Half-life
Biological half-life (denoted t1/2) is the time required for a peptide plasma concentration to fall by half after administration. It is one of the most critical pharmacokinetic parameters: it governs dosing frequency, duration of action, and dictates the dosing strategy of a molecule. For research peptides, half-life ranges from a few minutes (native GLP-1: 1.5 min) to several days (semaglutide: 160 h, retatrutide: 6 days), depending on structure and chemical modifications.
Three factors primarily determine a peptide's half-life. First, resistance to circulating proteases. Native peptides are rapidly degraded by enzymes such as DPP-4 (dipeptidyl peptidase-4), which cleaves after Ala/Pro at position 2, or by ubiquitous aminopeptidases and endopeptidases. Strategic substitutions — Aib2 in semaglutide, C-terminal cyclization, D-amino acids — drastically extend enzymatic resistance. Second, binding to plasma carriers. Acylation by a fatty acid chain (C18 diacid for semaglutide, C20 for tirzepatide and retatrutide) enables reversible binding to serum albumin, providing a circulating reservoir that slows clearance. Third, renal filtration. Small peptides (<30 kDa) are glomerular-filtered and excreted in urine. PEGylation or fusion to carrier proteins increases apparent mass above this threshold, thereby prolonging half-life.
Two distinct pharmacokinetic half-lives are distinguished. Distribution half-life (t1/2 alpha) corresponds to the initial, rapid phase during which the peptide redistributes between blood and peripheral tissues. Elimination half-life (t1/2 beta or terminal) reflects progressive disappearance via metabolism and excretion — this is the one typically reported in clinical studies. The ratio between these phases informs on peptide behavior: significant tissue distribution apparently extends terminal half-life by creating a peripheral reservoir.
Half-life directly determines the dosing schedule. A short half-life (<2h) requires multiple daily administrations, barely compatible with chronic use. A 12-24h half-life enables once-daily dosing (e.g., liraglutide, t1/2 = 13h). A 5-7 day half-life opens the door to weekly administration (semaglutide, tirzepatide, retatrutide) and revolutionizes therapeutic adherence. Beyond a week, we enter the domain of monthly formulations or sustained-release depots.
For a research peptide, knowing the half-life enables planning in vivo experiments and kinetic sampling. After 4-5 half-lives, concentration falls below 5% of the initial peak — the biological effect is then nearly extinct. This information, provided in reference publications (phase 1 studies of GLP-1 agonists, pharmacological data on PubMed), guides experimental protocol choice: single versus repeated dose, observation window, measurement timing.