Reading about receptor desensitisation and trying to work out which of the effects adapt over time and which do not, because people clearly experience both.
Numbers worth memorising for this class: Tmax one to three days for the weekly peptides, terminal half-life about a week for semaglutide and about five days for tirzepatide, steady state at four to five half-lives, subcutaneous bioavailability high enough that site choice is irrelevant.
What would genuinely help is knowing which effects tachyphylax and which persist, because the answer explains why tolerability improves while the appetite effect keeps working.
Not looking for reassurance. Looking for the part I have got wrong.
BrianDallas92 said:Reading about receptor desensitisation and trying to work out which of the effects adapt over time and which do not, because people clearly experience…
Receptor pharmacology relevant to the pharmacology: semaglutide is a GLP-1R agonist with a C-18 fatty acid chain that enables albumin binding (>99%), creating a depot effect with a ~168-hour half-life enabling weekly dosing[1].
Tirzepatide is a dual GIP/GLP-1R agonist with higher GIP affinity (5:1 GIP:GLP-1 potency ratio). The GIP component may enhance beta-cell function and adipocyte lipid metabolism beyond what GLP-1 alone achieves.
For the pharmacology, the pharmacology explains the clinical differences between these agents.
[1] Lau J, et al. J Med Chem. 2015;58(18):7370-7380.
LarryQC_SD said:Receptor pharmacology relevant to the pharmacology: semaglutide is a GLP-1R agonist with a C-18 fatty acid chain that enables albumin binding (>99%),…
That is correct as far as it goes, and here is where it stops going. The pharmacokinetics explain nearly every practical question asked here. Albumin binding above 99% slows clearance enough to make weekly dosing possible; a terminal half-life near a week means four to five weeks to steady state and therefore a four-week titration interval; subcutaneous bioavailability around 89% means injection site barely matters. Those three facts answer most timing questions before they are asked.
I would rather be corrected than agreed with, if it comes to it.
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Browse GL BiochemBrianDallas92 said:Reading about receptor desensitisation and trying to work out which of the effects adapt over time and which do not, because people clearly experience…
This matches mine closely enough to be worth saying so out loud.
Adding the clinical framing, because it changes how the question reads.
Amycretin (AMY/GLP-1 dual agonist) emerging data relevant to the pharmacology: Phase 1 showed -13.1% body weight at only 12 weeks, the fastest trajectory ever seen for an anti-obesity agent[1].
Amylin receptor agonism enhances satiety signaling through the area postrema and reduces glucagon secretion. Combined with GLP-1R agonism, this dual mechanism may produce even greater efficacy than current agents.
Early-stage data — interpret with caution. But the trajectory is extraordinary.
[1] Novo Nordisk investor presentation, September 2023.