This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1 · go to the accepted answer.
The bit of Clearance pathways that nobody enjoys is that the answer changes depending on what you are trying to decide with it. Say what the decision is and the thread will converge.
Second-hand on Clearance pathways, so weight it accordingly — someone whose method I trust told me this and I have not verified it myself.
Answering the question post #29 raises rather than the one it answers.
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.
Reframing Clearance pathways slightly, because I think the disagreement is about the question rather than the answer. If the question is "does it happen", yes. If it is "how often", nobody here knows.
The documentation on Clearance pathways is better than this thread and I say that as someone who has posted in the thread.
Post #33 is the version of this I will quote in future. One addition.
Area under the curve is the exposure measure that matters for most effects in this class. Peak concentration matters more for tolerability.
The answer changed when I changed how I was measuring, which was informative.
Adding what did not work for me on Clearance pathways, since the failures never get written up and they are half the useful information.
Moving an injection by a day changes the concentration-time profile very little at these half-lives. It can change when somebody notices symptoms, which is a different and real thing.
I am not the right person to answer the follow-up to this.
Worth separating two things that post #37 runs together.
My understanding of Clearance pathways is a few years old and may have been superseded. If it has been, I would genuinely like to know rather than keep repeating it.
Renal clearance: these compounds are cleared partly via the kidney. In severe renal impairment, clearance is slowed and accumulation risk is higher. Dose adjustments might be needed.
The arithmetic in post #38 is right; the assumption feeding it is the part to check.
Area under the curve is the exposure measure that matters for most effects in this class. Peak concentration matters more for tolerability.
Answering the question post #40 raises rather than the one it answers.
Taking Clearance pathways seriously for a moment rather than deflecting: the honest position is that the community has observations and no controlled comparison, and those two things support very different sentences.
Marking my uncertainty on Clearance pathways explicitly. I am confident about the direction, much less confident about the size, and not confident at all that it generalises past the case in the first post.
Renal impairment changes clearance for some compounds in this class and not others, and the published data is compound-specific rather than class-wide.
Two sources, same conclusion, and I could not rule out that one copied the other.
Everything in post #45 holds. The case it does not cover is the one I have.
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.
Right, and stated more narrowly than I would have dared to state it.
Genuine question rather than a rhetorical one: has anyone here actually observed Clearance pathways, as opposed to read about it? The thread is long and I cannot tell.
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.
On post #48 — agreed on the reasoning, with one qualification.
I think the Clearance pathways question is answerable and has not been answered, which is a more optimistic position than most of this thread.
Clearance pathways would be much easier to settle if anyone reported the denominator. Almost nobody reports the denominator.
What I would tell a new member reading about Clearance pathways for the first time: the confident posts are not the reliable ones, and the reliable ones are longer.
Post #51 describes the usual case. This is about the unusual one.
Renal clearance: these compounds are cleared partly via the kidney. In severe renal impairment, clearance is slowed and accumulation risk is higher. Dose adjustments might be needed.
No disagreement from me. Posting only so the question does not look ignored.
Clearance pathways sits at the boundary between what this community can usefully discuss and what it cannot, and I think it falls on the discussable side, narrowly.
A pharmacokinetic model fitted to trial data describes the population studied. Applying it to somebody outside the enrolled range is an extrapolation, and the model will not tell you it is.
I have left out the parts I could not verify.
Two claims get bundled together under Clearance pathways and they need separating. The descriptive one — this is what was observed — is usually well supported. The causal one — this is why — usually is not.
Almost every disagreement in threads like this one dissolves once you say which of the two you are making.