Tacrine
Tacrine. Reversible acetylcholinesterase inhibitor — first medication approved (1993) for Alzheimer disease. Withdrawn from US market in 2013… Oral half-life 2.9 h.
Reversible acetylcholinesterase inhibitor — first medication approved (1993) for Alzheimer disease. Withdrawn from US market in 2013 because of hepatotoxicity (asymptomatic ALT elevations in 30-50% of patients, with frank hepatitis in a minority). Almost entirely metabolized by CYP1A2, making it the textbook CYP1A2 victim in pharmacology education. Retained in the registry for reference data on CYP1A2 inhibitor potency despite the compound being clinically obsolete. PK (Cognex label, withdrawn 2013 for hepatotoxicity but PK well-characterized): Absolute F 17 ± 13% (low — extensive first-pass via CYP1A2), Tmax 1–2 h, t½ ~3 h (qid dosing). Apparent V 349 ± 193 L (large lipophilic distribution). Protein binding ~55%. Food reduces F by 30–40% (give ≥1 h before meals). The first FDA-approved AChE inhibitor for Alzheimer's, displaced by donepezil/rivastigmine/galantamine — kept in the registry for CYP1A2 victim modeling (fluvoxamine → tacrine 8.30× authored Wave 2a v1.1).
PK: A CLASS-6 CALL THAT REVERSES, AND THE DEFECT WAS IN OUR OWN PROSE. V 349 L beside F 0.17 reads as an apparent volume double-divided by bioavailability. It is not: that figure comes from an intravenous dose — "After an intravenous dose of 30 mg THA ... Volume of distribution, V alpha varied 100-680 l with a mean of 349 l" — so it is a TRUE volume and the pairing is correct modelling. The defect was that our own source_label described it as "apparent", wording that would license a future editor to break a correct record; that word is now removed and the provenance stated. Two caveats travel with it: the population is amyotrophic lateral sclerosis and surgical patients rather than Alzheimer disease, and it is an alpha-phase volume with a 100-680 L spread. The half-life is re-sourced to 2.91 h, which the literature supports only as a MULTIPLE-DOSE value; single doses give 1.5-2.5 h and long-term treatment 5-7 h. ka 1 collides with the label own "Tmax 1-2 h". AN OPEN INCONSISTENCY IS RECORDED RATHER THAN HIDDEN: the stored volume, the stored half-life and the cited interaction paper own clearance cannot all be true at once.
Pharmacokinetics
- Oral — t½ 2.9 h · F 17% · Vd 349 L
Sources: PMID:9209244, PMID:2340845, PMID:2598567, PMID:8973053