The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation

OBJECTIVE: The cytochrome P450 2D6 (CYP2D6) enzyme metabolizes risperidone. CYP2D6 poor metabolizers have no CYP2D6 activity (7% of whites and 1%-2% of other races). This study tested whether the CYP2D6 poor metabolizer phenotype was associated with adverse drug reactions (ADRs) and discontinuation due to ADRs. METHOD: Adult inpatients and outpatients were recruited from July 2000 to March 2003 including (1) 325 who were stabilized on risperidone therapy and classified as either expressing moderate-to-marked ADRs (22%, 73/325) or not (78%, 252/325) and (2) 212 who discontinued risperidone and were classified as discontinued due to ADRs (38%, 81/212) or for other reasons (62%, 131/212). Genetic tests were performed by allele-specific polymerase chain reaction and/or by the AmpliChip CYP450 microarray system for up to 34 separate CYP2D6 alleles. Two logistic regression models with dependent variables (moderate-to-marked ADRs while taking risperidone and risperidone discontinuation due to ADRs) were evaluated with respect to the CYP2D6 phenotype. RESULTS: The odds ratios (ORs) and 95% confidence intervals (CIs) for the CYP2D6 poor metabolizer phenotype in the univariate analyses and after correcting for clinical variables were (1) OR = 3.1 (CI = 1.4 to 7.0) and 3.4 (CI = 1.5 to 8.0) for moderate-to-marked ADRs on risperidone and (2) OR = 3.0 (CI = 0.85 to 10.6) and 6.0 (CI = 1.4 to 25.4) for discontinuation due to ADRs. CONCLUSIONS: The CYP2D6 poor metabolizer phenotype appears to be associated with risperidone ADRs and discontinuation due to ADRs; however, this finding requires further study in larger patient populations. The CYP3A5 and p-glycoprotein exon 21 and 26 genotypes were not significantly associated with risperidone response.     

Relationship between haloperidol plasma concentration, debrisoquine metabolic ratio, CYP2D6 and CYP2C9 genotypes in psychiatric patients

BACKGROUND: Around seven percent of Caucasians are poor metabolizers of cytochrome P450, CYP2D6 due to genetically impaired activity of the enzyme. Haloperidol in vitro and in vivo inhibits the activity of CYP2D6 and also the involvement of the enzyme in haloperidol metabolism has been reported. The present study was aimed to evaluate the possible inhibition of CYP2D6 during haloperidol treatment, and to determine the effect of CYP2D6 and CYP2C9 genotypes on the plasma concentration of haloperidol. METHODS: Thirty Caucasian psychiatric patients under haloperidol monotherapy were studied. CYP2D6 activity was evaluated by the debrisoquine metabolic ratio (MR), subjects with MR > 12.6 were named as poor metabolizers. Haloperidol plasma concentration was determined by high performance liquid chromatography. RESULTS: The number of patients with debrisoquine MR > 12.6 was higher than the expected comparing to healthy volunteers (13 % vs. 6.6 %, respectively). Debrisoquine MR was correlated with the dose of haloperidol (r = 0.40, p < 0.05), and also with the plasma concentration (r = 0.58, p < 0.001). Additionally, three patients comedicated with inhibitors of CYP2D6 were studied, all of them had a debrisoquine MR > 12.6, however only one was genetically poor metabolizer of CYP2D6. CYP2D6 and CYP2C9 genotypes were not related to the dose or plasma concentration of haloperidol. CONCLUSIONS: The present data support the dose-dependent inhibitory effect of haloperidol on CYP2D6, and the influence of this enzyme activity on haloperidol plasma concentration under steady-state conditions. The inhibitory effect of haloperidol on CYP2D6 enzyme activity may result in drug interactions and unexpected high plasma concentrations when drugs metabolized by the same enzyme are given concomitantly with haloperidol.     

