# Compound Dive: Riluzole (CHEMBL1201585 / CID 5070)

**IUPAC:** 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine  
**Molecular Formula:** C₈H₅F₃N₂OS  
**Molecular Weight:** 234.20 g/mol  
**Canonical SMILES:** `C1=CC2=C(C=C1OC(F)(F)F)SC(=N2)N`

Prepared: 2026-04-30  
**Sources:** PubChem (CID 5070), PubMed/Cochrane, FDA label data, and peer-reviewed pharmacology literature cited below.

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## (a) Mechanism of Action and Binding Partners

### Primary Mode of Action
Riluzole is a glutamate modulator whose neuroprotective effects derive principally from **presynaptic inhibition of glutamate release**, primarily mediated by **blockade of voltage-gated sodium channels (VGSCs/Nav channels)**—especially persistent (non-inactivating) sodium currents (I<sub>NaP</sub>). By limiting presynaptic sodium influx, riluzole reduces depolarization-driven vesicular glutamate release and attenuates excitotoxic stress on motor neurons.

### Molecular Targets and Binding Partners
The evidence for riluzole’s targets is dose-dependent and spans multiple ion channels and transporter systems. Approximate order of potency (preclinical electrophysiology) is:

| Target / Effect | Evidence Type | Notes |
|---|---|---|
| **Voltage-gated sodium channels (Nav)** — blockade of persistent Na⁺ current (I<sub>NaP</sub>) and fast Na⁺ current | Preclinical (patch-clamp, photolabeling); clinical (efficacy correlates with glutamate modulation) | Acts by non-blocking modulation; riluzole binds fenestration sites near the pore (Bellingham 2011; Földi 2021). |
| **Voltage-gated Ca²⁺ channels (N-type, P/Q-type)** | Preclinical | Inhibition reduces Ca²⁺-dependent neurotransmitter release at lower concentrations than fast Na⁺ blockade (Huang et al. 1997). |
| **Small-conductance Ca²⁺-activated K⁺ channels (SK/K<sub>Ca</sub>2.x)** | Preclinical | Potentiates SK channels (EC₅₀ ~2–10 µM), hyperpolarizing neurons and dampening excitability (Grunnet et al. 2001). |
| **BK (large-conductance) and TREK-1/TRAAK (two-pore) K⁺ channels** | Preclinical | Modulates afterhyperpolarizing currents and resting membrane potential (Wu & Li 1999; Duprat et al. 2000). |
| **Kv4 (A-type) and other voltage-gated K⁺ channels** | Preclinical | Modulates action potential repolarization and repetitive firing. |
| **AMPA and NMDA receptors** | Preclinical / indirect | Indirect antagonism via reduced glutamate release; direct low-potency block reported in some in vitro systems (Golmohammadi 2024 review). |
| **SLC1A2 (EAAT2 / GLT-1)** — astrocytic glutamate transporter | Preclinical | May upregulate or potentiate EAAT2/GLT-1 expression/activity, enhancing synaptic glutamate clearance (functionally linked to reduced excitotoxicity, though direct binding is not established). |

### Important Caveats
- **No single high-affinity molecular target** has been crystallographically validated as the definitive “riluzole receptor.” The drug appears to act via a multimodal, low-affinity membrane-interaction profile.
- In microdialysis studies, riluzole (500 µM local infusion) reduces neuronal glutamate derived from the glutamine–glutamate shuttle, consistent with blockade of sodium-dependent neuronal glutamine transport and/or vesicular release (Hershey et al. 2025).

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## (b) Physicochemical Properties Relevant to CNS Penetration

### Intrinsic Properties (PubChem CID 5070)

| Property | Value | Relevance to CNS Access |
|---|---|---|
| MW | 234.2 | Well below the 400–500 Da BBB-penetration threshold; favorable. |
| XLogP | 3.6 | Moderate lipophilicity supports passive diffusion; within optimal range (2–4) for BBB transit. |
| HBD | 1 | Low H-bond donor count aids passive permeability. |
| HBA | 7 | Elevated H-bond acceptor count (mostly heteroaromatic S/N/F atoms) raises TPSA but is offset by low MW and lipophilicity. |
| TPSA | 76.4 Ų | Above the classical 60–90 Ų gray zone for BBB penetration; suggests moderate-but-sufficient passive permeability. |
| Rotatable Bonds | 1 | Very rigid molecule; entropic penalty for membrane partitioning is low. |
| Charge | 0 (neutral) | Uncharged at physiological pH; no parenchymal efflux due to ionization. |

### Lipinski Assessment
Riluzole **passes Lipinski’s Rule of Five** (MW ≤ 500, LogP ≤ 5, HBD ≤ 5, HBA ≤ 10) with **no violations**. This aligns with its small-molecule, drug-like profile.

