# Compound Dive: Riluzole (CHEMBL1201585 / CID 5070)

**Date:** 2026-05-04
**Compound:** 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine
**Formula:** C8H5F3N2OS | **MW:** 234.2 Da
**Canonical SMILES:** C1=CC2=C(C=C1OC(F)(F)F)SC(=N2)N
**Status:** Approved (ALS); investigational in TBI, epilepsy, MSA, glioblastoma

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## (a) Mechanism of Action & Binding Partners

### Primary Mechanism
Riluzole is a **multitarget neuroprotective agent**. Its principal mechanism in ALS is the **use-dependent blockade of presynaptic voltage-gated sodium channels (Nav)**, particularly at high-frequency firing. By reducing inward sodium currents, riluzole attenuates membrane depolarization and thereby **decreases calcium-dependent presynaptic glutamate release**. This reduces excitotoxic stress on motor neurons.

**Targets / Binding Partners (established or proposed):**

| Target | Type | Evidence Level | Notes |
|--------|------|----------------|-------|
| **Voltage-gated Na+ channels (Nav)** | Channel blocker | Preclinical + accepted pharmacology | Use-dependent block; decreases glutamate release |
| **GRIA1 / GRIA2 (AMPA receptor subunits)** | Ionotropic glutamate receptor | Preclinical | Modulatory effects on AMPA receptor function reported |
| **GRM1 (mGluR1)** | Metabotropic glutamate receptor | Preclinical / pathway proximity | Receptor for glutamate in CNS; riluzole’s downstream effect reduces glutamatergic tone |
| **GABA-A receptor** | Ligand-gated Cl- channel | Preclinical | Potential positive modulation; may contribute to neuroprotection |
| **K+ channels** | Potassium channel modulation | Preclinical | Some reports suggest effects on outward K+ currents |
| **SOD1** |ALS disease protein|Observational|ALS patients with SOD1 mutations receive riluzole as standard of care, though riluzole does not bind SOD1 directly|

> **Evidence source note:** The presynaptic Nav/glutamate-release mechanism is the accepted clinical pharmacology taught in prescribing references. Direct biophysical binding studies (e.g., patch-clamp) underpinning this are **preclinical / in vitro**. Clinical trial data in ALS (see landmark trials) support efficacy consistent with this mechanism, but do not directly prove target engagement in human motor neurons.

### Pharmacodynamic Context in ALS
Glutamate excitotoxicity is a central hypothesis in ALS pathogenesis. Riluzole does **not** act as a competitive antagonist at postsynaptic glutamate receptors. Instead, it indirectly lowers synaptic glutamate concentration by reducing presynaptic release. This distinguishes it from agents like perampanel (AMPA antagonist) or memantine (NMDA antagonist).

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## (b) Physicochemical Properties Relevant to CNS Penetration

### PubChem / Computed Descriptors

| Property | Value | CNS Relevance |
|----------|-------|----------------|
| Molecular Weight | **234.2 Da** | Well below BBB cutoffs (~400–500 Da); favorable |
| XLogP | **3.6** | Lipophilic; optimal range for passive BBB permeation (logP 2–4) |
| TPSA | **76.4 Ų** | Moderate; below 90 Ų threshold associated with good CNS permeation |
| H-bond Donors (HBD) | **1** | Low; favors BBB crossing |
| H-bond Acceptors (HBA) | **7** | Moderate |
| Rotatable Bonds | **1** | Low; rigid molecule may have favorable permeation profile |
| Charge (pH 7.4) | **0** (neutral) | Neutral species cross BBB more readily |

### Lipinski’s Rule of Five
**Passes all four criteria**: MW ≤ 500 (yes), XLogP ≤ 5 (yes), HBD ≤ 5 (yes), HBA ≤ 10 (yes). Riluzole is drug-like and small-molecule CNS-penetrant.

### CNS Penetration Nuances
- **P-glycoprotein (P-gp / ABCB1) substrate:** Preclinical studies in mice (PMID: 39793633) demonstrate that brain uptake of riluzole is limited by **active efflux at the blood-brain barrier**. Co-administration of elacridar (a P-gp/BCRP inhibitor) substantially increased brain levels of intranasally delivered riluzole. This suggests that even with favorable lipophilicity, **efflux limits CNS exposure** in humans and may contribute to interindividual variability.
- **Intranasal delivery:** Preclinical work (mice) shows intranasal riluzole achieves **double the brain levels** at 30 min compared to oral delivery, with lower liver exposure (PMID: 39793633). This is research-stage.

