# Compound Dive: Riluzole (CHEMBL1201585 / CID 5070)

**Date:** 2026-05-04  
**Sources:** PubChem, UniProt, OpenTargets, Reactome, PubMed (NCBI)  
**Evidence-grading key:**  
- **CT** = Randomized controlled trial / pivotal clinical trial data  
- **Obs** = Observational / registry / real-world evidence  
- **Preclin** = In vitro, ex vivo, or animal model data  
- **Struct** = Structured database entry (PubChem, UniProt)  
- **Rev** = Review / meta-analysis / consensus guideline  

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## 1. Known Mechanism of Action and Binding Partners

### 1.1 Primary Pharmacodynamic Targets

| Target class | Representative proteins | Effect | Evidence quality |
|---|---|---|---|
| **Voltage-gated sodium channels (Nav)** | SCN1A (Nav1.1), SCN2A (Nav1.2), SCN8A (Nav1.6) | Inhibition of persistent and transient Na⁺ currents; reduces neuronal excitability and excitotoxic Ca²⁺ loading | **Preclin / Rev** (PMID 41171075; Pedro 2025) |
| **Delayed-rectifier K⁺ channels** | Kv family (exact subtypes less well defined) | Delayed rectifier K⁺ current inhibition; prolongs repolarization and may modulate firing patterns | **Preclin** (PMID 41171075) |
| **Glutamate release machinery** | Presynaptic VGCC / SNARE-associated processes (indirect) | Reduction of glutamate release into the synaptic cleft | **Rev / Preclin** (Pedro 2025; Tolochko 2025, PMID 40508048) |
| **Metabotropic glutamate receptor interplay** | GRM1-related pathways (indirect modulation) | Downstream modulation of excitatory transmission via reduced glutamate availability | **Rev** (Reactome glutamate release cycle context) |

**Detailed evidence:**
- Patch-clamp work in differentiated SH-SY5Y neurons shows that riluzole inhibits maximal activation and inactivation of voltage-dependent Na⁺ conductance and delays rectifier K⁺ conductance, with altered voltage sensitivity (hyperpolarizing shifts) **(Preclin; PMID 41171075, Cazzola et al., 2025)**.
- In vivo microdialysis studies demonstrate that riluzole (500 µM locally) reduces neuronal glutamine-to-glutamate shuttle output, supporting a presynaptic glutamate-release inhibitory effect **(Preclin; PMID 40838767, Hershey et al., 2025)**.
- Review literature consistently describes riluzole as a dual-mechanism agent: (i) voltage-gated sodium channel blockade, and (ii) modulation of glutaminergic transmission, both central to excitotoxicity in ALS and spinal cord injury **(Rev; Pedro et al. 2025, PMID 41117139; Tolochko et al. 2025, PMID 40508048)**.

### 1.2 Downstream Pathways
- **Glutamate neurotransmitter release cycle** (Reactome R-HSA-210500): Riluzole indirectly dampens this cycle by reducing presynaptic glutamate release.
- **NMDA/AMPA receptor activation** (Reactome R-HSA-438066, R-HSA-399721): By lowering extracellular glutamate, riluzole attenuates ionotropic receptor overactivation implicated in excitotoxic motor neuron death.

### 1.3 Binding Site Notes
- Riluzole is a **use-dependent / state-dependent blocker** of voltage-gated Na⁺ channels rather than a competitive ligand at a defined orthosteric site. No high-resolution co-crystal structure with a defined channel subtype was retrievable from the current query set.
- It does **not** act as a direct NMDA receptor antagonist; the glutamatergic effect is presynaptic.

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## 2. Physicochemical Properties Relevant to CNS Penetration

### 2.1 Core Properties (PubChem CID 5070)

| Property | Value | CNS-Penetration Interpretation |
|---|---|---|
| **Molecular formula** | C₈H₅F₃N₂OS | — |
| **Molecular weight** | 234.2 Da | Favorable (cutoff ≈ 400–500 Da for BBB) |
| **XLogP** | 3.6 | Optimal lipophilicity range for passive BBB diffusion (logP 1–4 typical) |
| **TPSA** | 76.4 Ų | Moderate; below 90 Ų favors BBB permeation |
| **H-bond donors (HBD)** | 1 | Low; favors CNS entry |
| **H-bond acceptors (HBA)** | 7 | Moderate; within acceptable range |
| **Rotatable bonds** | 1 | Low flexibility; favorable for oral absorption and BBB permeation |
| **Heavy atoms** | 15 | Compact small-molecule profile |

### 2.2 Lipinski Assessment
- **Result:** Passes all four Lipinski criteria (MW ≤ 500, logP ≤ 5, HBD ≤ 5, HBA ≤ 10) **(Struct; PubChem-based check)**.
- **Verdict:** Strongly drug-like oral small molecule with physicochemical features well suited for blood–brain barrier (BBB) penetration.

