DT-Web

DB00408 - Loxapine


Identification
Name Loxapine
Accession Number DB00408 (APRD00574)
Type small molecule
Description An antipsychotic agent used in schizophrenia. [PubChem]
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 327.808
Groups approved
Monoisotopic Weight 327.11383992
Pharmacology
Indication For the management of the manifestations of psychotic disorders such as schizophrenia
Mechanism of action Loxapine is a dopamine antagonist, and also a serotonin 5-HT2 blocker. The exact mode of action of Loxapine has not been established, however changes in the level of excitability of subcortical inhibitory areas have been observed in several animal species in association with such manifestations of tranquilization as calming effects and suppression of aggressive behavior.
Absorption Systemic bioavailability of the parent drug was only about one third that after an equivalent intramuscular dose (25 mg base) in male volunteers
Protein binding Not Available
Biotransformation Hepatic
Route of elimination Metabolites are excreted in the urine in the form of conjugates and in the feces unconjugated.
Toxicity LD50=65 mg/kg (Orally in mice)
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Artemether Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Donepezil Possible antagonism of action
Galantamine Possible antagonism of action
Lumefantrine Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Rivastigmine Possible antagonism of action
Rotigotine Pharmacodynamic antagonism may decrease the effects of rotigotine. Consider alternate therapy.
Tacrine The therapeutic effects of the central acetylcholinesterase inhibitor (AChEI), Tacrine, and/or the anticholinergic/antipsychotic, Loxapine, may be reduced due to antagonism. This interaction may be beneficial when the anticholinergic action is a side effect. AChEIs may also augment the central neurotoxic effect of antipsychotics. Monitor for extrapyramidal symptoms and decreased efficacy of both agents.
Tacrolimus Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Tetrabenazine May cause dopamine deficiency. Monitor for Tetrabenazine adverse effects.
Thiothixene May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
Toremifene Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.
Trimethobenzamide Trimethobenzamide and Loxapine, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.
Trimipramine Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Triprolidine Triprolidine and Loxapine, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.
Trospium Trospium and Loxapine, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.
Voriconazole Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Vorinostat Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Ziprasidone Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
Zuclopenthixol Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Food Interactions
  • Take with food to reduce irritation. Avoid alcohol.

Targets


D(2) dopamine receptor
Name D(2) dopamine receptor
Gene Name DRD2
Pharmacological action yes
Actions antagonist
References
  • Lee T, Tang SW: Loxapine and clozapine decrease serotonin (S2) but do not elevate dopamine (D2) receptor numbers in the rat brain. Psychiatry Res. 1984 Aug;12(4):277-85. - Pubmed
  • Hjerde E, Dahl SG, Sylte I: Atypical and typical antipsychotic drug interactions with the dopamine D2 receptor. Eur J Med Chem. 2005 Feb;40(2):185-94. - Pubmed
  • Kalkman HO, Neumann V, Nozulak J, Tricklebank MD: Cataleptogenic effect of subtype selective 5-HT receptor antagonists in the rat. Eur J Pharmacol. 1998 Feb 19;343(2-3):201-7. - Pubmed
  • Froimowitz M, Cody V: Biologically active conformers of phenothiazines and thioxanthenes. Further evidence for a ligand model of dopamine D2 receptor antagonists. J Med Chem. 1993 Jul 23;36(15):2219-27. - Pubmed
  • Froimowitz M, Cody V: The incorporation of butyrophenones and related compounds into a pharmacophore for dopamine D2 antagonists. Drug Des Discov. 1997 Aug;15(2):63-81. - Pubmed
  • Lang AE, Sandor P, Duff J: Remoxipride in Parkinson's disease: differential response in patients with dyskinesias fluctuations versus psychosis. Clin Neuropharmacol. 1995 Feb;18(1):39-45. - Pubmed
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
DTHybrid score 0.4351
D(1A) dopamine receptor
Name D(1A) dopamine receptor
Gene Name DRD1
Pharmacological action unknown
Actions antagonist
References
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
DTHybrid score 0.3424
5-hydroxytryptamine 2A receptor
Name 5-hydroxytryptamine 2A receptor
Gene Name HTR2A
Pharmacological action yes
Actions antagonist
References
  • Li Z, Ichikawa J, Meltzer HY: A comparison of the effects of loxapine with ziprasidone and thioridazine on the release of dopamine and acetylcholine in the prefrontal cortex and nucleus accumbens. Psychopharmacology (Berl). 2003 May;167(3):315-23. Epub 2003 Mar 28. - Pubmed
DTHybrid score 0.3674
5-hydroxytryptamine 2C receptor
Name 5-hydroxytryptamine 2C receptor
Gene Name HTR2C
Pharmacological action unknown
Actions antagonist
References
  • Herrick-Davis K, Grinde E, Teitler M: Inverse agonist activity of atypical antipsychotic drugs at human 5-hydroxytryptamine2C receptors. J Pharmacol Exp Ther. 2000 Oct;295(1):226-32. - Pubmed
DTHybrid score 0.243

