Clozapine
Clozapine. Atypical antipsychotic with broad receptor activity: 5-HT2A, D4, D2 (lower affinity than typicals), α1, H1, M1-5 antagonism. Indicated… Oral half-life 10 h.
Atypical antipsychotic with broad receptor activity: 5-HT2A, D4, D2 (lower affinity than typicals), α1, H1, M1-5 antagonism. Indicated for treatment-resistant schizophrenia and reduction of suicidal behavior. Narrow therapeutic index: agranulocytosis risk (~1%) mandates lifelong WBC monitoring under REMS. Primarily metabolized by CYP1A2 (major) and CYP3A4 (minor). Smoking induces CYP1A2 and substantially lowers clozapine exposure; smoking cessation is a clinical interaction. Active metabolite norclozapine. PK (Clozaril label, 100 mg PO bid SS): Cmax 319 ng/mL (range 102-771), Cmin 122 ng/mL (41-343), Tmax 2.5 h (range 1-6), t½ 12 h single-dose / 14 h SS, F 27-50% (avg 40%), protein binding 97%. Smoking induces CYP1A2 → lowers exposure ~50%; smoking cessation can produce toxicity at unchanged dose. Major fluvoxamine + ciprofloxacin DDIs (CYP1A2 inhibition).
PK: V 305 L WAS BACK-DERIVED AND MATRIX-MISMATCHED AT ONCE. The published BLOOD clearance is 250 mL/min = 15.0 L/h, and 15.0 divided by this record own elimination rate gives 303 — against a stored 305. Not a measurement: a literature clearance divided by the record own half-life. And it is blood-referenced, in a drug whose source states "the mean equilibrium-state concentration ratio between blood and plasma was experimentally determined to be 0.87". A real intravenous-and-oral study in ten patients supplies the whole row verbatim instead: "blood clearance, hepatic extraction ratio and oral bioavailability were 250 ml/min, 0.2 and 0.27 ... The mean volume of distribution at steady-state and the terminal half-life was 1.6 l/kg and 10.3 h". This converts the batch only label-only row into a cited one. F 0.4 was a self-declared range mean, and the spread is not noise — smoking moves exposure "-20% in patients not taking valproic acid, and -46% in patients taking valproic acid". ka 0.6 implies a 4.53 h peak against this record OWN label text of 2.5 h. THE NORCLOZAPINE CONTAMINATION CHECK IS NEGATIVE: no metabolite value reached this record.
Pharmacokinetics
- Oral — t½ 10.3 h · F 27% · Vd 112 L
Sources: PMID:18484549, PMID:19067475, PMID:8935801, PMID:1354163, PMID:3203703, PMID:31111332