Potential Role of Patients' CYP3A-Status in Clozapine Pharmacokinetics.
The atypical antipsychotic clozapine is effective in treatment-resistant schizophrenia; however, the success or failure of clozapine therapy is substantially affected by the variables that impact the clozapine blood concentration. Thus, elucidating the inter-individual differences in clozapine pharmacokinetics can facilitate the personalized therapy.



Since a potential role in clozapine metabolism is assigned to CYP1A2, CYP2C19, CYP2D6 and CYP3A enzymes, the association between the patients' CYP status (CYP genotypes, CYP expression) and clozapine clearance was evaluated in 92 psychiatric patients.



The patients' CYP2C19 or CYP2D6 genotypes and CYP1A2 expression seemed to have no effect on clozapine serum concentration, whereas CYP3A4 expression significantly influenced the normalized clozapine concentration (185.53±56.53 in low expressers vs 78.05±29.57 or 66.52±0.25 (ng/mL)/(mg/kg) in normal or high expressers, P<.0001), in particular that the patients expressed CYP1A2 at a relatively low level. The functional CYP3A5*1 allele seemed to influence clozapine concentrations in those patients who expressed CYP3A4 at low levels. The dose requirement for the therapeutic concentration of clozapine was substantially lower in low CYP3A4 expresser patients than in normal/high expressers (2.18±0.64 vs 4.98±1.40 mg/kg, P<.0001). Furthermore, significantly higher plasma concentration ratios of norclozapine/clozapine and clozapine N-oxide/clozapine were observed in the patients displaying normal/high CYP3A4 expression than in the low expressers.



Prospective assaying of CYP3A-status (CYP3A4 expression, CYP3A5 genotype) may better identify the patients with higher risk of inefficiency or adverse reactions and may facilitate the improvement of personalized clozapine therapy; however, further clinical studies are required to prove the benefit of CYP3A testing for patients under clozapine therapy.
Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest Hungary; Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest Hungary; Toxi-Coop Toxicological Research Center, Budapest Hungary; University of Ljubljana, Ljubljana Slovenia.
Katalin
K
Tóth
Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest Hungary; Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest Hungary; Toxi-Coop Toxicological Research Center, Budapest Hungary; University of Ljubljana, Ljubljana Slovenia.
Gábor
G
Csukly
Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest Hungary; Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest Hungary; Toxi-Coop Toxicological Research Center, Budapest Hungary; University of Ljubljana, Ljubljana Slovenia.
Dávid
D
Sirok
Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest Hungary; Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest Hungary; Toxi-Coop Toxicological Research Center, Budapest Hungary; University of Ljubljana, Ljubljana Slovenia.
Ales
A
Belic
Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest Hungary; Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest Hungary; Toxi-Coop Toxicological Research Center, Budapest Hungary; University of Ljubljana, Ljubljana Slovenia.
Ádám
Á
Kiss
Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest Hungary; Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest Hungary; Toxi-Coop Toxicological Research Center, Budapest Hungary; University of Ljubljana, Ljubljana Slovenia.
Edit
E
Háfra
Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest Hungary; Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest Hungary; Toxi-Coop Toxicological Research Center, Budapest Hungary; University of Ljubljana, Ljubljana Slovenia.
Máté
M
Déri
Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest Hungary; Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest Hungary; Toxi-Coop Toxicological Research Center, Budapest Hungary; University of Ljubljana, Ljubljana Slovenia.
Ádám
Á
Menus
Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest Hungary; Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest Hungary; Toxi-Coop Toxicological Research Center, Budapest Hungary; University of Ljubljana, Ljubljana Slovenia.
István
I
Bitter
Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest Hungary; Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest Hungary; Toxi-Coop Toxicological Research Center, Budapest Hungary; University of Ljubljana, Ljubljana Slovenia.
Katalin
K
Monostory
D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000097:blood* / Q000627:therapeutic use; D003024:Clozapine / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011446:Prospective Studies; D011618:Psychotic Disorders / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D055815:Young Adult
D014150:Antipsychotic Agents; D012333:RNA, Messenger; D051544:Cytochrome P-450 CYP3A; D003024:Clozapine
CYP1A2 expression; CYP3A4 expression; CYP3A5 genotype; personalized clozapine therapy