Treatment-Resistance to Clozapine in Association With Ultrarapid CYP1A2 Activity and the C → A Polymorphism in Intron 1 of the CYP1A2 Gene: Effect of Grapefruit Juice and Low-Dose Fluvoxamine

Özdemir, Vural; Kalow, W.; Okey, Allan B.; Lam, Maria S. M.; Albers, Lawrence J.; Reist, Christopher; Fourie, Jeanne; Posner, Paul; Collins, Evan; Roy, Rochelle

doi:10.1097/00004714-200112000-00011

Cited by 91 publications

(62 citation statements)

References 27 publications

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“…Clozapine clearance was found to be significantly correlated with the 17X/137X (r ¼ 0.89, po0.0013) and the 37X/137X ratio (r ¼ 0.85, po0.0023). Very high CYP1A2 activity as indicated by a urinary caffeine metabolic ratio of 17.9 (usual range 1.9-1.47) was reported in one patient; excessive CYP1A2 activity in this patient was associated with a subtherapeutic clozapine plasma concentration of 661 nmol/l (minimum threshold 1150 nmol/ l ¼ 350 ng/ml), despite a drug dose of 850 mg/day (Ozdemir et al, 2001a). Fluvoxamine 25 mg/day, a well-known CYP1A2 inhibitor, was added to the patient's regimen and a subsequent clozapine plasma concentration of 1600 nmol/l was reached and the patient's clinical status improved.…”

Section: Discussionmentioning

confidence: 79%

Correlation of Cytochrome P450 (CYP) 1A2 Activity Using Caffeine Phenotyping and Olanzapine Disposition in Healthy Volunteers

Shirley

Hon

Penzak

et al. 2002

Neuropsychopharmacol

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Olanzapine has previously been shown to have predominant metabolism by cytochrome (CYP) P450 1A2. Caffeine has been shown to provide an accurate phenotypic probe for measuring CYP1A2 activity. The purpose of this study is to determine if a significant correlation exists between olanzapine disposition and caffeine metabolic ratios. Subjects were phenotyped for CYP1A2 activity with caffeine probe methodology. After 200-mg caffeine administration, blood (4 h), saliva (6 and 10 h), and urine (8 h total) were collected for highperformance liquid chromatography (HPLC) analysis of caffeine and its metabolites.CYP1A2 activity was measured as plasma (PMR 4 h ), saliva (SMR 6 h and SMR 10 h ), and three urinary metabolic (UMR1 8 h , UMR2 8 h , and UMR3 8 h ) ratios. Each of the 14 healthy nonsmokers (13 male) received a single 10 mg olanzapine dose after which blood was collected for HPLC determination of olanzapine concentrations at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, and 120 h postdose. Olanzapine pharmacokinetic parameters in this study were similar to those previously published. All caffeine metabolic ratios (PMR 4 h , SMR 6 h , SMR 10 h , UMR1 8 h , and UMR2 8 h ) significantly correlated with each other (po0.001) except for UMR3 8 h , which did not correlate. A significant correlation (po0.05) was also found between olanzapine clearance and PMR 4 h (r ¼ 0.701), SMR 6 h (r ¼ 0.644), SMR 10 h (r ¼ 0.701), UMR1 8 h (r ¼ 0.745), and UMR2 8 h (r ¼ 0.710). A negative correlation was observed between olanzapine clearance and UMR3 8 h (r ¼ À0.029, p ¼ NS). A significant correlation was found between olanzapine clearance and various caffeine metabolic ratios. Interpatient variability in CYP1A2 activity may explain the wide interpatient variability in olanzapine disposition. Compounds that modulate CYP1A2 activity may be expected to alter olanzapine pharmacokinetics accordingly.

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Section: Discussionmentioning

confidence: 79%

Correlation of Cytochrome P450 (CYP) 1A2 Activity Using Caffeine Phenotyping and Olanzapine Disposition in Healthy Volunteers

Shirley

Hon

Penzak

et al. 2002

Neuropsychopharmacol

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“…191,192 Several studies have reported a better response to SSRIs in individuals carrying two (l)-alleles of the 44-bp insertion/deletion polymorphism in the regulatory region of the serotonin transporter (SERT). 168,169,[171][172][173][174][175]193 Two studies had contradictory results. 165,170 This discrepancy might be due to ethnic differences: the (s)-allele frequency is much higher in Orientals than in Caucasians (79 vs 42%), 194 and both studies showing an association of the (s) allele with better response were conducted in Oriental patients.…”

Section: Serotonin Transportermentioning

confidence: 99%

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

et al. 2004

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Genetic factors contribute to the phenotype of drug response. We systematically analyzed all available pharmacogenetic data from Medline databases on the impact that genetic polymorphisms have on positive and adverse reactions to antidepressants and antipsychotics. Additionally, dose adjustments that would compensate for genetically caused differences in blood concentrations were calculated. To study pharmacokinetic effects, data for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at least doubling of the dose in extensive metabolizers in comparison to poor metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of relevance. To study the effects of genetic variability on pharmacodynamic pathways, we reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the most part reveal significant associations between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions. In addition associations found in one study could not be replicated in other studies. For this reason, it is not yet possible to translate pharmacogenetic parameters fully into therapeutic recommendations. At present, antidepressant and antipsychotic drug responses can best be explained as the combinatorial outcome of complex systems that interact at multiple levels. In spite of these limitations, combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of relevance might contribute to identify genotypes associated with best and worst responders and they may also identify susceptibility to adverse drug reactions.

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“…70 However, CYP1A2 polymorphisms did not significantly influence individuals' clozapine metabolic capacity, 71 although delays in response to clozapine have been observed in individuals with the UM phenotype. 72,73 Also a combination of high inducibility CYP1A2 alleles and smoking may result in higher metabolic ratios and reduced clozapine plasma levels. 74 In these cases, an adjustment of therapeutic dose is recommended.…”

Section: Pharmacokinetic Factorsmentioning

confidence: 99%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and À141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (À759ÀT/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

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Treatment-Resistance to Clozapine in Association With Ultrarapid CYP1A2 Activity and the C → A Polymorphism in Intron 1 of the CYP1A2 Gene: Effect of Grapefruit Juice and Low-Dose Fluvoxamine

Cited by 91 publications

References 27 publications

Correlation of Cytochrome P450 (CYP) 1A2 Activity Using Caffeine Phenotyping and Olanzapine Disposition in Healthy Volunteers

Correlation of Cytochrome P450 (CYP) 1A2 Activity Using Caffeine Phenotyping and Olanzapine Disposition in Healthy Volunteers

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

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