Ketoconazole (oral)
Ketoconazole (oral). Imidazole antifungal — inhibits fungal CYP51 ergosterol synthesis. Potent CYP3A4 inhibitor in human liver — historically… Oral half-life 7.7 h.
Imidazole antifungal — inhibits fungal CYP51 ergosterol synthesis. Potent CYP3A4 inhibitor in human liver — historically the gold-standard "strong CYP3A4 perpetrator" for DDI studies. Oral use restricted by FDA 2013 to mycoses unresponsive to alternatives due to hepatotoxicity + adrenal suppression.
PK: THE ABSTRACT OWN WORDING SETTLES CLASS 6 WITHOUT INFERENCE — "The mean ORAL clearance of the solution dose was 209 ... ml/min, and the mean APPARENT volume of distribution was 88.31 ... liters" — and NO HUMAN INTRAVENOUS KETOCONAZOLE HAS EVER EXISTED, confirmed by a companion paper that gave the intravenous arm to DOGS while humans received oral only. So the human absolute bioavailability is unmeasurable, the volume must be apparent, and the stored 0.75 was in no abstract anyway; the only availability figures in the cited paper are RELATIVE, "81.2 ... and 89.0 ... % of that of the solution". Pinning bioavailability to 1 makes the record reproduce an INDEPENDENT paper verbatim human exposure almost exactly, 50.3 against "50.0 +/- 15.2 micrograms X h/ml" at 400 mg. THE Cmax-OVER-AUC IDENTITY NEVERTHELESS FAILS ON ALL THREE FORMULATIONS, and worst on the marketed tablet at 1.50x, WHICH NO ABSORPTION RATE CAN FIX and which a lag time cannot rescue either. The mechanism is transparent: this drug DISTRIBUTION half-life of 1.5-1.7 h EQUALS ITS TABLET PEAK TIME, so the peak happens inside a phase the model has no slot for. A further caveat is stated rather than hidden: exposure is genuinely superproportional across the approved range, "The mean oral clearance decreased from 244.9 to 123.6 and 80.0 ml/min ... as the dose increased from 200 to 400 and 800 mg", so a single linear set must pick a dose to be right at, and this one anchors at 400 mg. INTERACTIONS: A MIXTURE, AND ONLY ONE EDGE IS A CLEAN MEASUREMENT. The alprazolam entry is verbatim — "Ketoconazole was a potent inhibitor of ALP metabolism in vitro (Ki = 0.046 microM)" — and is declared as such. THE OTHER FIVE ARE NOT, AND ARE LEFT ALONE RATHER THAN RELABELLED ON A GUESS. Two take 0.015 from a verbatim RANGE of 0.011 to 0.045 µM, AND THE NIFEDIPINE NOTE CALLS THAT VALUE "(midpoint)" WHEN THE MIDPOINT OF THAT RANGE IS 0.028 — a range interior describing itself as something it is not. One takes 0.015 from "IC(50) values less than 0.02 microM", which is an INEQUALITY, and an inhibitory concentration is not an affinity. The remaining two derive from clinical exposure changes with no single assumed concentration reconstructing both.
Pharmacokinetics
- Oral — t½ 7.7 h · F 100% · ka 1.877 h⁻¹ · Vd 88.31 L
Related compounds
- Cyclosporine — major
- Midazolam — major
- Triazolam — major
- Alprazolam — major
- Sildenafil — major
- Nifedipine — warn
Sources: PMID:21235585, PMID:7946933, PMID:10725306, PMID:3735080