SS-31 (elamipretide; Szeto-Schiller Peptide 31; D-Arg-dimethylTyr-Lys-Phe-NH₂) has a plasma half-life of approximately 2 hours following intravenous administration in animal studies[1]. Limited human pharmacokinetic data from Phase 2 clinical trials in heart failure indicates a similar short half-life. SS-31 is a mitochondria-targeted antioxidant tetrapeptide that selectively partitions to the inner mitochondrial membrane via cardiolipin interaction, reducing mitochondrial reactive oxygen species (ROS) and restoring electron transport chain efficiency. Phase 2 trials in heart failure have been completed; SS-31 is not FDA-approved for any indication as of May 2026. Of the five compounds on this page, SS-31 has the strongest human evidence base — but remains a research compound.
| Parameter | Value | Source |
|---|---|---|
| Plasma Half-Life (IV, animal) | ~2 hours | Chatfield et al. 2019 [1] |
| Plasma Half-Life (SC, human) | Limited published data; similar order of magnitude | Phase 2 trial data (not fully published) |
| Time to Peak (Tmax) — SC | No comprehensive published data | — |
| Route(s) of Administration | SC injection, IV infusion | — |
| Plasma Protein Binding | No published data | — |
| Full Clearance (5 × t½) | ~10 hours (estimated from animal PK) | Calculated from animal data |
| Mitochondrial Retention | Longer than plasma — cardiolipin binding | Mechanism data [1] |
| Standard Research Protocol | Once daily SC injection; 40 mg/day in Phase 2 trials | PROGRESS-HF trial protocol |
| Data Quality | Animal Study + Early Human Trials (Phase 2) — Not FDA approved as of May 2026 | — |
SS-31 (elamipretide) has a plasma half-life of approximately 2 hours following intravenous administration in animal pharmacokinetic studies, as reviewed in Chatfield et al. (2019, PMID 30898597)[1], which examined elamipretide's effects in pediatric cardiomyopathy associated with Barth syndrome. Phase 2 clinical trials in heart failure have characterized limited human PK parameters, indicating a similar short systemic half-life in humans, though comprehensive published human pharmacokinetic studies are not available in the peer-reviewed literature as of May 2026.
SS-31's approximately 2-hour half-life is substantially longer than most small unmodified peptides of similar size (a tetrapeptide), due to two structural modifications that confer metabolic stability: (1) D-arginine at position 1 — D-amino acids are not substrates for L-amino acid-specific serum peptidases that rapidly degrade most peptides; (2) dimethyltyrosine (2′,6′-dimethyltyrosine) at position 2 — this sterically bulky modification provides additional protection against enzymatic N-terminal cleavage. Together, these features give SS-31 protease resistance that extends its plasma half-life from the seconds-to-minutes range expected for an unmodified tetrapeptide to approximately 2 hours[1].
SS-31's plasma half-life of ~2 hours is primarily derived from animal pharmacokinetic studies in which intravenous administration allowed direct measurement of the plasma concentration-time curve without the confounding absorption phase of subcutaneous injection. For human administration (subcutaneous), the absorption phase extends the apparent half-life, and Tmax shifts from minutes (IV) to approximately 1–4 hours post-injection. Comprehensive published human PK studies characterizing Tmax, AUC, volume of distribution, and clearance for subcutaneous elamipretide have not been published in the peer-reviewed literature, limiting direct human-to-animal extrapolation[1].
SS-31's most pharmacokinetically distinctive feature is its selective accumulation in mitochondria. The cationic amphipathic structure of SS-31 (alternating aromatic and cationic residues: D-Arg-dimethylTyr-Lys-Phe) enables it to selectively partition to the inner mitochondrial membrane by interacting with cardiolipin — a phospholipid almost exclusively located on the inner mitochondrial membrane. Once bound to cardiolipin, SS-31 localizes at the mitochondrial inner membrane at concentrations substantially higher than plasma, and its functional residence at this site outlasts plasma clearance. This means the ~2-hour plasma half-life underestimates the compound's functional half-life at its site of action[1].
Based on the approximately 2-hour plasma half-life from animal data, systemic plasma clearance would be expected within approximately 10 hours after the last dose:
| Half-Lives Elapsed | Time After Last Dose | % Remaining in Plasma |
|---|---|---|
| 1 | ~2 hours | 50% |
| 2 | ~4 hours | 25% |
| 3 | ~6 hours | 12.5% |
| 4 | ~8 hours | 6.25% |
| 5 (clearance threshold) | ~10 hours | ~3% |
| Mitochondrial retention | Longer than plasma (cardiolipin binding) | — |
After subcutaneous injection, SS-31 is absorbed over approximately 1–4 hours, reaches peak plasma concentration, then clears with a half-life of approximately 2 hours. Total plasma clearance occurs within ~10 hours. Mitochondrial functional effects — cardiolipin interaction, ROS reduction, electron transport chain efficiency — persist beyond plasma clearance through mitochondrial localization of the compound at its site of action[1].
