Editing Clozapine (section)

===Pharmacokinetics===
[[File:Desmethylclozapine.svg|class=skin-invert-image|thumb|150px|left|''N''-[[desmethylclozapine]] (norclozapine), clozapine's major active metabolite.]]

The absorption of clozapine is almost complete following oral administration, but the oral [[bioavailability]] is only 60 to 70% due to [[first-pass metabolism]]. The time to peak concentration after oral dosing is about 2.5 hours, and food does not appear to affect the bioavailability of clozapine. However, it was shown that co-administration of food decreases the rate of absorption.<ref>{{cite journal | vauthors = Disanto AR, Golden G | title = Effect of food on the pharmacokinetics of clozapine orally disintegrating tablet 12.5 mg: a randomized, open-label, crossover study in healthy male subjects | journal = Clinical Drug Investigation | volume = 29 | issue = 8 | pages = 539–549 | date = 1 August 2009 | pmid = 19591515 | doi = 10.2165/00044011-200929080-00004 | s2cid = 45731786 }}</ref> The [[elimination half-life]] of clozapine is about 14 hours at [[steady state]] conditions (varying with daily dose).{{medical citation needed|date=August 2021}}

Clozapine is extensively metabolized in the liver, via the [[cytochrome P450]] system, to [[Chemical polarity|polar]] metabolites suitable for elimination in the urine and feces. The major metabolite, ''norclozapine'' ([[demethylation|desmethyl]]-clozapine), is pharmacologically active. The cytochrome P450 [[isoenzyme]] [[CYP1A2|1A2]] is primarily responsible for clozapine metabolism, but 2C, [[CYP2D6|2D6]], [[CYP2E1|2E1]] and [[CYP3A4|3A3/4]] appear to play roles as well. Agents that [[enzyme induction and inhibition|induce]] (e.g., cigarette smoke) or [[enzyme inhibitor|inhibit]] (e.g., [[theophylline]], [[ciprofloxacin]], [[fluvoxamine]]) CYP1A2 may increase or decrease, respectively, the metabolism of clozapine. For example, the induction of metabolism caused by smoking means that smokers require up to double the dose of clozapine compared with non-smokers to achieve an equivalent plasma concentration.<ref name="ReferenceA" />

Clozapine and norclozapine (desmethyl-clozapine) plasma levels may also be monitored, though they show a significant degree of variation and are higher in women and increase with age.<ref>{{cite journal | vauthors = Lane HY, Chang YC, Chang WH, Lin SK, Tseng YT, Jann MW | title = Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics | journal = The Journal of Clinical Psychiatry | volume = 60 | issue = 1 | pages = 36–40 | date = January 1999 | pmid = 10074876 | doi = 10.4088/JCP.v60n0108 }}</ref> Monitoring of plasma levels of clozapine and norclozapine has been shown to be useful in assessment of compliance, metabolic status, prevention of toxicity, and in dose optimisation.<ref name="ReferenceA">{{cite journal | vauthors = Rostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ | title = Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients | journal = Journal of Clinical Psychopharmacology | volume = 24 | issue = 1 | pages = 70–78 | date = February 2004 | pmid = 14709950 | doi = 10.1097/01.jcp.0000106221.36344.4d | s2cid = 31923731 }}</ref>