Gemfibrozil
Gemfibrozil. Older PPARα agonist — similar TG/HDL profile to fenofibrate. Problematic CYP2C8 inhibition → raises statin levels → substantial… Oral half-life 1.5 h.
Older PPARα agonist — similar TG/HDL profile to fenofibrate. Problematic CYP2C8 inhibition → raises statin levels → substantial rhabdomyolysis signal. Fenofibrate preferred in statin combinations for this reason.
ka 1.0 REMOVED as an R6 stored default, and the reason is structural rather than a missing citation. PMID:2381138 states a peak TIME, not a rate: "maximal plasma levels of the parent drug were 46.1 +/- 15.8 micrograms/ml, attained after 2.2 +/- 1.1 h". A single Tmax gives ONE equation for TWO unknowns when a lag is also authored, and this row pairs ka with lag_hr 0.75: at t1/2 1.5 h and ka 1.0 the inversion returns 1.44 h, plus the 0.75 lag reproduces the verbatim 2.2 h. So the LAG was solved for and ka was left at the default to make the system determinate — an unidentifiable parameter presented as sourced. Removal is numerically a no-op. PK: THE PHARMACOKINETICS ARE FINE; THE INTERACTION BLOCK IS ALGEBRA ON A MISTYPED CONSTANT. I VERIFIED THE ARITHMETIC MYSELF: five of six stored affinities are EXACTLY 35 divided by one less than that entry own exposure fold-ratio, to two decimals — cerivastatin, montelukast, pioglitazone, rosiglitazone and loperamide. AND THE CONSTANT 35 IS WRONG THREE SEPARATE WAYS. It is called the midpoint of a verbatim "K(I) ... of 20 to 52 microM" AND THE MIDPOINT IS 36. That constant BELONGS TO GEMFIBROZIL GLUCURONIDE, NOT GEMFIBROZIL — the parent only number in that paper is a different one against a different enzyme — while the solver applies it against gemfibrozil own plasma concentrations. And it DOES DOUBLE DUTY as both an affinity in one entry and an inhibitor concentration in the five derivations, one source number in two fields, at a value that is not a gemfibrozil plasma concentration on any reading. THE SIXTH BREAKS EVEN THAT SCHEME: it should be 4.93 under the same formula, and "7.0-fold" appears verbatim at this record own dose — AN EXPOSURE FOLD-RATIO STORED AS AN AFFINITY IN MICROMOLAR. All seven are deleted; THE VERBATIM FOLD-CHANGES SURVIVE IN THE NOTES AND ARE THE HONEST QUANTITY. Separately, THE SIMVASTATIN MECHANISM IS WRONG: simvastatin is not a substrate of the enzyme named, and a paper not carried here concludes "the mechanism of the pharmacokinetic interaction is probably inhibition of non-CYP3A4-mediated metabolism of simvastatin acid". EVERY OTHER VERBATIM QUOTE IN THOSE NOTES VERIFIES, and I WAS WRONG TO SUSPECT the dose-response attribution, which is exactly right. On the absorption: an earlier pass declined to author a rate because the observed peak sits above the ceiling this half-life allows, WHICH WAS CORRECT ARITHMETIC AND THE WRONG CONCLUSION — the margin is under two percent against a spread six times larger, another study peak fits underneath, and the drug has no depot formulation. THAT IS A LAG, NOT AN IMPOSSIBILITY, and leaving the field empty rendered the peak at 1.44 h, wrong in exactly the direction the earlier pass was trying to avoid.
Pharmacokinetics
- Oral — t½ 1.5 h · F 98% · Vd 14 L
Related compounds
- Simvastatin / statins — major
- Repaglinide — contraindicated
- Cerivastatin — major
- Montelukast — warn
- Pioglitazone — caution
- Rosiglitazone — caution
- Loperamide — caution
Sources: PMID:10438259, PMID:15572716, PMID:12496749, PMID:21838784, PMID:15900286, PMID:12898007