> **Evidence levels:**
> - *Computed properties / Lipinski:* In silico (PubChem)
> - *Oral bioavailability / human PK:* Clinical pharmacokinetic study in healthy volunteers (PMID: 9549636)
> - *P-gp efflux / intranasal delivery:* Preclinical (mouse) (PMID: 39793633)

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

### Metabolic Pathway
Riluzole is **extensively metabolized by hepatic CYP1A2** and is also a substrate for glucuronidation. CYP1A2 activity is therefore the primary determinant of clearance.

### High-Fat Food
A high-fat meal significantly **reduces both the rate and extent** of riluzole absorption:
- Cmax reduced by ~44% (216 vs. 387 ng/mL)
- AUC reduced by ~17% (1,047 vs. 1,269 ng·h/mL)
- tmax delayed (~2 h vs. 0.8 h)

**Clinical implication:** Riluzole should be taken on an empty stomach (1 hour before or 2 hours after a meal) to ensure consistent exposure.

> **Evidence:** Clinical PK study in healthy volunteers (PMID: 9549636)

### CYP1A2 Interactions

| Interacting Agent | Effect on Riluzole | Clinical Action |
|-------------------|-------------------|---------------|
| **Cigarette smoking** | ↓ Levels (CYP1A2 induction) | May reduce efficacy; monitor clinical response |
| **CYP1A2 inducers** (e.g., carbamazepine, phenytoin, rifampicin) | ↓ Levels | Potential for reduced efficacy |
| **CYP1A2 inhibitors** (e.g., ciprofloxacin, fluvoxamine, enoxacin) | ↑ Levels / toxicity risk | Co-administration generally **contraindicated** or requires caution |
| **Theophylline, caffeine** | Mutual CYP1A2 competition | Possible altered clearance of both |

### Hepatotoxicity Risk
Riluzole carries a **black-box warning / prominent precaution for hepatotoxicity**. Concomitant use with other hepatotoxic agents (e.g., heavy alcohol use, high-dose acetaminophen, certain antiepileptics) may increase risk.

**Monitoring:** Baseline and periodic liver function tests (ALT/AST/bilirubin) are required.

### Commonly Co-Prescribed Agents in ALS
| Agent | Interaction Concern | Level |
|-------|---------------------|-------|
| **Baclofen / tizanidine** (spasticity) | Additive CNS depression possible | Theoretical / clinical experience |
| **Pyridostigmine** (if used) | None major documented | — |
| **NIV / ventilatory support meds** | None direct | — |
| **Edaravone** | No major metabolic interaction documented; both may affect oxidative stress pathways | Observational / clinical practice |
| **Statins** (for comorbid CV risk) | Observational data from PRO-ACT showed no significant association with survival when co-prescribed with riluzole (PMID: 42013513) | Observational cohort |

> **Evidence levels:**
> - *Food effect, bioavailability, CYP1A2 role:* Clinical pharmacokinetic study (PMID: 9549636)
> - *Statin co-prescription:* Observational cohort analysis (PRO-ACT database) (PMID: 42013513)
> - *Specific CYP1A2 drug-drug interaction predictions:* Prescribing information / pharmacology textbooks (extrapolated from CYP1A2 metabolism)

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## (d) Dosing Strategies to Improve Efficacy or Tolerability

### Standard Regimen
- **50 mg orally twice daily** (total 100 mg/day)
- Take on an empty stomach for optimal absorption

### Dose-Exposure Relationship
- Pharmacokinetics are **linear** over the clinically relevant range (PMID: 9549636).
- Cmax occurs at ~1–1.5 hours (fasted).
- Absolute oral bioavailability is **~60%**.
- Terminal half-life is dose-independent.
- Steady-state achieved within ~5 days of repeated dosing.

### Dosing Comparison
In one clinical PK study, **75 mg BID** produced significantly higher trough concentrations than **50 mg TID**, despite similar AUCs (PMID: 9549636). This has implications for sustained target coverage, though the clinical relevance of trough differences is not fully established.

### Hepatotoxicity-Driven Dose Adjustment
- If ALT exceeds 3× ULN, dose should generally be reduced or drug stopped per prescribing guidance.
- Rechallenge may be considered at a lower dose if hepatic enzymes normalize and benefits outweigh risks.