Paradoxical urinary phenytoin metabolite (S)/(R) ratios in CYP2C19*1/*2 patients

Phenytoin (PHT) is primarily metabolized to 5-(4'-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), accounting for 67-88% of an administered dose in humans. p-HPPH is formed by the cytochrome (CYP) 450 enzymes CYP2C9 and CYP2C19, then glucuronidated and excreted into the urine. CYP2C9 catalyses the prochiral formation of (R) and (S)-p-HPPH, and is approximately 40 times more stereoselective towards the formation of the (S) isomer whereas CYP2C19 is not stereoselective. Because of differential stereoselectivity, polymorphisms in the genes can alter the (S)/(R)-p-HPPH ratios. Genotyping for CYP2C9 and CYP2C19 was accomplished by a Taqman based assay. Twelve and twenty-four hour urine samples were collected from 45 epilepsy patients taking PHT under steady-state conditions and (S)/(R) ratios of p-HPPH were determined by chiral HPLC separation. The mean urinary (S)/(R) ratio in the 12-24h urine collection in subjects homozygous for CYP2C9*1/*1, CYP2C19*1/*1 was 24.2+/-3.1(n=21), whereas ratios in CYP2C9*1/*2 and CYP2C9*1/*3 subjects, were 11.1+/-3.3(n=7) and 2.7+/-0.6(n=2), respectively. One CYP2C9*2/*3 patient had a ratio of 2.1. Unexpectedly, CYP2C9*1/*1, CYP2C19*1/*2 subjects had a mean (S)/(R) ratio as low as 12.9+/-1.7(n=12). Our results are generally consistent with single dose PHT studies. However, the (S)/(R)-p-HPPH ratios for the CYP2C9*1/*1, CYP2C19*1/*2 subjects, expected to be in the range of 30-40, were only 12.9, suggesting some undetected linkage disequilibrium between CYP2C9 and CYP2C19 genes that could affect PHT elimination. Furthermore, our study suggests that measurement of urine ratios cannot be used as a marker for genotype determination.     

The relevance of genetically determined polymorphism CYP2D6 in psychopharmacology; the relationship between genotype and phenotype

Based on literature review the paper presents some clinical aspects of the genetically determined polymorphism of the CYP2D6. One of the main biotransformation processes of psychotropic drugs is oxidation catalysed by enzymes of cytochrome P-450. CYP2D6 is an isoenzyme of cytochrome P-450. Its activity is determined genetically and is characterised by interindividual variability. Genetically determined polymorphism of CYP2D6 is related to mutated alleles that code enzymatic proteins with different activity. Based on individual ability to oxidize drugs by CYP2D6 in population there are four phenotypically different groups: extensive (EM), ultra-rapid (UM), intermediate (IM) and poor metabolizers (PM). Each phenotype is determined by a given genotype. About 6-10% of the Caucasian population is known as PM phenotype. Drugs used in standard doses in this group may reach a markedly higher level in blood, even a toxic level. Compared to the group with EM phenotype persons with PM or IM phenotype are more likely to suffer from side effects that are related to impaired metabolic pathways that are catalyzed by CYP2D6. In the group with UM phenotype (1-7% of population) metabolism is very rapid, thus they need higher doses of psychotropic drugs to reach therapeutic blood level of drug.     

Cytochrome P-450 2D6*10 C188T polymorphism is associated with antipsychotic-induced persistent tardive dyskinesia in Chinese schizophrenic patients

Typical antipsychotic treatment had been postulated to be a risk factor for the susceptibility to tardive dyskinesia (TD). The cytochrome P-450 debrisoquine/sparteine hydroxylase (CYP2D6) metabolizes a majority of antipsychotics and exhibits various phenotypes on enzymatic activities from poor metabolizers to ultrarapid metabolizers. The various phenotypes are encoded by polymorphic genetic variants on the CYP2D6 gene. Although several studies had explored the association between the CYP2D6*10 C188T polymorphism, which encodes the phenotype intermediate metabolizers, and TD in Orientals, the findings were inconclusive. In the present study, we examined the relationship between the CYP2D6*10 C188T polymorphism and the TD occurrence in 216 Chinese schizophrenic patients (113 patients with TD and 103 patients without TD) and explored the correlation between the TD severity assessed by the Abnormal Involuntary Movement Scale (AIMS) and each C188T genotype in the 113 TD patients. Using logistic regression analysis, we found a modest association (p = 0.045) between TD and C188T genotypes. This positive finding was only observed in male patients (p = 0.001), but not in females. Our findings also support the correlation between AIMS scores and C188T polymorphism within the TD group after adjusting for confounding effects with the multiple regression analysis (p = 0.033). We concluded that the CYP2D6*10 C188T polymorphism may be associated with the susceptibility to the occurrence of TD induced by typical antipsychotics, especially in male patients, and may also be correlated with AIMS scores in TD patients.     

