Effects of various factors on steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone: lack of impact of MDR-1 genotypes.
OBJECTIVE
An in vitro study has suggested that risperidone is a substrate of P-glycoprotein, which is coded by MDR-1 gene. Thus, we studied the effects of major polymorphisms of the MDR-1 gene on plasma drug concentrations.


METHODS
Subjects were 85 schizophrenic patients receiving 3 mg twice daily of risperidone. Sample collections were conducted 12 h after the bedtime dosing. Plasma concentrations of risperidone and 9-hydroxyrisperidone were quantified using LC/MS/MS. MDR-1 genotypes (C3435T and G2677T/A) and CYP2D6 genotypes were identified using PCR-RFLP methods.


RESULTS
There was no difference in geometric mean (95% CI) of steady-state plasma concentration of risperidone between C3435T genotypes [C/C, C/T, T/T; 2.06 (1.63, 6.47), 2.96 (3.10, 7.91), 2.28 (1.81, 8.04) ng ml(-1), P = 0.759] or G2677T/A genotypes [G/G, G/T or A, T or A/T or A; 1.62 (0.08, 6.07), 2.64 (3.25, 7.10), 2.71 (2.77, 8.72) ng ml(-1), P = 0.625] or 9-hydroxyrisperidone between C3435T genotypes [38.3 (33.7, 50.1), 34.9 (32.9, 42.0), 35.7 (31.7, 42.3) ng ml(-1), P = 0.715] or G2677T/A genotypes [40.6 (33.0, 51.8), 35.0 (33.3, 42.4), 36.1 (32.8, 47.2) ng ml(-1), P = 0.601]. Multiple regression analyses including CYP2D6 genotypes, sex, and age revealed that steady-state plasma concentration of risperidone correlated with the number of mutated alleles for CYP2D6 (standardized partial correlation coefficients (beta) = 0.540, P < 0.001) and those of 9-hydroxyrisperidone (standardized beta = 0.244, P = 0.038) and active moiety (standardized beta = 0.257, P = 0.027) correlated with age.


CONCLUSIONS
These findings suggest that the MDR-1 variants are not associated with steady-state plasma concentration of risperidone or 9-hydroxyrisperidone, but CYP2D6 genotypes and age are determinants of these concentrations.
Yasui-Furukori
Norio
N
Department of Clinical Pharmacology, Hirosaki University School of Medicine, Hirosaki, Japan. yasufuru@cc.hirosaki-u.ac.jp
Mihara
Kazuo
K
Takahata
Takenori
T
Suzuki
Akihito
A
Nakagami
Taku
T
De Vries
Ronald
R
Tateishi
Tomonori
T
Kondo
Tsuyoshi
T
Kaneko
Sunao
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D014150:Antipsychotic Agents / Q000097:blood*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D005260:Female; D019450:Genes, MDR / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007555:Isoxazoles / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D000068882:Paliperidone Palmitate; D011110:Polymorphism, Genetic / Q000235:genetics; D011743:Pyrimidines / Q000097:blood; D018967:Risperidone / Q000097:blood*; D012559:Schizophrenia / Q000097:blood* / Q000188:drug therapy / Q000235:genetics
D014150:Antipsychotic Agents; D007555:Isoxazoles; D011743:Pyrimidines; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone; D000068882:Paliperidone Palmitate