Pharmacology - Neuromuscular - Detailed

Pharmacogenetic determinants of codeine induction by rifampin: the impact on codeine's respiratory, psychomotor and miotic effects.

Caraco Y et al., 1997. J Pharmacol Exp Ther. 281(1):330-6.

Our objective was to examine the effect of rifampin on codeine's pharmacodynamics and pharmacokinetics in extensive (EMs) and poor (PMs) metabolizers of debrisoquin. Fifteen healthy, nonsmoking males, 9 EMs and 6 PMs of debrisoquin, received codeine (120 mg) before and after rifampin (600 mg/d) for 3 weeks. The effects of codeine on respiration, pupil diameter and psychomotor performance were measured before codeine administration and during each study day. The pharmacokinetics of codeine were determined from the respective plasma and urine concentrations. Before the administration of rifampin, the pharmacodynamic effects of codeine were more prominent in the EMs (P < .01). Rifampin significantly enhanced codeine oral clearance by increasing its metabolic clearances through N-demethylation and glucuronidation in both phenotypes, but its O-demethylation was induced only in EMs. Relative to base-line values, codeine N-demethylation was induced to a greater extent, resulting in a marked reduction in the plasma concentrations of codeine and codeine metabolites and elevated plasma concentrations of norcodeine, norcodeine-glucuronide, and normorphine. The reduction in morphine plasma concentration was associated in the EMs with a significant attenuation of codeine's respiratory and psychomotor effects, whereas its miotic effect was unaltered. In PMs, codeine's respiratory and psychomotor effects were unaltered by rifampin, but its pupillary effect was reduced. Codeine O-demethylation to produce morphine can be significantly induced by rifampin, but this induction is phenotypically determined. However, because (relative to base-line values) rifampin enhanced codeine N-demethylation more than codeine O-demethylation, morphine plasma concentrations were reduced-and hence codeine's pharmacodynamic effects were attenuated-in EMs of debrisoquin.

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Pilot Study of the Cytochrome P450-2D6 Genotype in a Psychiatric State Hospital.

de Leon J et al., 1998. Am J Psychiatry 155:1278-1280.

The development and prospects of conventional therapeutic drug monitoring (TDM) and pharmacogenetic testing as aids in personalized treatment with antidepressants and antipsychotics are described. Our own experience is discussed in relation to international guidelines for rational TDM. Emphasis is put on the usefulness of TDM combined with genotyping of cytochrome P450 2D6 (CYP2D6), the key enzyme involved in the polymorphic metabolism of the majority of antidepressants (both tricyclics and selective serotonin reuptake inhibitors) and antipsychotic drugs. This combination of methods is particularly useful in verifying concentration-dependent adverse drug reactions (ADRs) due to poor metabolism, 'and diagnosing pharmacokinetic reasons (ultrarapid metabolism (UM)) for drug failure. This is because ADRs may mimic the psychiatric illness itself and therapeutic failure due to UM may be mistaken for poor compliance with the prescription.

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Increased incidence of CYP2D6 gene duplication in patients with persistent mood disorders: ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study.

Kawanishi C et al., 2004. Eur J Clin Pharmacol 59:803.

OBJECTIVE: Recent studies have revealed that genetic polymorphisms of cytochrome P(450) 2D6 (CYP2D6) are among the factors that determine the interindividual differences in the metabolism and response to antidepressants. We investigated the relationship between persistent mood disorders and the duplication of the CYP2D6 gene, which encodes an enzyme with increased activity. METHODS: We screened the prevalence of the CYP2D6 genotypes in 108 patients with persistent mood disorders using long polymerase chain reaction (PCR) and the real-time PCR methods. Clinical correlates with the genotypes were also analyzed. RESULTS: Among the 108 patients, 81 had failed to respond to antidepressants shown to be metabolized by CYP2D6. Of those 81, 8 had a CYP2D6 gene duplication (9.9%, 95% confidence interval 3.4-16.4%) which was higher than the 0.8-1.0% incidence previously observed in healthy Nordic Caucasians. The worst week scores of the Hamilton Depression Rating Scale were higher in the patients with the duplication compared with those without the duplication ( P=0.026, student's t-test). CONCLUSION: These results suggest that the CYP2D6 gene duplication is a possible factor that influences the development of persistence in patients with mood disorders probably by ultrarapid drug metabolism.

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Genetic Polymorphisms of Cytochrome P450 Enzymes and the Effect on Interindividual, Pharmacokinetic Variability in Extensive Metabolizers.

Ma JD et al., 2004. J. Clin. Pharmacol. 44(5):447-456.

