title: Pharmacogenetic study on risperidone long-acting injection: influence of cytochrome P450 2D6 and pregnane X receptor on risperidone exposure and drug-induced side-effects.
abstract: Risperidone is metabolized by polymorphic enzymes, and a large variability in plasma concentration and therapeutic response is observed. Risperidone long-acting injection (RLAI) avoids the first-pass effect, and little is known about the influence of gene polymorphisms involved in its pharmacokinetics. The influence on plasma concentrations of risperidone (RIS), its metabolite 9-hydroxy-risperidone, and on adverse effects were investigated for polymorphisms of cytochrome P450 2D6 (CYP2D6) (*3, *4, *5, *6), CYP3A (CYP3A4*1B, CYP3A4 rs4646437, CYP3A5*3, CYP3A7*1C), ABCB1 (1236C>T, 2677G>T, 3435C>T), NR1/2 coding for pregnane X receptor (rs1523130, rs2472677, rs7643645), and for CYP3A activity measured by a phenotyping test. Forty-two patients with at least 4 consecutive unchanged doses of RLAI were included in a multicenter cross-sectional study. A 55% lower dose-adjusted plasma levels of RIS were observed for CYP2D6 ultrarapid metabolizers (n = 5) as compared with CYP2D6 intermediate metabolizers (P < 0.007). NR1/2 polymorphism (rs7643645A>G) influenced RIS exposure with a 2.8-fold lower active moiety (P = 0.031) in GG compared with the AA genotype. This was confirmed in a second independent cohort (n = 16). Furthermore, high-density lipoprotein cholesterol was positively correlated with CYP3A activity (P = 0.01), and the NR1/2 (rs2472677) polymorphism was associated with different adverse effects including prolactin plasma levels adjusted for age and sex. In conclusion, our results confirmed the influence of CYP2D6 genotype on plasma levels of RIS. This is the first report on the influence of NR1/2 polymorphisms on RLAI exposure and on drug-induced adverse effects. These results should be validated in larger cohorts.
authors.affiliation: Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, University Hospital Centre and University of Lausanne, Prilly, Switzerland.
authors.forename: Eva
authors.initials: E
authors.lastname: Choong
authors.forename: Andrea
authors.initials: A
authors.lastname: Polari
authors.forename: Rigobert Hervais
authors.initials: RH
authors.lastname: Kamdem
authors.forename: Nicola
authors.initials: N
authors.lastname: Gervasoni
authors.forename: Caesar
authors.initials: C
authors.lastname: Spisla
authors.forename: Eveline
authors.initials: E
authors.lastname: Jaquenoud Sirot
authors.forename: Graziella Giacometti
authors.initials: GG
authors.lastname: Bickel
authors.forename: Guido
authors.initials: G
authors.lastname: Bondolfi
authors.forename: Philippe
authors.initials: P
authors.lastname: Conus
authors.forename: Chin B
authors.initials: CB
authors.lastname: Eap
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D007267:Injections; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics*; D018967:Risperidone / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone