Drug Information

Drug (ID: DG00312) and It's Reported Resistant Information

• Name: Clozapine
• Synonyms: Asaleptin; CLOZARIL; Clorazil; Clozapin; Clozapina; Clozapinum; Fazaclo; Iprox; Leponex; Lepotex; Fazaclo ODT; C 6305; HF1854; Clopine (TN); Clozapina [INN-Spanish]; Clozapine(tautomer); Clozapinum [INN-Latin]; Clozaril (TN); Denzapine (TN); Fazaclo (TN); Froidir (TN); HF-1854; KS-1166; Klozapol (TN); LEX-123; LX 100-129; Leponex (TN); W-801; Zaponex (TN); Clozapine [USAN:INN:BAN]; Clozapine (JAN/USP/INN); 3-chloro-6-(4-methylpiperazin-1-yl)-5H-benzo[b][1,4]benzodiazepine; 8-Chloro-11-(4-methyl)-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine; 8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo (b,e)(1,4)diazepine; 8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepine; 8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]-diazepine; 8-Chloro-11-(4-methyl-piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine; 8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine
• Indication:
  In total 1 Indication(s)
  Schizophrenia [ICD-11: 6A20]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Agranulocytosis [ICD-11: 4B00]; [1]
• Target: Dopamine D4 receptor (D4R); DRD4_HUMAN; [1]
• Formula: C18H19ClN4
• IsoSMILES: CN1CCN(CC1)C2=NC3=C(C=CC(=C3)Cl)NC4=CC=CC=C42
• InChI: 1S/C18H19ClN4/c1-22-8-10-23(11-9-22)18-14-4-2-3-5-15(14)20-16-7-6-13(19)12-17(16)21-18/h2-7,12,20H,8-11H2,1H3
• InChIKey: QZUDBNBUXVUHMW-UHFFFAOYSA-N
• PubChem CID: 135398737
• ChEBI ID: CHEBI:3766
• TTD Drug ID: D0Z1RV
• VARIDT ID: DR00474
• INTEDE ID: DR0363
• DrugBank ID: DB00363

Type(s) of Resistant Mechanism of This Drug

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-04: Immune system diseases

Agranulocytosis [ICD-11: 4B00]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1]

• Molecule Alteration: Missense mutation; 3435CC genotype
• Resistant Disease: Agranulocytosis [ICD-11: 4B00.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: PCR
• Mechanism Description: It was shown that 3435CC genotype carriers require greater doses of clozapine to achieve same plasma concentrations compared with 3435CT and 3435TT carriers. Similarly, a study carried out in Switzerland reported that 3435TT carriers had higher clozapine plasma concentrations.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1]

• Molecule Alteration: Missense mutation; 3435TT genotype
• Sensitive Disease: Agranulocytosis [ICD-11: 4B00.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: PCR
• Mechanism Description: It was shown that 3435CC genotype carriers require greater doses of clozapine to achieve same plasma concentrations compared with 3435CT and 3435TT carriers. Similarly, a study carried out in Switzerland reported that 3435TT carriers had higher clozapine plasma concentrations.

ICD-06: Mental/behavioural/neurodevelopmental disorders

Psychosis [ICD-11: 6D8Z]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [2]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Psychosis [ICD-11: 6D8Z.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: L-MDR1 cells(Sus scrofa (Pig)); Kidney; Homo sapiens (Human); CVCL_0391
• In Vitro Model: LLC-Pk1 cells(Sus scrofa (Pig)); Kidney; Homo sapiens (Human); CVCL_0391
• Experiment for Drug Resistance: Flow cytometric assay
• Mechanism Description: The multidrug resistance transporter, P-glycoprotein (P-gp), is involved in efflux transport of several antipsychotics in the blood-brain barrier (BBB). All the antipsychotics showed various degrees of inhibitory effects on P-gp activity at concentrations ranging from 1 to 100 uM. However, risperidone and olanzapine are the most likely agents that may inhibit P-gp activity.

References

• Ref 1: Relation of the Allelic Variants of Multidrug Resistance Gene to Agranulocytosis Associated With Clozapine. J Clin Psychopharmacol. 2016 Jun;36(3):257-61. doi: 10.1097/JCP.0000000000000495.
• Ref 2: Evaluation of antipsychotic drugs as inhibitors of multidrug resistance transporter P-glycoprotein. Psychopharmacology (Berl). 2006 Sep;187(4):415-23. doi: 10.1007/s00213-006-0437-9. Epub 2006 Jun 30.