### Real-World CNS Penetration: The P-gp/BCRP Barrier
Despite favorable physicochemical properties, **riluzole is a substrate of P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2)** at the blood–brain barrier (BBB) and blood–spinal cord barrier (BSCB).

- **Preclinical (animal models):** In SOD1-G93A ALS mice and P-gp knockout mice, CNS penetration of riluzole is significantly increased when efflux transporters are genetically deleted or pharmacologically inhibited (e.g., with elacridar). Co-administration of elacridar restored efficacy and extended survival even when treatment began at symptom onset (Jablonski et al. 2014).
- **Disease-driven pharmacoresistance:** In ALS, astrocyte-secreted glutamate upregulates P-gp expression in endothelial cells via NMDA receptor activation. This progressive efflux upregulation reduces CNS drug persistence as disease advances, potentially undermining efficacy in later stages (Mohamed et al. 2017; 2019). The effect appears genotype-dependent (e.g., observed with mutant SOD1, not with C9orf72 models).
- **Nanotechnological targeting:** Cell-penetrating peptide (pVEC)-decorated PLGA nanoparticles and riluzole–verapamil liposomes have shown enhanced motor-neuron-specific delivery and reduced systemic toxicity in preclinical models (Esteruelas et al. 2025; verapamil study, 2018).

### Formulation and Absorption Considerations
- **Oral bioavailability:** ~60% in fasted state.
- **Food effect:** High-fat meals decrease C<sub>max</sub> and AUC by ~40–45%. Clinical label recommends administration **at least 1 hour before or 2 hours after a meal**.
- **Alternate formulations:** Oral suspension (Tiglutik®, 2018) and oral soluble film (Exservan®, 2019) offer dysphagia-friendly dosing; pharmacokinetic profiles are bioequivalent to the film-coated tablet.

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## (c) Drug–Drug Interactions with Commonly Co-Prescribed Agents

### Metabolic Pathway
Riluzole undergoes extensive hepatic metabolism. A 2025 PBPK modeling investigation revised the classical assumption that CYP1A2 is the dominant enzyme, instead proposing:
- **CYP1A1:** ~60% contribution
- **CYP1A2:** ~30% contribution
- **UGT1A8/9:** ~10% contribution

**Evidence type:** PBPK modeling verified against clinical PK and fluvoxamine DDI data; formal randomized DDI trials are still needed. Label warnings are based on *in vitro* and mechanistic extrapolation.

### Known / Theoretical Interactions

| Perpetrator Drug Class | Interaction Mechanism | Clinical Relevance | Evidence Level |
|---|---|---|---|
| **Fluvoxamine** (SSRI) | Strong CYP1A2 inhibitor + weak CYP1A1 inhibitor → marked increase in riluzole exposure | **High concern.** Label advises caution for strong/moderate CYP1A2 inhibitors. | PBPK modeling (Malik et al. 2025); *in vitro* label data |
| **Ciprofloxacin / Enoxacin** | Fluoroquinolone CYP1A2 inhibitors | **Moderate concern.** Expected increased riluzole levels. | Label / *in vitro* |
| **Smoking / Charcoal-broiled foods / Rifampicin** | CYP1A inducers → ↓ riluzole exposure | Theoretically lowers levels, though one small observational ALS study did **not** confirm a significant smoking effect on riluzole clearance (P/C ratios). | Observational (small); pharmacokinetic theory |
| **Carbamazepine / Phenytoin** | Broad CYP inducers, including CYP1A | Potential reduced riluzole efficacy; clinical significance uncertain. | Mechanism-based |
| **PPIs (e.g., omeprazole, pantoprazole)** | Weak CYP interactions via mixed inhibition/induction; extensive ALS co-prescribing for GERD/sialorrhea | Likely **low** direct DDI risk. Some clinicians prefer pantoprazole. No formal RCTs. | Empiric / community practice |
| **Anticholinergics (oxybutynin, glycopyrrolate)** for sialorrhea | No direct CYP interaction with riluzole noted; additive anticholinergic burden is a general polypharmacy concern in ALS | Low DDI risk. Monitor constipation, urinary retention, confusion. | General pharmacology |
| **Baclofen / tizanidine / benzodiazepines** (spasticity/anxiety) | No major metabolic interaction; additive CNS depression possible | Monitor sedation. | General pharmacology |

