Effects of various factors on steady‐state plasma concentrations of risperidone and 9‐hydroxyrisperidone: lack of impact of MDR‐1 genotypes

Article date: May 2004

By: Norio Yasui‐Furukori, Kazuo Mihara, Takenori Takahata, Akihito Suzuki, Taku Nakagami, Ronald De Vries, Tomonori Tateishi, Tsuyoshi Kondo, Sunao Kaneko, in Volume 57, Issue 5, pages 569-575


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.


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.


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.


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.

DOI: 10.1111/j.1365-2125.2003.02061.x

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