[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to evaluate genetic and pharmacokinetic factors affecting the initial pharmacotherapeutic effect of paroxetine (PAX) in Japanese patients with panic disorder (PD).
Plasma concentration of PAX was determined by high performance liquid chromatography. Serotonin transporter gene-linked polymorphic region (5-HTTLPR) variants were determined by polymerase chain reaction techniques. PD severity was assessed using the Panic and Agoraphobia Scale (PAS).
Multiple regression analysis revealed that the plasma concentration of PAX, 5-HTTLPR genotype, and comorbid physical illness were significant factors affecting the initial pharmacotherapeutic effect of PAX in PD and indicated that these factors accounted for 52.4% (R(2) = 0.524) of the variability in the percent reduction in PAS score. The final model was described by the following equation (P = 0.001): percent reduction in PAS score (%) = 68.5 - 1.2 x [plasma concentration of PAX (ng/ml)] - 33.0 x (L/S = 1, S/S = 0) - 21.8 x (with comorbid physical illness = 1, without comorbid physical illness = 0).
The high plasma concentration of PAX, the L/S genotype of 5-HTTLPR, and comorbid physical illness might be associated with a poor response to the initial phase of pharmacotherapy of PD with PAX.
No preview · Article · Apr 2009 · European Journal of Clinical Pharmacology
[Show abstract][Hide abstract] ABSTRACT: Selective serotonin reuptake inhibitors are thought to interact with serotonergic neurons and be effective for treatment of panic disorder. In the present study, the authors investigated an association between plasma concentrations of paroxetine in patients with panic disorder and clinical response to initial treatment with paroxetine. Subjects were 21 unrelated Japanese patients who fulfilled DSM-IV-TR criteria for a diagnosis of panic disorder (6 males, 15 females, mean age 35.9 +/- 11.3 years). Subjects were administered 10 mg/day of paroxetine for 2 weeks as initial treatment. Improvement of the symptoms of the disorder was assessed with the Panic and Agoraphobia Scale (PAS). In the range of plasma levels >20 ng/mL, none of the subjects showed the reduction ratio in PAS score >0.2. The subjects whose plasma concentrations of paroxetine were less than 20 ng/mL had a significantly higher mean reduction ratio in PAS score than the subjects whose plasma concentrations of paroxetine were >20 ng/mL. Multiple regression analysis showed that the plasma concentration of paroxetine was the only significant factor and accounted for 28.0% of the variability in the reduction ratio of PAS score of the subjects. The final model of correlation was: reduction ratio in PAS score = 0.423 - 0.009 x (plasma concentrations of paroxetine) (R = 0.529, P = 0.014, coefficient of determination (R2) = 0.280). Assuming that the reduction ratio in PAS score was 0.2 in the equation above, plasma concentration of paroxetine is calculated to be about 25 ng/mL, which is suggested to be the upper end of the therapeutic window for the initial phase of the treatment with paroxetine for panic disorder.
No preview · Article · Mar 2007 · Therapeutic Drug Monitoring
[Show abstract][Hide abstract] ABSTRACT: The authors investigated the impact of the CYP2D6 genotypes on the plasma concentration of paroxetine (PAX) in 55 Japanese psychiatric patients. They were administered 10 to 40 mg/day (24+/-10.0 mg/day) of PAX and maintained at the same daily dose for at least two weeks to obtain the steady-state concentrations. The plasma levels of PAX were 15.8+/-15.0, 47.4+/-32.0, 101.2+/-59.9 and 177.5+/-123.6 ng/ml at the daily dose of 10, 20, 30 and 40 mg, respectively, which suggested dose dependent kinetics of PAX. The allele frequencies of the CYP2D65, CYP2D610 and CYP2D641 were 1.8%, 41.8% and 1.8%, respectively. Significantly higher PAX concentrations were observed in the patients having one functional allele compared with those with two functional alleles (150.9+/-20.6 vs. 243.6+/-25.2 ng/ml mg(-1) kg(-1), p<0.05, Newman-Keuls multiple comparison test) or no functional (243.6+/-25.2 vs. 76.7+/-6.1 ng/ml mg(-1) kg(-1), p<0.05, Newman-Keuls multiple comparison test) in the subjects with 30 mg/day of paroxetine. The same trend of findings as in the subjects treated with 30 mg/day were observed in the subjects with 40 mg/day of PAX. The present results suggest that having one non-functional allele is the marker for high plasma concentration of PAX when relatively high daily dose of PAX is administered.