### 2.3 CNS Penetration Clinical Evidence
- Riluzole is **FDA-approved for ALS**, a disease requiring robust CNS activity. Its efficacy in ALS, traumatic brain injury, and spinal cord injury trials implies meaningful CNS exposure **(CT / Rev)**.
- Standard pharmacology references report a **high volume of distribution** (~ extensive tissue distribution) and CNS distribution consistent with BBB permeation. Peak plasma concentrations occur ~1 hour post-dose in the fasted state; food delays Tmax and reduces AUC by approximately 20 %.

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## 3. Drug–Drug Interactions with Commonly Co-Prescribed Agents

### 3.1 Metabolic Pathway
- **Primary enzyme:** Cytochrome P450 1A2 (**CYP1A2**; UniProt P05177) **(Struct / Rev)**.
- **Major metabolite:** N-hydroxyriluzole (active metabolite with neuroprotective properties in some preclinical assays).
- **Secondary contribution:** CYP2E1 (minor) and direct glucuronidation.
- **Protein binding:** ~93 % (primarily to albumin); displacement interactions are theoretically possible but not clinically prominent.

### 3.2 Interaction Categories and Agents

| Co-prescribed agent class | Examples | Interaction mechanism | Clinical implication | Evidence quality |
|---|---|---|---|---|
| **CYP1A2 strong inhibitors** | Ciprofloxacin, fluvoxamine | ↓ clearance of riluzole; ↑ AUC and Cmax | Increased risk of adverse effects (nausea, dizziness, hepatic enzyme elevations); monitor or avoid strong inhibitors | **Struct / Rev** (CYP1A2 substrate classification; no direct RCT of ciprofloxacin + riluzole retrieved) |
| **CYP1A2 inducers** | Smoking (tobacco), omeprazole, rifampin, carbamazepine | ↑ CYP1A2 expression / activity; ↑ clearance of riluzole | May reduce riluzole exposure and potentially efficacy; smoking is a notable factor in ALS populations | **Rev / Obs** (well-established CYP1A2 pharmacogenetics; direct riluzole studies not retrieved in this query set) |
| **Proton pump inhibitors (PPIs)** | Omeprazole, esomeprazole | CYP1A2 induction (omeprazole); possible gastric pH effect on absorption | Variable; exposure reductions reported for some CYP1A2 substrates; monitor clinical response | **Obs / Rev** (no specific riluzole–PPI RCT retrieved) |
| **Caffeine / theophylline** | Caffeine-containing products, theophylline | Shared CYP1A2 substrate; competitive inhibition possible | Theophylline levels may increase modestly; caffeine effect generally minor at dietary doses | **Rev** (CYP1A2 competitive substrate mechanism) |
| **Hepatotoxic co-medications** | Alcohol, acetaminophen (chronic/high-dose), valproate | Additive hepatic stress | Riluzole carries a black-box / label warning for hepatotoxicity; avoid additive hepatotoxins where possible | **Rev / Obs** (label-based safety warning) |
| **Anesthetics / sedatives** | Sevoflurane | Pharmacodynamic: riluzole blocks persistent sodium currents involved in respiratory rhythmogenesis | Preclin data show riluzole attenuates sevoflurane-induced gasping dose-dependently; clinical relevance in perioperative setting requires caution | **Preclin** (PMID 41015483, Taiji et al., 2025) |

### 3.3 Co-Prescription Context in ALS
Commonly co-prescribed agents in ALS include:
- **PPIs / H2 blockers** (for gastroesophageal reflux and dysphagia-related aspiration risk)
- **Quinine / baclofen** (for cramps/spasticity)
- **Antidepressants** (e.g., SSRIs, TCAs) — many are CYP2D6 substrates/inhibitors; interaction with riluzole is generally minor because riluzole is primarily CYP1A2 dependent.
- **Riluzole + edaravone** — no major metabolic interaction; used together in ALS without compelling DDI evidence.

**Summary:** The dominant DDI axis for riluzole is **CYP1A2-mediated**. Smoking status and strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) are the most clinically actionable variables.

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## 4. Dosing Strategies to Improve Efficacy or Tolerability

### 4.1 Approved and Trial-Tested Dosing

| Regimen | Context | Evidence quality |
|---|---|---|
| **50 mg orally twice daily (100 mg/day)** | Standard approved dose for ALS | **CT** (pivotal Bensimon and Lacomblez trials; referenced in review literature) |
| **100 mg orally twice daily (200 mg/day)** | Higher-dose exploratory arms in ALS trials | **CT** (tested in dose-ranging studies; not superior in survival and less tolerable) |

### 4.2 Food Effect / Administration Timing
- **Fasted vs. fed:** Food decreases riluzole AUC by approximately 20 % and delays Tmax. For maximal and consistent exposure, riluzole is recommended to be taken **on an empty stomach** (1 hour before or 2 hours after a meal) **(Rev / PK data)**.
- **Timing:** BID dosing is typically spaced ~12 hours apart to maintain steady-state concentrations given the ~12-hour elimination half-life.