### Tolerability Strategies
Common adverse effects include:
- Asthenia
- Nausea / gastrointestinal upset
- Elevated transaminases
- Dizziness

**Practical strategies (clinical practice / supportive care):**
1. **Administer on empty stomach** — improves predictability of exposure (not necessarily tolerability, but avoids variable absorption).
2. **Dose timing around meals** — if nausea is problematic, some clinicians allow administration with a light snack, recognizing this lowers Cmax and may reduce efficacy predictability. Evidence for this trade-off is **expert opinion / clinical practice**, not RCT-derived.
3. **Liver enzyme monitoring** — baseline, then periodically; earlier and more frequent if symptoms arise.

### Emerging / Investigational Strategies
| Strategy | Status | Evidence Base |
|----------|--------|---------------|
| **Intranasal delivery** | Preclinical only | Mouse study (PMID: 39793633); aimed at bypassing BBB efflux and first-pass metabolism |
| **Efflux pump inhibition (elacridar co-administration)** | Research-stage | Mouse study; increased brain levels but also increased liver/blood exposure — selectivity challenge |
| **TBD formulations / nanoparticle delivery** | Preclinical | Carbon-dot riluzole in glioblastoma spheroids (PMID: 42009312) — research tool, not clinical dosing strategy |

### Evidence Hierarchy for Dosing
- **RCT evidence for 50 mg BID:** Landmark ALS randomized controlled trials (Bensimon et al., 1994; Lacomblez et al., 1996) established this dose as effective versus placebo for survival prolongation.
- **Food effect / absorption:** Single- and multiple-dose PK study in healthy volunteers (PMID: 9549636) — clinical trial level evidence for pharmacokinetics.
- **Hepatic monitoring / dose modification:** Derived from post-marketing surveillance and prescribing information; largely observational / regulatory.
- **Intranasal / P-gp inhibition:** Preclinical (mouse) only; no human dosing recommendation supported.

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## Summary Table: Evidence Levels

| Claim | Evidence Source | Level |
|-------|-----------------|-------|
| Presynaptic Nav block → ↓ glutamate release | Patch-clamp / electrophysiology literature | Preclinical (accepted MoA) |
| AMPA / GABA-A / K+ channel modulation | Receptor pharmacology literature | Preclinical / mixed |
| MW 234, logP 3.6, passes Lipinski | PubChem / in silico | Computational |
| 60% oral bioavailability, food reduces absorption | Le Liboux et al., J Clin Pharmacol 1997 (PMID: 9549636) | Clinical PK trial (healthy volunteers) |
| P-gp efflux limits BBB penetration | Baker et al., Int J Pharm 2025 (PMID: 39793633) | Preclinical (mouse) |
| CYP1A2 metabolism | Prescribing references / FDA label | Clinical pharmacology (accepted) |
| Statin co-prescription neutral on survival | Saldanha-Castro et al., J Neurol Sci 2026 (PMID: 42013513) | Observational cohort (PRO-ACT) |
| 50 mg BID prolongs survival in ALS | Bensimon et al., Lacomblez et al. | RCT (landmark ALS trials) |
| Intranasal dosing doubles brain exposure | Baker et al., 2025 | Preclinical (mouse) |
| Hepatotoxicity precaution | Post-marketing / FDA label | Observational / regulatory |

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## References (Key)
1. Le Liboux A, Lefebvre P, et al. *J Clin Pharmacol*. 1997;37(10):915–927. (PMID: 9549636) — Human PK, single + multiple dose, food effect.
2. Baker RS, Wang JTW, et al. *Int J Pharm*. 2025;XXX:125195. (PMID: 39793633) — Intranasal delivery, P-gp efflux in mice.
3. Saldanha-Castro P, Vyas MV, et al. *J Neurol Sci*. 2026;XXX:125916. (PMID: 42013513) — Statin use & ALS survival (observational).
4. PubChem CID 5070. https://pubchem.ncbi.nlm.nih.gov/compound/5070 — Physicochemical properties.
5. Bensimon G, et al. *N Engl J Med*. 1994;330(9):585–591. — Landmark ALS RCT (cited as standard-of-care evidence).
6. Lacomblez L, et al. *Lancet*. 1996;347(9013):1425–1431. — Confirmatory ALS RCT.
7. Riluzole FDA Prescribing Information (Rilutek / Exservan / Tiglutik). — Hepatotoxicity, CYP1A2, dosing guidance.