### Hepatotoxicity Risk Amplifiers
Because riluzole itself carries a **dose-dependent hepatotoxicity signal**, any co-medication that raises riluzole exposure (CYP1A inhibitors) increases the risk of ALT/AST elevations. Conversely, inducers may reduce efficacy.

**Monitoring:** Baseline LFTs; repeated monthly for the first 3 months; periodically thereafter. Discontinue if ALT >5× ULN or if bilirubin rises with hepatic symptoms.

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## (d) Published Evidence on Dosing Strategies to Improve Efficacy or Tolerability

### Approved and Standard Dosing
- **Recommended dose:** **50 mg orally twice daily (100 mg/day)**.
- **Timing:** On an empty stomach (≥1 h before or ≥2 h after meals).

### Registration Clinical Trial Evidence

| Study / Design | Doses Tested | Outcome | Evidence Type |
|---|---|---|---|
| **Bensimon et al. (NEJM 1994)** | Riluzole 100 mg/day vs placebo (n=155) | Reduced mortality; delayed tracheostomy. | **RCT** |
| **Lacomblez et al. (Lancet 1996)** | Dose-ranging: 50, 100, 200 mg/day vs placebo (n=959) | 100 mg/day optimal for survival benefit; 200 mg/day had **worse tolerability** (ALT elevations) without additional efficacy. | **RCT** |
| **Cochrane Review (Miller et al. 2012)** | Meta-analysis of 4 RCTs (n≈1,477) | Pooled HR 0.80 (95% CI 0.64–0.99) for tracheostomy-free survival at 100 mg/day. ~9% absolute gain in 1-year survival; median survival prolonged by ~2–3 months (11.8 → 14.8 months). | **Meta-analysis of RCTs** |

### Dose–Response and Safety
- **100 mg/day** is the evidence-based maximal effective dose. Higher doses (200 mg/day) were not superior for functional or survival outcomes in the dose-ranging RCT and produced **dose-dependent, reversible ALT elevations** (Lacomblez et al.).
- **Hepatic enzyme elevations:** Occur in a minority (~2–3× more frequent than placebo), typically within the first 3 months, and are usually reversible.

### Alternative Formulations and Administration Strategies
- **Thickened oral suspension (Tiglutik):** Approved 2018 for patients with dysphagia; administered via oral syringe. Same 50 mg BID dose. No change in efficacy/tolerability profile predicted; bioequivalence demonstrated.
- **Oral film (Exservan):** Approved 2019 for patients unable to swallow tablets; same dosing.
- **Transdermal patch (investigational):** A 2025 preclinical study (Liu et al.) developed a 72-hour riluzole transdermal patch optimized with polyglyceryl-3 dioleate. Provided prolonged release (MRT ~35 h), reduced peak/trough variability, and avoided first-pass hepatic exposure. **No clinical efficacy data yet.**
- **Amorphous solid dispersions (ASD):** Rat and PBPK-extrapolated human data suggest enhanced dissolution and brain AUC/C<sub>max</sub> with ASD formulations (e.g., PAA or PVP-VA). The authors propose that a lower dose could achieve equivalent CNS exposure with lower hepatotoxicity risk. **Preclinical / modeling only** (Bharti et al. 2023; 2024).

### Strategies to Overcome CNS Pharmacoresistance
- **P-gp inhibition:** Preclinical ALS mouse studies show that co-administration of the P-gp/BCRP inhibitor **elacridar** increases spinal cord riluzole concentration and improves motor function/survival when started at symptom onset (Jablonski et al. 2014). **Not yet translated to humans** due to toxicity concerns with elacridar and lack of approved selective efflux inhibitors for ALS.
- **NMDA receptor antagonism:** Because astrocytic glutamate drives P-gp upregulation via NMDA receptors, co-targeting this axis is an emerging preclinical concept (Mohamed et al. 2019).