No preview · Article · Jun 2006 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
[Show abstract][Hide abstract] ABSTRACT: We investigated the effect of CYP2D6 genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 88 Japanese schizophrenic inpatients being treated with HAL. Some subjects carrying CYP2D6*5 allele (CYP2D6*1/CYP2D6*5, CYP2D6*5/CYP2D6*10) showed extremely high concentrations of both HAL and RHAL, and the groups with CYP2D6*5 allele seemed to have higher plasma concentrations of HAL (1.14+/-0.69 ng/ml/mg) and RHAL (1.10+/-1.05 ng/ml/mg) than the other groups. Among those without CYP2D6*5 allele, there were no significant differences in plasma concentrations of HAL and RHAL between those without CYP2D6*10 allele (HAL=0.68+/-0.31 ng/ml/mg, RHAL=0.28+/-0.37 ng/ml/mg), those with one CYP2D6*10 (HAL=0.70+/-0.23 ng/ml/mg, RHAL=0.31+/-0.16 ng/ml/mg) and those with two CYP2D6*10 alleles (HAL=0.69+/-0.14 ng/ml/mg, RHAL=0.40+/-0.09 ng/ml/mg), although there was a tendency of higher plasma concentration of RHAL in those with two CYP2D6*10 alleles. At a lower daily dosage of HAL (<10 mg/day), the subjects with two or one CYP2D6*10 allele(s) showed significantly higher plasma concentrations of RHAL (0.43+/-0.23 ng/ml/mg, 0.34+/-0.16 ng/ml/mg) than those without CYP2D6*10 allele (0.18+/-0.16 ng/ml/mg). The results of this study indicate that CYP2D6*10 allele plays significant but modest role in HAL metabolism in Japanese; nevertheless, we should not lump CYP2D6*10 allele with CYP2D6*5 allele because these two mutated alleles seem to have different impacts in the metabolism of HAL.
No preview · Article · Aug 2003 · Neuropsychopharmacology
[Show abstract][Hide abstract] ABSTRACT: We investigated the effect of the CYP2C19 and CYP2D6 genotypes on the metabolism of amitriptyline (AT) in Japanese psychiatric patients. Steady-state concentrations of AT and its metabolites (nortriptyline [NT], trans-10-hydroxy-nortriptyline [EHNT], cis-10-hydroxy-nortriptyline [ZHNT], trans-10-hydroxy-amitriptyline [EHAT], and cis-10-hydroxy-amitriptyline [ZHAT]) in 50 patients were determined by high-performance liquid chromatography. Significantly higher plasma concentrations of AT corrected for dose and body weight in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 were observed (no mutated alleles vs. two mutated alleles: 36.0 +/- 18.2 vs. 64.0 +/- 25.2 ng/mL/mg/kg, p = 0.025). A significantly higher AT/NT ratio was seen in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 (no mutated alleles vs. two mutated alleles: 1.27 +/- 0.59 vs. 3.40 +/- 1.02, p = 0.001). A trend for higher NT/EHNT ratio in the subjects with two mutated alleles of CYP2D6 than in those with no mutated alleles of CYP2D6 was observed (no mutated alleles vs. two mutated alleles: 0.73 +/- 0.39 vs. 1.31 +/- 0.81, p = 0.068). A trend for higher plasma concentrations of total hydroxylated metabolites of AT (EHAT + ZHAT) corrected for dose and body weight in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 was found (no mutated alleles vs. two mutated alleles: 9.5 +/- 5.8 vs. 17.8 +/- 8.9, p = 0.051). Therefore, the genotype of CYP2C19 is one of the important determinants of the plasma concentrations of AT and the capacity to desmethylate AT. Mother compound AT is shunted via hydroxylation pathways from AT to EHAT and ZHAT in the subjects with homozygotes of mutated alleles of CYP2C19 in order to compensate for the decreased capacity to desmethylate AT.
No preview · Article · Sep 2002 · Journal of Clinical Psychopharmacology
[Show abstract][Hide abstract] ABSTRACT: The impact of genetic polymorphism of CYP1A2 that are related to the induction of the isozyme on the plasma levels of haloperidol (HAL) in 40 male smokers with schizophrenia was investigated. A point mutation from C to A in intron 1 at position 734 and a point mutation from G to A at position -2964 in the 5'-flanking region of CYP1A2 were identified by polymerase chain-reaction-restricted fragment length polymorphism method. Regarding C/A polymorphism in intron 1 at position 734, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight among the subjects with A/A (n = 21), A/C (n = 14) and C/C (n = 5) genotypes (one-way analysis of variance: 63.1 +/- 18.5, 47.8 +/- 12.5 and 50.8 +/- 15.1 ng/ml/mg/kg, respectively, F(2,37) = 2.556, P = .09). Regarding G/A polymorphism at position -2964 in the 5'-flanking region, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight between subjects with G/G (n = 24) and G/A (n = 15) (two-tailed t test: G/G and G/A = 51.2 +/- 16.6 and 59.0 +/- 17.6 ng/ml/mg/kg, respectively, df = 28, P = .22). The present study suggests that the genotyping of CYP1A2 cannot predict the steady state plasma levels of HAL in male smoking schizophrenics.
No preview · Article · Mar 2002 · Progress in Neuro-Psychopharmacology and Biological Psychiatry