A pilot study on risperidone metabolism: the role of cytochromes P450 2D6 and 3A.

BACKGROUND: The limited available information on plasma risperidone levels shows a stable relationship between daily doses of risperidone and total plasma concentration (risperidone plus its active metabolite 9-hydroxyrisperidone). The ratio between risperidone and 9-hydroxyrisperidone characterizes cytochrome P450 2D6 (CYP2D6) status. According to the manufacturer, the CYP2D6 genotype or drugs that influence CYP2D6 or other cytochrome P450 isoenzyme activity are not expected to be clinically significant. One case report suggests that CYP3A participates in the metabolism of risperidone. METHOD: A case series of 13 risperidone patients (the initial case and 12 new cases) who were genotyped for CYP2D6 were followed, and another 20 risperidone patients from a case-control study for the CYP2D6 genotype were reviewed. RESULTS: The CYP2D6 poor metabolizers, who are enzyme deficient (2/13 in the case series and 3/20 in the case-control study), did not appear to tolerate risperidone well. Drugs affecting CYP3A, in particular powerful inducers and inhibitors, resulted in at least a 2-fold decrease or increase in plasma risperidone levels. CONCLUSION: The anecdotal nature of this study is clearly a limitation. Drugs influencing CYP3A and CYP2D6 metabolic activity may significantly affect risperidone levels. Thus, plasma level monitoring of risperidone in a clinical setting may be useful, especially if patients are taking multiple medications or a CYP2D6 deficiency is suspected. New prospective studies under more controlled conditions are needed to verify these hypotheses.     

Association of A313 G polymorphism (GSTP1*B) in the glutathione-S-transferase P1 gene with sporadic Parkinson's disease

Genetic predisposition, environmental toxins and aging contribute to Parkinson's disease (PD) multifactorial etiology. Weak environmental neurotoxic factors may accumulate over time increasing the disease risk in genetically predisposed subjects. Polymorphic genes encoding drug-metabolizing-enzymes (DMEs) are considered to account for PD susceptibility by determining individual toxic response variability. In this work, the allelic distributions and genotype associations of three major brain-expressed DMEs were characterized, in sporadic PD cases and controls. No significant association was found between CYP2D6 genotype and PD, but subjects with extensive metabolizer (EM) CYP2D6 phenotype, and the variant GSTP1 *B genotype were at significantly higher PD risk than the corresponding poor or intermediary metabolizers ( CYP2D6 poor metabolizer phenotype+intermediary metabolizers). A significant association was observed between the GSTP1*B allele and zygosity with PD ( GSTP1*A/*B – 51.58%/34.37%, odds ratio (OR) = 2.29; 95% confidence interval (95% CI) = 1.25–4.18; * B /* B – 6.32%/1.05%, OR = 10.67; 95% CI = 1.19–94.79). This association was particularly strong in the elder patients group (≥69 year) who showed double PD risk for GSTP1*B heterozygous, whilst GSTP1*B/*B homozygous were exclusively found amongst patients. An interaction between GSTM1 and GSTP1 was observed in this late onset PD group. The present results suggest that native GSTP1 encoding the fully active transferase variant should play a relevant role in dopaminergic neuroprotection.     

CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages

OBJECTIVE: This review aimed to provide distinct dose recommendations for antidepressants based on the genotypes of cytochrome P450 enzymes CYP2D6 and CYP2C19. This approach may be a useful complementation to clinical monitoring and therapeutic drug monitoring. METHOD: Our literature search covered 32 antidepressants marketed in Europe, Canada, and the United States. We evaluated studies which had compared pharmacokinetic parameters of antidepressants among poor, intermediate, extensive and ultrarapid metabolizers. RESULTS: For 14 antidepressants, distinct dose recommendations for extensive, intermediate and poor metabolizers of either CYP2D6 or CYP2C19 were given. For the tricyclic antidepressants, dose reductions around 50% were generally recommended for poor metabolizers of substrates of CYP2D6 or CYP2C19, whereas differences were smaller for the selective serotonin reuptake inhibitors. CONCLUSION: We have provided preliminary average dose suggestions based on the phenotype or genotype. This is a first attempt to apply the new pharmacogenetics to suggest dose-regimens that take the differences in drug metabolic capacity into account.     

Analysis of CYP2D6 genotype and response to tetrabenazine

Tetrabenazine is effective in the treatment of the chorea associated with Huntington disease and other hyperkinetic movement disorders. Following oral administration, tetrabenazine is hepatically transformed into 2 active metabolites that are CYP2D6 substrates. There are 4 CYP2D6 genotypes: poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultrarapid metabolizers. CYP2D6 genotyping was performed on sequential subjects treated with tetrabenazine, but results were not known at the time of titration. Duration of titration to a stable dose, total daily dose, response rating scores, and adverse events were retrospectively collected and subsequently analyzed. Of 127 patients, the majority (n = 100) were categorized as extensive metabolizers, 14 as intermediate metabolizers, 11 as poor metabolizers, and 2 as ultrarapid metabolizers. Ultrarapid metabolizer patients needed a longer titration (8 vs 3.3, 4.4, and 3 weeks, respectively; P < .01) to achieve optimal benefit and required a higher average daily dose than the other patients, but this difference did not reach statistical significance. The treatment response was less robust in the intermediate metabolizer group when compared with the extensive metabolizer patients (P = .013), but there were no statistically significant differences between the various groups with regard to adverse effects. Our findings demonstrate that, aside from the need for a longer titration in the ultrarapid metabolizers, there are no distinguishing features of patients with various CYP2D6 genotypes, and therefore the current recommendation to systematically genotype all patients prescribed more than 50 mg/day of tetrabenazine should be reconsidered. © 2012 Movement Disorder Society     

CYP2D6 and clinical response to atomoxetine in children and adolescents with ADHD

BACKGROUND: Atomoxetine, a selective norepinephrine reuptake inhibitor effective in the treatment of attention-deficit/hyperactivity disorder (ADHD), is metabolized through the cytochrome P-450 2D6 (CYP2D6) enzyme pathway, which is genetically polymorphic in humans. Variations in plasma atomoxetine exposures can occur because of genetic variation or as a consequence of coadministration with drugs that inhibit CYP2D6. METHOD: We examined the effects of CYP2D6 on the efficacy, safety, and tolerability of atomoxetine in children and adolescents using pooled data from atomoxetine clinical trials. RESULTS: At endpoint, poor metabolizers had markedly greater reductions in mean symptom severity scores compared with extensive metabolizers (p < .05). Poor metabolizers had greater increases in heart rate and diastolic blood pressure (p < .001) and smaller increases in weight (p < .05) than extensive metabolizers. Several adverse events, including decreased appetite and tremor, were more frequent in poor metabolizers (p < .05). CONCLUSIONS: These results suggest that CYP2D6 poor metabolizers taking atomoxetine in doses up to 1.8 mg/kg/day are likely to have greater efficacy, greater increases in cardiovascular tone, and some differences in tolerability compared with CYP2D6 extensive metabolizers taking similar doses.     