### 4.3 Efficacy-Supporting Evidence
- **ALS survival:** Pivotal RCTs (Bensimon et al.; Lacomblez et al.) demonstrated a modest but significant survival prolongation (~2–3 months) and slower decline in bulbar function with riluzole 100 mg/day vs. placebo **(CT; cited in review sources retrieved: Pedro 2025, Tolochko 2025)**.
- **Spinal cord injury (SCI):** The RISCIS and CSM-PROTECT multicenter RCTs tested riluzole in acute and degenerative cervical myelopathy; sub-studies established PK/PD frameworks for individualized dosing, with promising motor-function trends **(CT; PMID 41117139, Pedro et al. 2025)**.
- **Traumatic brain injury (TBI):** A randomized controlled trial evaluated riluzole for cognitive/functional outcomes after severe TBI; abstract unavailable in the retrieved set, limiting mechanistic detail **(CT; PMID 42045834, Shojaei et al., 2026)**.

### 4.4 Tolerability-Optimizing Strategies

| Strategy | Rationale / Evidence | Evidence quality |
|---|---|---|
| **Monitor hepatic enzymes at baseline and periodically** | Riluzole can cause reversible ALT/AST elevations; discontinuation may be required if >3× ULN or clinical jaundice occurs | **Rev / Obs** (product label; registry practice) |
| **Start at standard 50 mg BID; avoid empiric uptitration** | Dose-ranging trials showed 200 mg/day did not confer additional survival benefit and increased adverse events (asthenia, nausea, dizziness) | **CT** (dose-ranging studies referenced in ALS reviews) |
| **Administer on an empty stomach** | Improves bioavailability consistency and reduces variability | **Rev** (PK label data) |
| **Screen smoking status and adjust expectations** | Smoking induces CYP1A2 and may lower exposure; heavy smokers may have subtherapeutic levels, though formal dose-adjustment algorithms are not established | **Obs / Rev** (CYP1A2 pharmacogenetics) |
| **Avoid strong CYP1A2 inhibitors** | Reduces risk of supratherapeutic exposure and hepatotoxicity | **Rev** (metabolic pathway knowledge) |
| **Combination therapy** | Preclinical data (ATH-1105 + riluzole in TDP-43 mouse model) show additive neuroprotection, suggesting future multimodal dosing paradigms may improve efficacy without increasing riluzole dose **(Preclin; PMID 41586107, Berthiaume et al., 2025)** | **Preclin** |

### 4.5 Special Populations
- **Hepatic impairment:** Avoid or use with extreme caution in patients with baseline elevated transaminases or clinical liver disease; dose reduction not formally defined but prudent.
- **Renal impairment:** Limited data; no major active renal excretion pathway, but caution advised.
- **Elderly:** No specific RCT-driven dose adjustment; standard dosing used, with closer monitoring for AEs.

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## 5. Evidence Map and Gaps

| Question | Available evidence | Source type |
|---|---|---|
| Mechanism (Na⁺ channel blockade + glutamate modulation) | Strong | Preclin + Reviews |
| ALS survival benefit at 100 mg/day | Moderate–strong | Pivotal CT (Bensimon, Lacomblez) referenced in reviews |
| SCI efficacy signals | Emerging | Phase II/III RCTs (RISCIS, CSM-PROTECT) |
| TBI efficacy | Early / abstract unavailable | RCT (2026) |
| CYP1A2 DDI framework | Strong metabolic data; fewer direct riluzole DDI RCTs | UniProt / label / general CYP1A2 literature |
| Optimal timing (fasted vs. fed) | Moderate | PK label / review data |
| Higher-dose benefit (>100 mg/day) | Negative / no additional benefit | Dose-ranging CT (historical) |
| Combination dosing (e.g., + edaravone, + HGF modulators) | Preclinical promise; limited clinical dosing guidance | Preclin / small trials |

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## 6. Bottom Line

Riluzole is a **CNS-penetrant, CYP1A2-metabolized small molecule** with a dual mechanism: (1) voltage-gated sodium channel blockade and (2) presynaptic glutamate release inhibition. Its physicochemical profile (MW 234, logP 3.6, TPSA 76, 1 rotatable bond) is favorable for BBB permeation, consistent with its CNS indications. The principal drug–interaction axis is **CYP1A2** (inhibitors reduce clearance; smoking/omeprazole increase clearance). The **standard dose is 50 mg BID on an empty stomach**; higher doses lack efficacy advantage and worsen tolerability. Hepatic monitoring is mandatory. Evidence for efficacy is strongest in **ALS (pivotal RCTs)** and **SCI (phase II/III trials)**, with emerging data in TBI.

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*Document compiled from PubChem (CID 5070), UniProt (CYP1A2, SCN1A/2A/8A), OpenTargets, Reactome, and NCBI PubMed queries. Where specific RCT manuscripts were not individually retrieved, evidence is attributed to review sources that cite the pivotal trials.*