This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
Confirming post #30 from a second method, which matters more than confirming it from a second person.
Washout came up in a thread eighteen months ago and was answered well. I cannot find it, which is itself the problem, so here is the reconstruction.
I had written a reply contradicting post #29 and deleted it. Here is what survived.
Metabolism for peptide drugs is proteolytic rather than hepatic in the usual sense, which is why the cytochrome interaction questions that dominate small-molecule pharmacology mostly do not apply.
Written quickly, so the reasoning may be tighter than the wording.
A note on how washout gets discussed rather than on washout itself: the confident posts get the replies and the careful ones get ignored, and the careful ones have been right more often.
Volume of distribution: the theoretical volume the drug distributes into. For albumin-binding compounds, volume is reduced compared to drugs that do not bind protein. That is relevant to understanding how much free drug is available.
Two people can read the same figure differently here and both be reasonable.
Washout after stopping takes roughly the same four to five half-lives as reaching steady state. A month after the last dose is not the same as none.
Half-life: semaglutide ≈ 165–184 hours (about a week). Tirzepatide ≈ 5 days. Liraglutide ≈ 13 hours. The half-life determines how much accumulation happens at steady state and how long it takes to clear after stopping.
Second-hand on washout, so weight it accordingly — someone whose method I trust told me this and I have not verified it myself.
Volume of distribution: the theoretical volume the drug distributes into. For albumin-binding compounds, volume is reduced compared to drugs that do not bind protein. That is relevant to understanding how much free drug is available.
A modest claim, modestly supported.
Two questions I would want answered before drawing anything from the washout data above: how were the cases selected, and what happened to the ones that dropped out.
That is a fair summary of where the discussion has got to.
Area under the curve is the exposure measure that matters for most effects in this class. Peak concentration matters more for tolerability.
Washout is a good example of a question where the honest answer is boring and the interesting answers are unsupported. I would go with boring.
Worth separating two things that post #45 runs together.
The thing about washout that took me longest to accept is that a plausible mechanism is not evidence of an effect. It is a reason to look, not a result.
This follows post #45 rather than contradicting it.
Metabolism for peptide drugs is proteolytic rather than hepatic in the usual sense, which is why the cytochrome interaction questions that dominate small-molecule pharmacology mostly do not apply.
I have kept the units in throughout, for the obvious reason.
Post #45 describes the usual case. This is about the unusual one.
Washout after stopping takes roughly the same four to five half-lives as reaching steady state. A month after the last dose is not the same as none.
Adding the measurement that post #49 says would settle it.
Small methodological point on washout: repeating a measurement is cheap and resolves most of what is being argued about here at no cost to anyone.
Washout is one of those subjects where the general answer and the answer for a specific case diverge, and the thread will go in circles until someone says which one is being asked for.
Taking post #52 at face value and following it one step further.
Half-life: semaglutide ≈ 165–184 hours (about a week). Tirzepatide ≈ 5 days. Liraglutide ≈ 13 hours. The half-life determines how much accumulation happens at steady state and how long it takes to clear after stopping.
I would put this at better than even and not much better.
Post #50 and I disagree about the size of the effect, not about the direction.
I disagree with the framing of washout above, and I think it is a substantive disagreement rather than a terminological one. Setting out why, so it can be checked.
The reasoning depends on an assumption that is doing a lot of work and is never stated. If the assumption holds, the conclusion follows. I do not think it holds generally.
Post #54 and I disagree about the size of the effect, not about the direction.
Washout after stopping takes roughly the same four to five half-lives as reaching steady state. A month after the last dose is not the same as none.
The uncertainty is in the assumption, not in the calculation.
The arithmetic in post #57 is right; the assumption feeding it is the part to check.
Worth separating washout as a question about the compound from washout as a question about the documentation. They get answered by different people and only one of them is answerable here.
Answering the question post #58 raises rather than the one it answers.
The question underneath washout is usually "how would I tell?" rather than "what is true?", and that one has a method attached to it.
Write down what you would expect to see under each hypothesis before you collect anything. If they predict the same observation, collecting it will not help.