| 1 | Ther Drug Monit 2006 Oct 28: 599-602 |
|---|---|
| PMID | 17038872 |
| Title | Effect of adjunctive lamotrigine treatment on the plasma concentrations of clozapine, risperidone and olanzapine in patients with schizophrenia or bipolar disorder. |
| Abstract | The effect of lamotrigine on the steady-state plasma concentrations of the atypical antipsychotics clozapine, olanzapine, and risperidone was investigated in patients with schizophrenia or bipolar disorder stabilized on chronic treatment with clozapine (200-500 mg/day; n = 11), risperidone (3-6 mg/day; n = 10) or olanzapine (10-20 mg/day; n = 14)). Lamotrigine was titrated up to a final dosage of 200 mg/day over 8 weeks, and pharmacokinetic assessments were made at baseline and during treatment weeks 6 and 10, at lamotrigine dosages of 100 and 200 mg/day respectively. The plasma concentrations of clozapine, norclozapine, risperidone, and 9-hydroxy-risperidone did not change significantly during treatment with lamotrigine. The mean plasma concentrations of olanzapine were 31 +/- 7 ng/mL at baseline, 32 +/- 7 ng/mL at week 6, and 36 +/- 9 ng/mL at week 10, the difference between week 10 and baseline being statistically significant (P < 0.05). Adjunctive lamotrigine therapy was well tolerated in all groups. These findings indicate that lamotrigine, at the dosages recommended for use as a mood stabilizer, does not affect the plasma levels of clozapine, risperidone, and their active metabolites. The modest elevation in plasma olanzapine concentration, possibly due to inhibition of UGT1A4-mediated olanzapine glucuronidation, is unlikely to be of clinical significance. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Ther Drug Monit 2008 Feb 30: 35-40 |
| PMID | 18223460 |
| Title | The relationship between the response of clinical symptoms and plasma olanzapine concentration, based on pharmacogenetics: Juntendo University Schizophrenia Projects (JUSP). |
| Abstract | The monitoring of plasma olanzapine concentrations has been found to be an important and useful tool for optimizing psychiatric treatment. The present study investigated the effect that clinical factors, such as smoking and age, and functional polymorphisms of UGT1A4, CYP1A2, and CYP2D6 genes have on plasma olanzapine concentration, as well as the effects of plasma olanzapine concentrations on Japanese schizophrenic patients' clinical symptoms. The subjects included 51 chronic schizophrenic patients whose symptoms were not controlled with chronic conventional antipsychotics and therefore were switched to olanzapine. Male smokers had a significantly lower olanzapine concentration-dose ratio and olanzapine/4'-N-desmethyl olanzapine ratio (which reflects CYP1A2 activity) than male nonsmokers and female nonsmokers. The results of a 2-way analysis of covariance showed that smoking had the main effect, rather than gender or age. The functional gene polymorphisms that were studied had no effect on the plasma olanzapine and metabolite concentrations. An improved total Brief Psychiatric Rating Scale (BPRS) score was not correlated with the plasma olanzapine concentration, but individual BPRS scores related to improvement of suspiciousness, hallucinations, and blunted affect were significantly correlated with plasma olanzapine concentration. Clinical factors, especially smoking, were more important modulators of olanzapine metabolism than the functional genotypes. Long-term olanzapine treatment with adequate plasma olanzapine concentrations could be more effective in improving some symptoms than treatment with conventional antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Ther Drug Monit 2008 Feb 30: 35-40 |
| PMID | 18223460 |
| Title | The relationship between the response of clinical symptoms and plasma olanzapine concentration, based on pharmacogenetics: Juntendo University Schizophrenia Projects (JUSP). |