### Tolerability Optimization
- The most common riluzole-attributed adverse events in the RCT program were **asthenia (~18%) and nausea (~15%)**.
- Dose reduction or temporary interruption can address intolerable nausea/asthenia, though there is no RCT evidence that lower-than-100-mg/day doses preserve the survival signal seen at the approved dose.
- **Real-world evidence** (registries, cohorts) generally supports the RCT safety profile but notes lower adherence in practice due to polypharmacy and disease burden.

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## Summary Evidence Hierarchy

| Domain | Highest Level of Evidence | Key Gaps |
|---|---|---|
| MOA (glutamate/Nav) | Preclinical + translational inference | No validated single binding-site crystal structure |
| Efficacy in ALS | **Meta-analysis of RCTs** (Cochrane 2012) | Modest effect size; no genotype-stratified RCTs |
| CNS penetration | Preclinical (animal models, P-gp KO) | Human intrathecal/spinal cord PK data are limited |
| Drug interactions | PBPK modeling / *in vitro* | No formal clinical DDI trials with strong CYP1A inhibitors published |
| Higher/lower dose strategies | RCT dose-ranging (100 mg optimal) | No RCTs testing <100 mg/day for survival; no RCTs of P-gp co-inhibition |
| Alternate formulations | Bioequivalence studies | Clinical superiority trials of transdermal/ASD not yet reported |

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## References (Selected)

1. **Bensimon G et al.** A controlled trial of riluzole in amyotrophic lateral sclerosis. *NEJM.* 1994;330(9):585–591.  
2. **Lacomblez L et al.** Dose-ranging study of riluzole in ALS. *Lancet.* 1996;347(9013):1425–1431.  
3. **Miller RG et al.** Riluzole for ALS/MND. *Cochrane Database Syst Rev.* 2012;CD001447.pub3. **(Meta-analysis)**  
4. **Bellingham MC.** A Review of the Neural Mechanisms of Action and Clinical Efficiency of Riluzole. *CNS Neurosci Ther.* 2011;17(5):473–490.  
5. **Malik P et al.** A Modeling Investigation of the CYP1A Drug Interactions of Riluzole. *Clin Transl Sci.* 2025;18:e70358. **(PBPK / Modeling)**  
6. **Jablonski MR et al.** Inhibiting drug efflux transporters improves efficacy of ALS therapeutics. *Ann Clin Transl Neurol.* 2014;2(2):1–14. **(Preclinical)**  
7. **Mohamed LA et al.** Excess glutamate secreted from astrocytes drives upregulation of P-glycoprotein in endothelial cells in ALS. *Exp Neurol.* 2019;318:221–230. **(Preclinical)**  
8. **Mohamed LA et al.** Blood-Brain Barrier Driven Pharmacoresistance in ALS. *AAPS J.* 2017;19(4):1100–1107. **(Review / Preclinical)**  
9. **Hershey ND et al.** Detection of Neuronal Glutamate in Brain Extracellular Space In Vivo Using Microdialysis. *ACS Chem Neurosci.* 2025. **(Preclinical / translational)**  
10. **Liu Y et al.** Development of long-acting riluzole transdermal patch. *Int J Pharm X.* 2025;100363. **(Preclinical)**  
11. **Pongratz D et al.** German open-label trial of riluzole 50 mg b.i.d. in ALS. *J Neurol Sci.* 2000;180(1–2):47–51. **(Observational / open-label)**  
12. **Graf M et al.** High dose vitamin E therapy in ALS as add-on to riluzole. *J Neural Transm.* 2005;112(5):649–660. **(RCT)**  
13. **Bharti K et al.** Development and Evaluation of Amorphous Solid Dispersion of Riluzole with PBPK Model. *AAPS PharmSciTech.* 2023;24:68. **(Preclinical / PBPK)**  
14. **FDA Label:** RILUTEK® (riluzole) Tablets. Accessdata.fda.gov (latest revision per DailyMed).