The effect of cytochrome P450 2D6 genotypes on haloperidol metabolism: a preliminary study in a psychiatric population

We investigated the effect of cytochrome P450 (CYP2D6) genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 47 Japanese male schizophrenic inpatients being treated with HAL. Mutation-specific polymerase chain reaction (PCR) analysis was used to detect CYP2D6*10 as the C188C1T mutation in exon 1. A long-PCR analysis method was used to detect CYP2D6*5. Allele frequencies of CYP2D6*5 and CYP2D6*10 were 4.3% and 34.0%, respectively. Plasma concentrations of HAL and RHAL were measured using high-performance liquid chromatography. The ranges of the plasma concentration of HAL and RHAL corrected to the dose were 0.28-1.60 (mean +/- SD, 0.66+/-0.25, n = 47) ng/mL/mg and 0.03-3.00 (mean+/-SD, 0.36+/-0.46, n = 47) ng/mL, respectively. Plasma RHAL/HAL ratios (R/H ratios) ranged from 0.06 to 1.88 (mean +/- SD, 0.48+/-0.32, n = 47). The analysis was performed among the four genotype groups: CYP2D6*1/CYP2D6*1 (n = 11), CYP2D6*1/CYP2D6*10 (n = 11), CYP2D6*10/CYP2D6*10 (n = 6) and those who have CYP2D6*5 allele (CYP2D6*1/ CYP2D6*5 or CYP2D6*5/CYP2D6*10 (n = 4). We observed significant tendency in effects of CYP2D6 genotypes on plasma concentration of HAL and significant effects on plasma concentration of RHAL, and R/H ratio. These results we obtained suggested that the plasma concentration of HAL and RHAL were determined partly by CYP2D6 polymorphic activity.     

The Effects of Genetic Polymorphisms of CYP2C9 and CYP2C 19 on Phenytoin Metabolism in Japanese Adult Patients with Epilepsy: Studies in Stereoselective Hydroxylation and Population Pharmacokinetics

Summary: Purpose : The aim of this study was to clarify the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C9 and 2C19 on the metabolism of phenytoin (PHT). In addition, a population pharmacokinetic analysis was performed.
Methods: The genotype of CYP2C9 (Arg¹⁴⁴/Cys, Ile³⁵⁹/Leu) and CYP2C19 (*1, *2 or *3) in 134 Japanese adult patients with epilepsy treated with PHT were determined, and their serum concentrations of 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) enantiomers, being major metabolites of PHT, were measured. A population pharmacokinetic analysis (NONMEM analysis) was performed to evaluate whether genetic polymorphism of CYP2C9/19 affects the clinical use of PHT by using the 336 dose-serum concentration data.
Results: The mean maximal elimination rate (Vmax) was 42% lower in the heterozygote for Leu359 allele in CYP2C9, and the mean Michaelis-Menten constants (K,) in the heterozygous extensive metabolizers and the poor metabolizers of CYP2C19 were 22 and 54%, respectively, higher than those without the mutations in CYP2C9/19 genes. (R)- and (5')- p -HPPHPHT ratios were lower in patients with mutations in CYP2C9 or CYP2C19 gene than those in patients without mutations.
Conclusions: Although the hydroxylation capacity of PHT was impaired with mutations of CYP2C9/19, the impairment was greater for CYP2C9. In view of the clinical use of PHT, two important conclusions were derived from this population study. First, the serum PHT concentration in patients with the Leu359 allele in CYP2C9 would increase dramatically even at lower daily doses. Second, the patients with CYP2C19 mutations should be treated carefully at higher daily doses of PHT.     

Effect of tolterodine on sleep structure modulated by CYP2D6 genotype

OBJECTIVE: Tolterodine, a drug for the treatment of overactive bladder symptoms, has a limited entry into the brain, which makes cognitive side effects seldom. However, some case reports have described central-nervous side effects such as sleepiness. The aim of this retrospective analysis was to investigate whether tolterodine-related effects on sleep stage parameters could be explained by different CYP2D6 metabolizer characteristics of subjects. METHODS: Data were taken from two randomized, double-blind, placebo-controlled studies conducted in a cross-over design. Forty-eight volunteers underwent 4 two-night attended polysomnographic studies. Subjective quality of sleep and cognitive function were assessed. A single dose of 4 mg tolterodine or placebo was administered before sleep. Forty-four volunteers gave informed consent for genotyping. We found 19 extensive metabolizers (EM), 20 intermediate metabolizers (IM), 4 poor metabolizers (PM) and 1 ultrarapid metabolizer. There were no significant differences between the groups regarding demographic data. RESULTS: Rapid eye movement (REM) sleep duration as a percentage of total sleep time showed significant reduction (p=0.019) in the group carrying one or more deficient alleles (IM+PM). No significant difference was found with two active alleles of CYP2D6 in the EM group. REM latencies under tolterodine displayed a tendency towards prolongation, which was irrespective of the metabolizer status. Subjective sleep parameters did not show statistically significant changes after tolterodine. Cognitive skills were not affected. CONCLUSION: Our retrospective analysis reveals that a decrease of REM sleep under tolterodine is found only in individuals carrying one or two deficient CYP2D6 alleles.     