| Abstract | The monitoring of plasma olanzapine concentrations has been found to be an important and useful tool for optimizing psychiatric treatment. The present study investigated the effect that clinical factors, such as smoking and age, and functional polymorphisms of UGT1A4, CYP1A2, and CYP2D6 genes have on plasma olanzapine concentration, as well as the effects of plasma olanzapine concentrations on Japanese schizophrenic patients' clinical symptoms. The subjects included 51 chronic schizophrenic patients whose symptoms were not controlled with chronic conventional antipsychotics and therefore were switched to olanzapine. Male smokers had a significantly lower olanzapine concentration-dose ratio and olanzapine/4'-N-desmethyl olanzapine ratio (which reflects CYP1A2 activity) than male nonsmokers and female nonsmokers. The results of a 2-way analysis of covariance showed that smoking had the main effect, rather than gender or age. The functional gene polymorphisms that were studied had no effect on the plasma olanzapine and metabolite concentrations. An improved total Brief Psychiatric Rating Scale (BPRS) score was not correlated with the plasma olanzapine concentration, but individual BPRS scores related to improvement of suspiciousness, hallucinations, and blunted affect were significantly correlated with plasma olanzapine concentration. Clinical factors, especially smoking, were more important modulators of olanzapine metabolism than the functional genotypes. Long-term olanzapine treatment with adequate plasma olanzapine concentrations could be more effective in improving some symptoms than treatment with conventional antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Eur. J. Clin. Pharmacol. 2010 May 66: 465-74 |
| PMID | 20143052 |
| Title | Carriers of the UGT1A4 142T>G gene variant are predisposed to reduced olanzapine exposure--an impact similar to male gender or smoking in schizophrenic patients. |
| Abstract | The impact of the UGT1A4, CYP1A2, and MDR1 genetic variants on olanzapine plasma levels, in relation to those of other individual factors, such as gender, smoking status, body weight, and age, was investigated in patients with schizophrenia. A total of 121 patients were recruited from psychosis-specialized outpatient departments in Stockholm County. Olanzapine plasma concentrations were determined by high-performance liquid chromatography. Genotyping was carried out by PCR-restriction fragment length polymorphism or minisequencing, and haplotypes were analyzed using specialized computer software on population genetics. Multiple regression analysis was performed to investigate the combined effect of patient characteristics and genotypes/haplotypes on daily dose-corrected plasma concentrations of olanzapine. In addition to , the results indicate that inter-patient differences in olanzapine exposure were explained by the known factor of time of sampling from last dose intake and by the following individual factors in order of relative impact: (1) male gender, (2) carrier of the UGT1A4 142T>G single nucleotide polymorphism (SNP), and (3) smoking. Each of these three factors predicted a decrease in daily dose-corrected plasma concentrations of 35, 25, and 21%, respectively. In contrast, age, body weight, and MDR1 or CYP1A2 haplotype did not have a significant impact. At 12 h after dose intake, the regression model predicted a 5.1-fold higher olanzapine plasma level in a non-smoking female patient who did not carry the UGT1A4 142T>G SNP compared to a smoking man treated with the same dose but heterozygous for UGT1A4 142T>G SNP. Whether these combined genetic and environmental factors influence the risk of therapeutic failure remains to be established. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Eur. J. Clin. Pharmacol. 2010 May 66: 465-74 |
| PMID | 20143052 |
| Title | Carriers of the UGT1A4 142T>G gene variant are predisposed to reduced olanzapine exposure--an impact similar to male gender or smoking in schizophrenic patients. |