In Phase 2 clinical trials (PROGRESS-HF and related studies), elamipretide was administered as once-daily subcutaneous injections at 40 mg/day. The once-daily dosing interval is longer than the ~2-hour plasma half-life, reflecting the reliance on mitochondrial localization for sustained effect rather than continuous plasma concentration maintenance. SS-31's mitochondrial accumulation via cardiolipin binding creates a functional depot at the site of action that supports once-daily dosing despite the short plasma half-life[1].
| Compound | Plasma Half-Life | Data Quality | Primary Mechanism |
|---|---|---|---|
| SS-31 (Elamipretide) | ~2 hr IV (animal/limited human) | Animal + Phase 2 trials | Cardiolipin binding, mitochondrial ROS reduction |
| BPC-157 | ~15 min (SC, rat) | Animal Study | VEGFR2, Akt-eNOS signaling |
| TB-500 | Not established | Inferred — no published PK | Actin polymerisation, VEGF |
| GHK-Cu | ~0.5–1 hr (estimated) | Animal/In-vitro | TGF-β, collagen synthesis |
| Route | Half-Life | Bioavailability | Tmax | Notes |
|---|---|---|---|---|
| Subcutaneous | ~2 hr (similar to IV, animal est.) | No published data | ~1–4 hours (estimated) | Used in Phase 2 trials (40 mg/day); once-daily protocol |
| Intravenous | ~2 hours (animal studies) | 100% | Minutes (end of infusion) | Reference route; used in some trial protocols |
| Oral | Not viable | Very low (peptide degradation) | Unknown | Not used in research or trials |
SS-31 (elamipretide) is not detected by standard workplace urine drug screens, WADA anti-doping panels, or any broadly deployed drug testing platform. Standard immunoassay and GC-MS drug test panels do not include elamipretide. SS-31 is not on WADA's monitoring program as of May 2026.
No published forensic detection study has characterized the urinary detection window for SS-31. Given the approximately 2-hour plasma half-life, any urine detection window using specialized LC-MS/MS would likely be limited to within hours of the last dose. The D-amino acid composition may produce metabolites distinguishable from endogenous L-amino acid-containing peptides, potentially enabling detection, but no published method exists for SS-31 urinary testing.
SS-31's approximately 2-hour plasma half-life reflects the balance between its structural protease resistance and the clearance mechanisms available for modified peptides. The D-Arg at position 1 resists exopeptidase cleavage (aminopeptidases are L-amino acid specific), and the dimethyltyrosine at position 2 provides steric hindrance against endopeptidase action. These modifications extend SS-31's plasma half-life from the seconds-to-minutes range of unmodified tetrapeptides to approximately 2 hours[1]. Clearance ultimately occurs via renal filtration (the tetrapeptide is small enough for glomerular filtration) and residual endopeptidase activity at the amide bonds between positions 2-3 and 3-4.
SS-31's primary mechanism is its selective accumulation at the inner mitochondrial membrane via cardiolipin interaction. Cardiolipin is a unique phospholipid almost exclusively found on the inner mitochondrial membrane. SS-31's alternating aromatic and cationic residues (D-Arg-dimethylTyr-Lys-Phe) create an amphipathic structure that binds selectively to cardiolipin's polar head groups. This cardiolipin interaction has two functional consequences: (1) SS-31 acts as a mitochondrial antioxidant by scavenging reactive oxygen species (ROS) at the site of their primary production (electron transport chain complexes I and III); (2) SS-31 stabilizes cardiolipin's role in organizing electron transport chain complexes into supercomplexes (respirasomes), improving oxidative phosphorylation efficiency[1].
Chatfield et al. (2019)[1] demonstrated that elamipretide improved mitochondrial function in lymphoblasts from pediatric patients with Barth syndrome — a condition characterized by cardiolipin deficiency and mitochondrial dysfunction. This study, alongside the PROGRESS-HF program, established that SS-31's mitochondrial mechanism translates from in vitro models to animal studies to human clinical outcomes — making SS-31 unique among the compounds on this page in having a mechanistic chain of evidence from biochemistry to Phase 2 human trials.
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