Disease Information

General Information of the Disease (ID: DIS00261)

• Name: Epilepsy
• ICD: ICD-11: 8A60

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Carbamazepine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

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

• Resistant Disease: Epilepsy [ICD-11: 8A60.0]
• Resistant Drug: Carbamazepine
• Molecule Alteration: SNP; rs1128503
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: ABCB1 polymorphisms were previously demonstrated to be associated with the metabolism and resistance of carbamazepine (CBZ) in epilepsy. ABCB1 rs1045642 and rs2032582 polymorphisms were associated with CBZ metabolism for epilepsy, and rs1128503 was related to carbamazepine resistance.

Lamotrigine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [3]

• Resistant Disease: Epilepsy [ICD-11: 8A60.0]
• Resistant Drug: Lamotrigine
• Molecule Alteration: Missense mutation; p.V2424G
• Experiment for Molecule Alteration: Genotyping assay; RT-PCR
• Experiment for Drug Resistance: High-performance liquid chromatography assay; Diode-array assay
• Mechanism Description: Polymorphism ABCG2 c.421C>A moderately reduces lamotrigine concentrations in adults with epilepsy.

Oxcarbazepine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [4]

• Resistant Disease: Epilepsy [ICD-11: 8A60.0]
• Resistant Drug: Oxcarbazepine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: In patients with oxcarbazepine (OXC)-resistant epilepsy, the brain tissue expression of ABCB1 mRNA was found to be inversely correlated with brain levels of 10,11-dihydro-10-hydroxy-5H-dibenzo(b,f)azepine-5-carboxamide, the active metabolite of OXC, indicating that Pgp may play a role in the pharmacoresistance to OXC by causing insufficient concentrations of its active metabolite at neuronal targets.

Phenytoin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [4]

• Resistant Disease: Epilepsy [ICD-11: 8A60.0]
• Resistant Drug: Phenytoin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: Comparing phenytoin brain/plasma ratio in mdr1 knockout mice with this ratio in mice with kainate-induced overexpression of Pgp indicated that Pgp can affect up to about 70% of phenytoin brain uptake. In epileptic rats, van Vliet et al reported decreased brain levels of phenytoin that were restricted to brain regions with increased expression of Pgp, which could be counteracted by inhibiting Pgp.

Sitagliptin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Protein kinase C gamma type (PRKCG) [5]

• Sensitive Disease: Epilepsy [ICD-11: 8A60.0]
• Sensitive Drug: Sitagliptin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: Wistar rats model; Rattus norvegicus
• Experiment for Molecule Alteration: Protein kinase assay; RT-qPCR
• Experiment for Drug Resistance: Experimental Animal Model
• Mechanism Description: Mechanistic insights revealed sitagliptin's ability to modulate the seizure grade and first myoclonic jerk latency via oxidative stress markers, like reduced glutathione and glutathione peroxidase emphasizing its antioxidative role in epilepsy. Additionally, it demonstrated anti-inflammatory effects by significantly reducing proinflammatory markers interleukin-1beta and interleukin-6. The modulation of key genes of the long-term potentiation pathway, particularly protein kinase C-gamma and metabotropic glutamate receptor 5, was evident through mRNA expression levels. Finally, sitagliptin showed potential neuroprotective properties, limiting pentylenetetrazolium-induced neuronal loss in the hippocampal region. Collectively, our findings suggest sitagliptin's multidimensional therapeutic potential for drug-resistant epilepsy specifically via a long-term potentiation pathway by inhibiting protein kinase C-gamma.

References

• Ref 1: Peimine promotes microglial polarization to the M2 phenotype to attenuate drug-resistant epilepsy through suppressing the TLR4/NF-kappaB/HIF-1alpha signaling pathway in a rat model and in BV-2 microglia. Heliyon. 2024 Jul 20;10(15):e34987.
• Ref 2: Association of ABCB1 polymorphisms with carbamazepine metabolism and resistance in epilepsy: A meta-analysis .Epilepsy Res. 2021 Nov;177:106785. doi: 10.1016/j.eplepsyres.2021.106785. Epub 2021 Oct 7. 10.1016/j.eplepsyres.2021.106785
• Ref 3: The Loss-of-Function ATP Binding Cassette Subfamily G Member 2 Polymorphism ABCG2 c.421C>A Reduces Lamotrigine Trough Concentrations in Adults with Epilepsy. Eur J Drug Metab Pharmacokinet. 2025 Jan;50(1):17-22.
• Ref 4: Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options .Pharmacol Rev. 2020 Jul;72(3):606-638. doi: 10.1124/pr.120.019539. 10.1124/pr.120.019539
• Ref 5: Unlocking the Therapeutic Potential: Sitagliptin's Multifaceted Approach in Drug-Resistant Epilepsy through a Novel Mechanism Inhibiting Protein Kinase C-gamma and a Long-Term Potentiation Pathway. ACS Pharmacol Transl Sci. 2024 May 14;7(6):1856-1863.