| Abstract | The impact of the UGT1A4, CYP1A2, and MDR1 genetic variants on olanzapine plasma levels, in relation to those of other individual factors, such as gender, smoking status, body weight, and age, was investigated in patients with schizophrenia. A total of 121 patients were recruited from psychosis-specialized outpatient departments in Stockholm County. Olanzapine plasma concentrations were determined by high-performance liquid chromatography. Genotyping was carried out by PCR-restriction fragment length polymorphism or minisequencing, and haplotypes were analyzed using specialized computer software on population genetics. Multiple regression analysis was performed to investigate the combined effect of patient characteristics and genotypes/haplotypes on daily dose-corrected plasma concentrations of olanzapine. In addition to , the results indicate that inter-patient differences in olanzapine exposure were explained by the known factor of time of sampling from last dose intake and by the following individual factors in order of relative impact: (1) male gender, (2) carrier of the UGT1A4 142T>G single nucleotide polymorphism (SNP), and (3) smoking. Each of these three factors predicted a decrease in daily dose-corrected plasma concentrations of 35, 25, and 21%, respectively. In contrast, age, body weight, and MDR1 or CYP1A2 haplotype did not have a significant impact. At 12 h after dose intake, the regression model predicted a 5.1-fold higher olanzapine plasma level in a non-smoking female patient who did not carry the UGT1A4 142T>G SNP compared to a smoking man treated with the same dose but heterozygous for UGT1A4 142T>G SNP. Whether these combined genetic and environmental factors influence the risk of therapeutic failure remains to be established. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Pharmacogenet. Genomics 2011 Sep 21: 539-51 |
| PMID | 21750471 |
| Title | Olanzapine metabolism and the significance of UGT1A448V and UGT2B1067Y variants. |
| Abstract | Olanzapine is an antipsychotic used in the treatment of schizophrenia, bipolar disorder, and treatment-resistant depression. Glucuronidation by the UDP-glucuronosyltransferase (UGT) family of enzymes is the major mode of olanzapine metabolism, and polymorphisms in these enzymes could contribute to interindividual variability in olanzapine metabolism and therapeutic response. Cell lines overexpressing individual UGT enzymes were used to determine which UGTs have enzymatic activity against olanzapine, characterize the kinetics of this reaction, and examine the effects of UGT variants on olanzapine metabolism. A bank of 105 human liver microsomes (HLM) were used to perform a phenotype-genotype study comparing glucuronidation activity against UGT genotype. Cell lines overexpressing the individual UGTs 1A4 and 2B10 exhibited glucuronidation activity against olanzapine. The UGT1A4 variant exhibited a 3.7-fold (P<0.0001) higher Vmax/KM for the formation of the olanzapine-10-N-glucuronide isomer 1, and a 4.3-fold (P<0.0001) higher Vmax/KM for the formation of the olanzapine-10-N-glucuronide isomer 2 than wild-type UGT1A4. The UGT2B10 variant exhibited no glucuronidation activity against olanzapine. In a screening of 105 HLM specimens, there was a 2.1-fold (P=0.04) and 1.6-fold (P=0.0017) increase in the rate of olanzapine-10-N-glucuronide isomer 1 and olanzapine-4'-N-glucuronide formation, and a 2-fold (P=0.02) increase in the overall olanzapine glucuronidation formation, in HLM with the UGT1A4 (*3/*3)/UGT2B10 (*1/*1) genotype compared with HLM with the UGT1A4 (*1/*1)/UGT2B10 (*1/*1) genotype. There was a 1.9-fold (P<0.003) decrease in the formation of both isomers of the olanzapine-10-N-glucuronide, a 2.7-fold (P<0.0001) decrease in olanzapine-4'-N-glucuronide formation, and a 2.1-fold (P=0.0002) decrease in the overall olanzapine glucuronide formation in HLM with at least one UGT2B10*2 allele. In regression analysis, the UGT1A4*3 (P<0.02) and UGT2B10*2 (P<0.002) alleles were significant predictors of the formation of all olanzapine glucuronide isomers. The UGTs 1A4 and 2B10 glucuronidate olanzapine and functional variants of these UGTs significantly alter olanzapine glucuronidation in vitro. These data suggest that the UGT1A4*3 and UGT2B10*2 alleles contribute significantly to interindividual variability in olanzapine metabolism. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Pharmacogenet. Genomics 2012 Aug 22: 561-76 |
