Tirzepatide — pharmacology
Molecular targets, mechanism of action, pharmacokinetics and interactions as characterised in humans.
§2Pharmacology
§2.1Molecular targets
Table 2. Molecular targets recorded for Tirzepatide, with the character of the interaction and the potency where the Institute holds it.
| Target | Interaction | Note |
|---|---|---|
| GIP receptor (GIPR) | Full agonist | Affinity comparable to native GIP |
| GLP-1 receptor (GLP1R) | Biased partial agonist | Approximately five-fold lower affinity than native GLP-1, with signalling bias towards cyclic AMP over beta-arrestin recruitment |
| Albumin (non-receptor) | Reversible binding via C20 diacid | Supports weekly dosing |
§2.2Mechanism of action
Tirzepatide engages both incretin receptors from a single molecule. GLP-1 receptor agonism reproduces the insulinotropic, glucagonostatic, gastric and central appetite effects of the selective class. Concurrent GIP receptor agonism contributes additional insulinotropic action at hyperglycaemia and, in preclinical work, acts on adipose tissue and on central GIP receptor populations in a way that appears to improve tolerability relative to equipotent selective GLP-1 exposure. The relative contribution of each arm to the weight effect in humans remains unresolved, and the Institute treats mechanistic attribution here as an open question rather than a settled matter.[1,2]
§2.3Pharmacokinetics
- Terminal half-life
- ≈5 days
- Time to maximum concentration
- 8–72 h after subcutaneous injection
- Volume of distribution
- ≈10.3 L
- Plasma protein binding
- ≈99 % (albumin)
- Clearance
- ≈0.06 L/h
- Bioavailability
- ≈80 % absolute bioavailability
Proteolysis of the peptide backbone with beta-oxidation of the C20 diacid; metabolites excreted in urine and faeces. Steady state is reached in approximately four weeks.
§2.4Interactions
- Oral contraceptives — reduced exposure after dose escalation
- Insulin and secretagogues — hypoglycaemia risk
- Delayed gastric emptying may alter absorption rate of concomitant oral medicines
References cited on this page
References are numbered in order of first citation in this document. Each superscript in the text links to its entry below.
- Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A. Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine 2022;387(3):205–216. doi:10.1056/NEJMoa2206038 · PMID 35658024
- Garvey WT, Frias JP, Jastreboff AM, le Roux CW, Sattar N, Aizenberg D, Mao H, Zhang S, Ahmad NN, Bunck MC, Benabbad I, Zhang XM. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. The Lancet 2023;402(10402):613–626. doi:10.1016/S0140-6736(23)01200-X · PMID 37385275
Identifiers are reproduced only where the Institute holds them. Where a digital object identifier or PubMed identifier is not shown, the Institute has recorded the journal and year and has not constructed an identifier.