Assessment of CYP2D6 activity as a form of optimizing antidepressant therapy

Cytochrome 2D6 catalyzes oxidation processes of many antidepressants (TCAs, SSRIs, maprotyline, mianserine, nefazodon, trazodon, venlafaxine). CYP2D6 is characterized by genetically determined polymorphism which may lead to serious clinical consequences. Based on CYP2D6 activity four phenotypes are distinguished: poor metabolism (PM), intermediate (IM), extensive (normal) EM and ultrarapid (UM). In case of PM and IM increased plasma concentration of a drug and adverse events or toxicity may appear. Decreased plasma level and lack of clinical effect may be connected with the ultrarapid phenotype. CYP2D6 activity may be assessed by phenotyping or genotyping . Model drugs such as sparteine, debrisoquine, dextromethorphan and metoprolol are used in the phenotyping method. Based on the metabolic ratio of model drug the phenotype status is established. Genotyping consists in an assessment of genotype i.e. an identification of alleles coding the CYP2D6 protein. The environmental factors may modify the CYP2D6 activity and have influence on phenotyping but not genotyping results. The knowledge of CYP2D6 phenotype is of special value when drugs characterized by a narrow therapeutic index are used and in polymedicated and older patients.     

Genetic determinants of high on-treatment platelet reactivity in clopidogrel treated Chinese patients

Introduction

Cytochrome P450 (CYP), ATP-binding cassette transporters (ABCB1), and paraoxonase-1 (PON1) play crucial roles in clopidogel absorption and bioactivation. Genetic polymorphisms in these genes have been associated with the variability of the response to clopidogrel, however their contribution to high on-treatment platelet reactivity (HPR) in clopidogrel treated Chinese patients is less known.

Materials and methods

Five-hundred Chinese-Han patients treated with clopidogrel for acute coronary syndrome (ACS) were consecutively recruited from the Department of Geriatric Cardiology, General Hospital of Chinese People’s Liberation Army, from September 2010 to September 2012. We assessed the relations of CYP2C19*2 (rs4244285), CYP2C19*3 (rs4986893), CYP2C19*17 (rs12248560), PON1Q129R (rs662) and ABCB1C3435T (rs1045642) to the platelet aggregation after 5 days maintenance dose of clopidogrel administration, and the risk for HPR. The cutoff of HPR was defined as 20 μmol/L adenosine diphosphate (ADP)-induced platelet aggregation > 50%.

Results

Both CYP2C19*2 and *3 alleles were significantly associated with higher platelet aggregation after 5 days maintenance dose of clopidogrel administration (P < 0.00001and P = 0.042, respectively). The platelet aggregation in carriers of at least one CYP2C19 loss-of-function allele (*2 or *3, accounted for 58% of the study population) was obviously higher than that in non-carriers (P < 0.00001). Patients with the CYP2C19*2 allele had a higher risk of HPR than those with the CYP2C19 wild-type genotype [adjusted hazard ratio (HR), 1.56; 95% confidence interval(CI), 1.04–2.33, P = 0.03]. The carriers of at least one CYP2C19 loss-of-function allele could also predict significantly greater risk of HPR compared with non-carriers (adjusted HR1.79,95% CI: 1.33–2.4,P = 0.003). However, the carriage of CYP2C19*3 alone could not predict the risk of HPR significantly (adjusted HR, 1.5; 95% CI: 0.83–3, P = 0.16). Significant relation of CYP2C19*17, PON1Q129R and ABCB1C3435T to the platelet aggregation was not found.