Predictions


Id Partner name Gene Name Score
4119 Cytochrome P450 2D6 CYP2D6 0.159
320 5-hydroxytryptamine 1A receptor HTR1A 0.1508
638 D(3) dopamine receptor DRD3 0.1386
556 Alpha-1A adrenergic receptor ADRA1A 0.1378
318 Alpha-2A adrenergic receptor ADRA2A 0.1346
432 D(4) dopamine receptor DRD4 0.1319
436 5-hydroxytryptamine 2B receptor HTR2B 0.1177
163 D(1B) dopamine receptor DRD5 0.1115
4512 Cytochrome P450 3A4 CYP3A4 0.1049
632 Alpha-1B adrenergic receptor ADRA1B 0.1013
629 Alpha-2B adrenergic receptor ADRA2B 0.0996
378 Alpha-2C adrenergic receptor ADRA2C 0.0987
4200 Cytochrome P450 1A2 CYP1A2 0.0941
103 Muscarinic acetylcholine receptor M1 CHRM1 0.0822
492 Histamine H1 receptor HRH1 0.0821
725 5-hydroxytryptamine 1D receptor HTR1D 0.0787
716 5-hydroxytryptamine 7 receptor HTR7 0.0728
885 5-hydroxytryptamine 1B receptor HTR1B 0.0702
824 Sodium-dependent serotonin transporter SLC6A4 0.0667
1588 Multidrug resistance protein 1 ABCB1 0.0616
617 Muscarinic acetylcholine receptor M2 CHRM2 0.0542
51 Muscarinic acetylcholine receptor M3 CHRM3 0.0519
274 Muscarinic acetylcholine receptor M5 CHRM5 0.0497
450 Muscarinic acetylcholine receptor M4 CHRM4 0.0483
1256 5-hydroxytryptamine 6 receptor HTR6 0.0479
789 Alpha-1D adrenergic receptor ADRA1D 0.0463
4757 Cytochrome P450 2C9 CYP2C9 0.0433
540 Sodium-dependent noradrenaline transporter SLC6A2 0.0405
6016 Cytochrome P450 2C19 CYP2C19 0.0405
6145 Solute carrier family 22 member 1 SLC22A1 0.0402
587 Serum albumin ALB 0.0329
4118 Cytochrome P450 3A5 CYP3A5 0.0314
6013 Cytochrome P450 2E1 CYP2E1 0.03
6107 Cytochrome P450 3A7 CYP3A7 0.0284
341 5-hydroxytryptamine 3 receptor HTR3A 0.0231
94 5-hydroxytryptamine 4 receptor HTR4 0.023
6030 Cytochrome P450 2B6 CYP2B6 0.0228
528 5-hydroxytryptamine 1E receptor HTR1E 0.0208
3876 Aromatic-L-amino-acid decarboxylase DDC 0.0206
4924 Cytochrome P450 2C8 CYP2C8 0.0203
713 Sodium-dependent dopamine transporter SLC6A3 0.0198
174 Sigma 1-type opioid receptor SIGMAR1 0.0194
3941 Amine oxidase [flavin-containing] A MAOA 0.0189
131 Synaptic vesicular amine transporter SLC18A2 0.0187
706 Glutamate [NMDA] receptor subunit 3A GRIN3A 0.0183
465 Calmodulin CALM1 0.0183
734 D1 dopamine receptor-interacting protein calcyon CALY 0.0178
750 Voltage-dependent calcium channel gamma-1 subunit CACNG1 0.0175
101 Potassium voltage-gated channel subfamily H member 2 KCNH2 0.0165
1181 Alpha-1-acid glycoprotein 1 ORM1 0.0158
923 Glutamate receptor 3 GRIA3 0.0149
3923 Cholinesterase BCHE 0.0146
474 Acetylcholinesterase ACHE 0.0124
5251 Carbonyl reductase [NADPH] 1 CBR1 0.0119
5718 Cytochrome P450 2A6 CYP2A6 0.011
6025 UDP-glucuronosyltransferase 1-4 UGT1A4 0.0107
6144 Solute carrier family 22 member 2 SLC22A2 0.0105
124 Histamine H2 receptor HRH2 0.0104
362 Melatonin receptor type 1B MTNR1B 0.0103
571 Melatonin receptor type 1A MTNR1A 0.0103
872 Gamma-aminobutyric-acid receptor subunit alpha-1 GABRA1 0.0101
3426 Glutamine synthetase glnA 0.0099
3987 Glutamine synthetase GLUL 0.0099
