P-Glycoprotein Substrate Antiepileptic Drugs
Based on the most recent comprehensive evidence, the antiepileptic drugs that are P-glycoprotein substrates and have increased brain/plasma concentrations when P-gp is inhibited include: phenytoin, phenobarbital, oxcarbazepine (and its active metabolite licarbazepine), lamotrigine, topiramate, carbamazepine-10,11-epoxide (the active metabolite of carbamazepine), and likely lacosamide 1.
High-Confidence P-gp Substrates
The following antiepileptics demonstrate clear evidence of P-gp-mediated transport:
Confirmed Substrates with Strong Evidence:
Phenytoin: Demonstrated increased cortical extracellular fluid concentrations when P-gp is blocked by verapamil in epileptic rats 2. Multiple studies confirm substrate status 1.
Phenobarbital: Local perfusion of verapamil significantly increased extracellular brain concentrations via microdialysis 3. Consistently identified as a P-gp substrate 1.
Oxcarbazepine and its active metabolite (S)-licarbazepine: Both the parent drug and metabolite are transported by P-gp in bidirectional transport assays using MDR1-transfected cells 4. Flavonoid P-gp inhibitors significantly increased intracellular accumulation 5.
Lamotrigine: Despite some conflicting data, verapamil increased brain extracellular concentrations in microdialysis studies 3, and recent comprehensive review supports substrate status 1.
Topiramate: Identified as a probable P-gp substrate in the most recent systematic review 1.
Important Nuance - Carbamazepine:
Carbamazepine itself is NOT a P-gp substrate 4, but its active metabolite carbamazepine-10,11-epoxide IS transported by P-gp 4. This explains why P-gp inhibition affects carbamazepine's clinical efficacy—the active metabolite accumulates in the brain when P-gp is blocked 5, 2.
Non-Substrates (Not Affected by P-gp Inhibition)
The following are probably NOT P-gp substrates and would not have increased concentrations with P-gp inhibition 1:
- Brivaracetam
- Zonisamide
- Valproic acid
- Perampanel
- Gabapentin
- Vigabatrin
Clinical Implications
When P-gp Inhibition Occurs:
P-gp inhibitors (verapamil, tariquidar, certain flavonoids like quercetin and kaempferol) can increase brain penetration of substrate antiepileptics by 30-50% based on experimental data 5, 2, 3. This mechanism is particularly relevant in:
- Drug-resistant epilepsy: Overexpression of P-gp at the blood-brain barrier limits drug access to epileptic foci 2, 3
- Drug interactions: Co-administration with P-gp inhibitors (calcium channel blockers, certain antibiotics, antifungals) may unexpectedly increase antiepileptic levels
- Polytherapy considerations: Carbamazepine itself induces P-gp activity 6, potentially reducing brain concentrations of other P-gp substrate antiepileptics
Common Pitfall:
Do not assume all antiepileptics in the same class behave similarly regarding P-gp transport. For example, carbamazepine is not a substrate while its metabolite and structural analogs (oxcarbazepine, eslicarbazepine) are substrates 4. Lamotrigine showed no P-gp-mediated transport in some cellular studies 5 but did show increased brain concentrations with P-gp inhibition in vivo 3, highlighting the importance of prioritizing animal and human data over cell line studies.
Ranking of P-gp Substrate Affinity:
Among confirmed substrates, transport efficiency follows: eslicarbazepine acetate > oxcarbazepine > S-licarbazepine > carbamazepine-10,11-epoxide 4.