Conclusion

In clopidogrel treated Chinese patients with ACS, carriers of at least one CYP2C19 loss-of-function allele could predict greater risk of HPR, with the impact mainly attributing to CYP2C19*2. Neither ABCB1 nor PON1 genotype could influence the antiplatelet response of clopidogrel in the cohort of Chinese patients.     

An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients

The objective of this study was to assess the relative influence of VKORC1 and CYP2C9 genetic variants on several clinical outcomes related to warfarin treatment. We conducted a retrospective cohort analysis of 172 anticoagulation clinic patients followed from warfarin initiation. We assessed the following clinical outcomes: time to stable dose; time in, above, and below therapeutic range; the probability of overanticoagulation (international normalized ratio [INR] >5); frequency of anticoagulation clinic visits; and the contribution of genetics to maintenance dose. Patients with CYP2C9 variants, compared to those without, achieved stable dose 48% later (p < 0.01), spent a higher proportion of time above range in the first month of therapy (14% vs. 25%, p = 0.07), and had a higher odds ratio (OR) of an INR >5 (OR: 4.15, p = 0.03). In contrast, the only statistically significant effect with VKORC1 was a higher odds of an INR >5 (OR: 4.47, p = 0.03) for patients homozygous for the VKORC1 low-dose haplotype (AA) compared to heterozygotes. We did not detect an influence of CYP2C9 nor VKORC1 on the frequency of clinic visits. CYP2C9 alone, VKORC1 alone, and a combination of genetic and clinical factors explained 12%, 27%, and 50%, respectively, of the variation in warfarin maintenance dose. In conclusion, genetic variation in VKORC1 appears to have a different influence than CYP2C9 on anticoagulation-related outcomes such as bleeding events and time in therapeutic range. This difference may be due, in part, to pharmacokinetics factors (e.g. drug half-life), which are influenced primarily by CYP2C9; these findings should be confirmed in additional studies.     

Cytochrome P450 2D6 deficiency and its clinical relevance in a patient treated with risperidone

In contrast to several authors who found hepatic cytochrome P 450 2D6 (CYP2D6) metabolising status to be clinically unimportant in treatment with the CYP2D6 substrate, risperidone, we report on a 17-year-old schizophrenic patient who suffered from severe extrapyramidal side effects (EPS) while being treated with risperidone at 4 mg per day. He was genotyped as a CYP2D6 poor metaboliser (PM). The active moiety of risperidone (sum of risperidone and 9-hydroxyrisperidone) was elevated and increased even further under co-medication with haloperidol and biperiden. We conclude that the PM phenotype for CYP2D6 of this patient had major clinical importance in treatment with risperidone. Most likely metabolic pathways other than CYP2D6 were also involved that are probably inhibited by haloperidol.     

Influence of CYP2C9 polymorphism and phenytoin co-administration on acenocoumarol dose in patients with cerebral venous thrombosis

Background

The study aimed at evaluating the contribution of genetic variations in the drug metabolizing enzyme, CYP2C9, and the influence of co-medication with the antiepileptic drug, phenytoin, to variability in acenocoumarol response, in patients with cerebral venous thrombosis (CVT).

Methods

476 acenocoumarol-treated CVT patients (153 males and 323 females) were genotyped for CYP2C9*2 and CYP2C9*3 polymorphisms by PCR-RFLP method. Mean acenocoumarol dose required for achieving and maintaining a stable international normalized ratio (INR) was calculated for different genotypes. The effect of co-administration with phenytoin was determined.