921 Glutamate receptor 2 GRIA2 0.0092
6024 Cytochrome P450 1A1 CYP1A1 0.009
193 Beta-1 adrenergic receptor ADRB1 0.0087
696 Kappa-type opioid receptor OPRK1 0.0078
6176 UDP-glucuronosyltransferase 1-3 UGT1A3 0.0078
6432 Transporter snf 0.0077
3939 Amine oxidase [flavin-containing] B MAOB 0.0075
6101 Dimethylaniline monooxygenase [N-oxide-forming] 3 FMO3 0.0067
866 Large neutral amino acids transporter small subunit 2 SLC7A8 0.0057
6106 Cytochrome P450 2C18 CYP2C18 0.0056
464 Glutamate [NMDA] receptor subunit epsilon-2 GRIN2B 0.0055
245 Large neutral amino acids transporter small subunit 1 SLC7A5 0.0053
6104 Dimethylaniline monooxygenase [N-oxide-forming] 1 FMO1 0.0051
1656 CYP2B protein CYP2B 0.0049
766 Beta-2 adrenergic receptor ADRB2 0.0045
6164 POU domain, class 5, transcription factor 1 POU5F1 0.0043
904 Glutathione S-transferase P GSTP1 0.0042
164 Histamine H4 receptor HRH4 0.0042
6018 UDP-glucuronosyltransferase 1-9 UGT1A9 0.0041
6859 Protein S100-A4 S100A4 0.0041
694 Matrix protein 2 M 0.0039
6151 Monocarboxylate transporter 10 SLC16A10 0.0038
776 Bile salt export pump ABCB11 0.0038
5878 Alpha-7 nicotinic cholinergic receptor subunit CHRFAM7A 0.0038
6147 Solute carrier family 22 member 3 SLC22A3 0.0037
6023 Cytochrome P450 11B2, mitochondrial CYP11B2 0.0036
1539 Oligopeptide transporter, small intestine isoform SLC15A1 0.0036
380 Cytochrome P450 17A1 CYP17A1 0.0035
427 Substance-P receptor TACR1 0.0034
153 Dopamine beta-hydroxylase DBH 0.0034
467 Delta-type opioid receptor OPRD1 0.0032
805 Cytochrome P450 11B1, mitochondrial CYP11B1 0.0031
3810 Catechol O-methyltransferase COMT 0.0027
1561 Troponin C, slow skeletal and cardiac muscles TNNC1 0.0027
118 Organic cation/carnitine transporter 2 SLC22A5 0.0027
847 Mu-type opioid receptor OPRM1 0.0025
20 Prostaglandin G/H synthase 1 PTGS1 0.0024
1898 Cytochrome P450 1B1 CYP1B1 0.0024
3947 Xanthine dehydrogenase/oxidase XDH 0.002
6098 Potassium voltage-gated channel subfamily D member 2 KCND2 0.002
6099 Potassium voltage-gated channel subfamily D member 3 KCND3 0.002
4113 Voltage-dependent L-type calcium channel subunit alpha-1F CACNA1F 0.0018
15 Voltage-dependent T-type calcium channel subunit alpha-1I CACNA1I 0.0018
535 Voltage-dependent T-type calcium channel subunit alpha-1G CACNA1G 0.0017
964 Voltage-dependent T-type calcium channel subunit alpha-1H CACNA1H 0.0016
4115 Voltage-dependent L-type calcium channel subunit alpha-1D CACNA1D 0.0015
4111 Voltage-dependent L-type calcium channel subunit alpha-1S CACNA1S 0.0015
478 Voltage-dependent L-type calcium channel subunit alpha-1C CACNA1C 0.0014
1360 Sphingomyelin phosphodiesterase SMPD1 0.0014
833 Organic cation/carnitine transporter 1 SLC22A4 0.0014
6100 BDNF/NT-3 growth factors receptor NTRK2 0.0012
1618 High affinity nerve growth factor receptor NTRK1 0.001
1086 Potassium voltage-gated channel subfamily KQT member 2 KCNQ2 0.0009
858 Potassium voltage-gated channel subfamily A member 1 KCNA1 0.0007
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