| PMID | 22565219 |
| Title | Glucuronidation of the second-generation antipsychotic clozapine and its active metabolite N-desmethylclozapine. Potential importance of the UGT1A1 A(TA)?TAA and UGT1A4 L48V polymorphisms. |
| Abstract | Clozapine (CLZ) is an FDA approved second-generation antipsychotic for refractory schizophrenia, and glucuronidation is an important pathway in its metabolism. The aim of this study was to fully characterize the CLZ glucuronidation pathway and examine whether polymorphisms in active glucuronidating enzymes could contribute to variability in CLZ metabolism. Cell lines overexpressing wild-type or variant uridine diphosphate-glucuronosyltransferase (UGT) enzymes were used to determine which UGTs show activity against CLZ and its major active metabolite N-desmethylclozapine (dmCLZ). Human liver microsomes (HLM) were used to compare hepatic glucuronidation activity against the UGT genotype. Several UGTs including 1A1 and 1A4 were active against CLZ; only UGT1A4 showed activity against dmCLZ. UGT1A1 showed a 2.1-fold (P <0.0001) higher V(max)/K(M) for formation of the CLZ-N?-glucuronide than UGT1A4; UGT1A4 was the only UGT for which CLZ-5-N-glucuronide kinetics could be determined. The UGT1A4(24Pro/48Val) variant showed a 5.2-, 2.0-, and 3.4-fold (P < 0.0001 for all) higher V(max)/K(M) for the formation of CLZ-5-N-glucuronide, CLZ-N?-glucuronide, and dmCLZ-5-N-glucuronide, respectively, as compared with that of wild-type UGT1A4(24Pro/48Leu). There was a 37% (P< 0.05) decrease in the rate of CLZ-N?-glucuronide formation in HLM with the UGT1A1 (*28/*28)/UGT1A4 (*1/*1) genotype, and a 2.2- and 1.8-fold (P < 0.05 for both) increase in the formation of CLZ-5-N-glucuronide and CLZ-N?-glucuronide in UGT1A1 (*1/*1)/UGT1A4 (*3/*3) HLM compared with UGT1A1 (*1/*1)/UGT1A4 (*1/*1) HLM. The UGT1A1*28 allele was a significant (P = 0.045) predictor of CLZ-N?-glucuronide formation; the UGT1A4*3 allele was a significant (P < 0.0001) predictor of CLZ-5-N-glucuronide and dmCLZ-glucuronide formation. These data suggest that the UGT1A1*28 and UGT1A4*3 alleles contribute significantly to the interindividual variability in CLZ and dmCLZ metabolism. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Clin. Pharmacol. Ther. 2012 Aug 92: 221-7 |
| PMID | 22713701 |
| Title | UGT1A4*3 encodes significantly increased glucuronidation of olanzapine in patients on maintenance treatment and in recombinant systems. |
| Abstract | Olanzapine, a world leader in antipsychotic drugs, is used in the treatment of schizophrenia and bipolar disorder. There is considerable interpatient variability in its hepatic clearance. Polymorphic glucuronidation of olanzapine by uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4) was investigated retrospectively in patient samples taken for routine therapeutic drug monitoring (TDM) and in recombinant metabolic systems in vitro. Multivariate analyses revealed that patients who were heterozygous as well as those who were homozygous for the UGT1A4*3 allelic variant had significantly higher concentrations of the major metabolite olanzapine 10-N-glucuronide in serum (+38% (P = 0.011) and +246% (P < 0.001), respectively). This finding was in line with the significant increases in glucuronidation activity of olanzapine observed with recombinant UGT1A4.3 (Val-48) as compared with UGT1A4.1 (Leu-48) (1.3-fold difference, P < 0.001). By contrast, serum concentrations of the parent drug were not significantly influenced by UGT1A4 genotype. Our findings therefore indicate that UGT1A4-mediated metabolism is not a major contributor to interpatient variability in olanzapine levels. However, with respect to other drugs for which UGT1A4 has a dominant role in clearance, increased glucuronidation encoded by UGT1A4*3 might impact the risk for subtherapeutic drug exposure. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Expert Opin Drug Metab Toxicol 2014 Jun 10: 893-903 |