Results

Genotype distributions of CYP2C9 were as follows: 83%CYP2C9*1/*1, 8.6%CYP2C9*1/*3, 5.9%CYP2C9*1/*2, 1.9%CYP2C9*3/*3, 0.4%CYP2C9*2/*3 and 0.2%CYP2C9*2/*2. During the initiation phase of anticoagulation the CYP2C9*2 allele was independently associated with low acenocoumarol dose requirement (Adjusted OR 5.38; 95%CI 1.65-17.49; p = 0.005). Similarly, the adjusted odds ratio for requiring a low dose during the induction phase in patients bearing the CYP2C9*3 allele was 12.79 (95%CI 4.74-34.57; p < 0.0001). During the maintenance phase, CYP2C9*2 and CYP2C9*3 alleles were associated with 19-fold (Adjusted OR 19.67; 95%CI 2.46-157.19; p = 0.005) and 11.9-fold odds (Adjusted OR 11.98; 95%CI 2.61-55.08; p = 0.001) of requiring a low dose. Clinical covariates such as age, alcohol consumption, postpartum state and oral contraceptive intake also influenced acenocoumarol dosage. Co-medication with phenytoin was associated with lower dose requirement across genotypes during the initiation phase. However, during the maintenance phase, phenytoin-treated patients of all genotypes required higher doses of acenocoumarol.

Conclusion

This study emphasizes the fact that polymorphisms in CYP2C9 gene and co-medication with phenytoin alter the anticoagulant effect of acenocoumarol.     

CYP2D6 phenotypes and Parkinson's disease risk: A meta-analysis

BackgroundCYP2D6 polymorphisms have been reported to be associated with Parkinson's disease (PD) susceptibility, but the results of these previous studies were inconsistent.ObjectivesTo explore whether PD patients with CYP2D6 gene variation have different risk to PD to those with normal function of CYP2D6.MethodsSystematic review with meta-analysis of case-controlled studies on the association between CYP2D6 and PD risk was conducted. Studies published up to August 1, 2013 were identified by searching electronic databases PubMed and Embase. Odds ratios (ORs) together with their corresponding 95% confidence intervals (CIs) were used to estimated the association between CYP2D6 polymorphisms and PD risk in different phenotype models. Meta-regression, subgroup analysis, sensitivity analysis and publication bias were also performed.ResultsA total of 3521 PD Patients and 4476 controls from 29 case–control studies were identified. Overall, a borderline significant influence of the CYP2D6 polymorphisms on PD risk was observed (OR: 1.07, 95%CI: 0.99–1.16, p = 0.106). Significant association was found when comparisons were performed in different phenotypes in PM versus EM (OR = 1.33, 95% CI = 1.01–1.74, p = 0.044) and PM versus IM + EM (OR = 1.32, 95% CI = 1.11–1.56, p = 0.002). In subgroup analysis stratified by country, significant association was demonstrated in British but not in other white subjects. No significant association was detected in subgroup analysis according to the age of onset and the source of patients.ConclusionThe present meta-analysis demonstrated that the poor metabolizer phenotype of CYP2D6 confers a significant genetic susceptibility to PD in Caucasians, especially in British white subjects.     

Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer

Codeine is metabolized by the cytochrome P450 2D6 (CYP2D6) to morphine. Codeine is a much weaker agonist at mu opioid receptors than morphine. Therefore, codeine analgesia is highly dependent on CYP2D6 activity. Large prospective studies in the clinical environment do not exist, but it appears reasonable to avoid codeine use in CYP2D6 poor metabolizers (PMs). CYP2D6 metabolizes other opioid analgesics, including tramadol, dihydrocodeine, oxycodone and hydrocodone, although they have been less systematically studied. It is unclear whether these other pro-drugs may be as completely dependent on CYP2D6 for their analgesia as codeine. We describe a patient identified as a CYP2D6 PM with a history of problems with opioid analgesics. The patient was an 85-year-old female Caucasian who had hip surgery. The patient had a long-standing intolerance to codeine. In her first admission, she couldn't tolerate the regimen of oxycodone combined with tramadol prns (as needed). She was genotyped as a CYP2D6 PM and after the information was provided to the treating physician in her second admission, she seemed to have a better response to hydrocodone. Large case-control naturalistic studies followed by randomized trials in patients taking opioid analgesics may be needed to definitively establish that CYP2D6 genotyping has clinical relevance in the use of several opioid analgesics.