psychiatry 148 (1991): 790-2. [PMID: 2035723]
8 Ketai R "Interaction between fluoxetine and neuroleptics." Am J Psychiatry 150 (1993): 836-7. [PMID: 8480836]
9 Lock JD, Gwirtsman HE, Targ EF "Possible adverse drug interactions between fluoxetine and other psychotropics." J Clin Psychopharmacol 10 (1990): 383-4. [PMID: 2258459]
10 Spina E, Avenoso A, Scordo MG, et al. "Inhibition of Risperidone Metabolism by Fluoxetine in Patients With Schizophrenia: A Clinically Relevant Pharmacokinetic Drug Interaction." J Clin Psychopharmacol 22 (2002): 419-423. [PMID: 12172343]
11 Stein MH "Tardive dyskinesia in a patient taking haloperidol and fluoxetine." Am J Psychiatry 148 (1991): 683. [PMID: 2018175]
12 Tate JL "Extrapyramidal symptoms in a patient taking haloperidol and fluoxetine." Am J Psychiatry 146 (1989): 399-400. [PMID: 2784039]
13 Tyndale RF, Kalow W, Inaba T "Oxidation of reduced haloperidol to haloperidol: involvement of human P450IID6 (sparteine/debrisoquine monooxygenase)." Br J Clin Pharmacol 31 (1991): 655-60. [PMID: 1867960]