| PMID | 24793403 |
| Title | Asenapine review, part I: chemistry, receptor affinity profile, pharmacokinetics and metabolism. |
| Abstract | Asenapine is a second-generation (atypical) antipsychotic currently marketed for the treatment of schizophrenia and bipolar mania/mixed episodes. The purpose of this review is to describe the chemistry, pharmacodynamics, and pharmacokinetics of asenapine. Asenapine has a complex pharmacodynamic profile with affinities at multiple dopamine, serotonin, histamine, and ?-adrenergic receptors, all at which asenapine functions as an antagonist. Sublingual asenapine tablets are absorbed in the oral mucosa, with a Tmax occurring between 30 and 90 min. Terminal half-life is approximately 24 h. Asenapine has multiple inactive metabolites, produced via direct glucuronidation (primarily via UGT1A4), demethylation, and oxidative metabolism (primarily via CYP1A2). Hepatic and renal routes contribute approximately equally to the elimination of asenapine and its metabolites. Two notable drug-drug interactions are evident: asenapine (an inhibitor of CYP2D6) can increase plasma levels of paroxetine, and fluvoxamine (a CYP1A2 inhibitor) can increase plasma levels of asenapine. Caution is required when coadministering asenapine with drugs that are both substrates and inhibitors of CYP2D6. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Drug Metab. Dispos. 2015 Nov 43: 1806-14 |
| PMID | 26329789 |
| Title | In Vitro Characterization of the Human Liver Microsomal Kinetics and Reaction Phenotyping of Olanzapine Metabolism. |
| Abstract | Olanzapine (OLZ) is an atypical antipsychotic used in the treatment of schizophrenia and related psychoses. The metabolism of OLZ is complex and incompletely characterized. This study aimed to elucidate the enzymes and pathways involved in the metabolism of OLZ and to determine the kinetics of OLZ oxidation and glucuronidation by human liver microsomes, recombinant cytochrome P450 (rP450) enzymes, and recombinant UDP-glucuronosyltransferase (rUGT) enzymes. An ultra-performance liquid chromatography-mass spectrometry method was developed and validated to quantify OLZ, its four oxidative metabolites (N-desmethyl-OLZ, 2-hydroxymethyl-OLZ, 7-hydroxy-OLZ, and OLZ-N-oxide), and two N-glucuronides (OLZ-10-N-glucuronide and OLZ-4'-N-glucuronide). Consistent with previous reports, UGT1A4, CYP1A2, and flavin-containing monooxygenase 3 play major roles in catalyzing the formation of OLZ-10-N-glucuronide, 7-hydroxy-OLZ, and OLZ-N-oxide, respectively. In addition, a previously uncharacterized major contribution of CYP2C8 to OLZ-N-demethylation was demonstrated. The kinetics of OLZ metabolite formation (Km and Vmax) by human liver microsomes, rP450 enzymes, and rUGT enzymes were characterized in the presence of bovine serum albumin [2% (w/v)]. Consistent with the known effect of bovine serum albumin on CYP1A2, CYP2C8, and UGT1A4 activities, Km values reported here are lower than previously reported values for OLZ metabolic pathways. In addition to CYP1A2-mediated OLZ-N-demethylation, these results suggest that other P450 enzymes, particularly CYP2C8, contribute significantly to oxidative OLZ metabolism through catalysis of OLZ-N-demethylation. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Ther Drug Monit 2015 Apr 37: 152-60 |
| PMID | 25090458 |
| Title | CYP1A2*1D and *1F polymorphisms have a significant impact on olanzapine serum concentrations. |
| Abstract | Although several polymorphisms in olanzapine-metabolizing enzymes have been identified, the clear role and benefit for pharmacotherapy remain uncertain. The aim of the study was to investigate the potential influence of polymorphisms in the CYP1A2 gene (*1D,*1F), in the UGT1A4 gene (*3), and in the POR gene (rs2302429) on olanzapine serum concentrations and the clinical outcome. Ninety-eight white inpatients who received olanzapine as part of their treatment for at least 4 weeks were included in the retrospective investigation. Moreover, a sample of 209 inpatients receiving olanzapine or clozapine was built to investigate the influence of the relevant polymorphisms CYP1A2*1F, *1D, and CYP1A2 inducers on the clinical outcome. Carriers of the delT-allele (*1D) developed significantly higher dose-corrected olanzapine serum concentrations (analysis of covariance; P < 0.001, delT + delTdelT: 3.1, TT: 1.6 ng·mL·mg, adjusted model including the confounding factors age, sex, baseline weight, CYP1A2*1F genotype, and concomitant CYP1A2 inducers). Moreover, the CYP1A2*1F (AA) genotype also revealed a significant impact on olanzapine serum concentrations according to the analysis of covariance model (P = 0.028; CC + CA: 2.05, AA: 1.44 ng·mL·mg). The other polymorphisms studied revealed no significant influence. Regarding response and adverse effects, a higher increase of weight could be observed in schizophrenic Paranoid Depressive Scale (responder: +5.7 vs nonresponder: +1.8 kg; P = 0.007) and Clinical Global Impression responders (4.6 vs 1.8 kg; P = 0.017). No direct correlation between olanzapine serum concentrations and response or weight gain could be detected. Patients with at least 2 factors promoting higher serum concentrations (no CYP1A2 inducer, *1D deltT-allele, or *1F C-allele) showed a better response according to the Paranoid Depressive Scale (P = 0.002) and a significant correlation with the Clinical Global Impression Scale-2 after 4 weeks (n = 193, r = -0.177; P = 0.005). We, for the first time, identified a significant influence of polymorphisms in CYP1A2 in combination with CYP1A2 inducer status on the clinical outcome. Therefore, genotyping for CYP1A2*1D and *1F may be a useful tool for dose optimization and identification of high-risk patients. Further and larger studies are needed before genotype-based dosage recommendations can help patients treated with CYP1A2 metabolized drugs. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | J. Pharmacol. Exp. Ther. 2015 Feb 352: 358-67 |
| PMID | 25503386 |
| Title | A UGT2B10 splicing polymorphism common in african populations may greatly increase drug exposure. |
| Abstract | RO5263397 [(S)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine], a new compound that showed promising results in animal models of schizophrenia, is mainly metabolized in humans by N-glucuronidation. Enzyme studies, using the (then) available commercial uridine 5'-diphosphate-glucuronosyltransferases (UGTs), suggested that UGT1A4 is responsible for its conjugation. In the first clinical trial, in which RO5263397 was administered orally to healthy human volunteers, a 136-fold above-average systemic exposure to the parent compound was found in one of the participants. Further administration in this trial identified two more such poor metabolizers, all three of African origin. Additional in vitro studies with recombinant UGTs showed that the contribution of UGT2B10 to RO5263397 glucuronidation is much higher than UGT1A4 at clinically relevant concentrations. DNA sequencing in all of these poor metabolizers identified a previously uncharacterized splice site mutation that prevents assembly of full-length UGT2B10 mRNA and thus functional UGT2B10 protein expression. Further DNA database analyses revealed the UGT2B10 splice site mutation to be highly frequent in individuals of African origin (45%), moderately frequent in Asians (8%) and almost unrepresented in Caucasians (<1%). A prospective study using hepatocytes from 20 individual African donors demonstrated a >100-fold lower intrinsic clearance of RO5263397 in cells homozygous for the splice site variant allele. Our results highlight the need to include UGT2B10 when screening the human UGTs for the enzymes involved in the glucuronidation of a new compound, particularly when there is a possibility of N-glucuronidation. Moreover, this study demonstrates the importance of considering different ethnicities during drug development. |
| SCZ Keywords | schizophrenia, schizophrenic |