Genetic polymorphisms of cytochrome P450 (CYP) enzymes are one of the factors that contribute to the pharmacokinetic (PK) variability of drugs. PK variability is observed in the bimodal distribution between extensive metabolizers (EMs) and poor metabolizers (PMs). PK variability may also exist between individuals genotyped as homozygous EMs and heterozygous EMs. This may carry implications for drug dosing and drug response (e.g., risk of therapeutic failure or drug toxicity). Studies have reported significant PK differences between homozygous and heterozygous EMs. Some literature suggests that this distinction may be of clinical relevance. Due to study design limitations and data that are either sparse or conflicting, generalizations regarding the potential impact of the CYP genotype, within EMs, are difficult. Optimally designed clinical trials are needed. This review evaluates the potential impact of CYP genetic polymorphisms on interindividual PK variability of drugs within an EM population.

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The influence of the CYP2D6 polymorphism on psychopathological and extrapyramidal symptoms in the patients on long-term antipsychotic treatment.

Plesnicar BK et al., 2006. J Psychopharmacol. 20(6):829-33.

Poor response to antipsychotics treatment and extrapyramidal side effects (EPS) are the most challenging problems in the treatment of schizophrenia. Several studies were investigating the impact of polymorphic cytochrome P450 2D6 gene (CYP2D6) on EPS but the results were conflicting. There are practically no clinical studies of long-term treatment of schizophrenia and CYP2D6 polymorphism. Our aim was to evaluate the influence of CYP2D6 genotype on psychopathological symptoms and the occurrence of EPS in Slovenian outpatients with schizophrenia or schizoaffective disorder in stable remission, receiving long-term maintenance antipsychotic treatment. In total 131 outpatients meeting the DSM IV criteria for schizophrenia or schizoaffective disorder and receiving maintenance therapy with haloperidol, fluphenazine, zuclopethixole or risperidone were genotyped for 14 polymorphic CYP2D6 alleles. Psychopathological symptoms were assessed with the Positive and Negative Symptom Scale for Schizophrenia (PANSS). EPS were assessed with the Simpson Angus Scale (SAS), the Barnes Akathisia Scale and the Abnormal Involuntary Movement Scale (AIMS). Six patients (4.6%) were genotyped as poor metabolizers (PMs). PMs scored significantly higher on the negative subscale for PANSS. There were no statistically significant differences between the group of PMs and the group of patients with at least one functional CYP2D6 allele in view of patient's characteristics or any of the items of the AIMS, the SAS or the Barnes Akathisia Scale. CYP2D6 genotype may not be the major factor that determines the susceptibility to antipsychotic-induced EPS in Slovenian patients in stable remission and on maintenance therapy with antipsychotics that are mainly CYP2D6 substrates. However, CYP2D6 genotype might be a factor contributing to the persistent negative symptoms of schizophrenia.

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The Convergence of Conventional Therapeutic Drug Monitoring and Pharmacogenetic Testing in Personalized Medicine: Focus on Antidepressants.

Sjöqvist F et al., 2007. Clin Pharm & Ther, 81:899–902.

The development and prospects of conventional therapeutic drug monitoring (TDM) and pharmacogenetic testing as aids in personalized treatment with antidepressants and antipsychotics are described. Our own experience is discussed in relation to international guidelines for rational TDM. Emphasis is put on the usefulness of TDM combined with genotyping of cytochrome P450 2D6 (CYP2D6), the key enzyme involved in the polymorphic metabolism of the majority of antidepressants (both tricyclics and selective serotonin reuptake inhibitors) and antipsychotic drugs. This combination of methods is particularly useful in verifying concentration-dependent adverse drug reactions (ADRs) due to poor metabolism, 'and diagnosing pharmacokinetic reasons (ultrarapid metabolism (UM)) for drug failure. This is because ADRs may mimic the psychiatric illness itself and therapeutic failure due to UM may be mistaken for poor compliance with the prescription.

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Effects of Fluvoxamine on Lansoprazole Pharmacokinetics in Relation to CYP2C19 Genotypes.

Yasui-Furukori N et al., 2004. J. Clin. Pharmacol. 44(11):1223-1229.

Lansoprazole is a substrate of CYP2C19 and CYP3A4. The aim of this study was to compare the inhibitory effects of fluvoxamine, an inhibitor of CYP2C19, on the metabolism of lansoprazole between CYP2C19 genotypes. Eighteen volunteers--of whom 6 were homozygous extensive metabolizers (EMs), 6 were heterozygous EMs, and 6 were poor metabolizers (PMs) for CYP2C19--received three 6-day courses of either daily 50 mg fluvoxamine or placebo in a randomized fashion with a single oral 60-mg dose of lansoprazole on day 6 in all cases. Plasma concentrations of lansoprazole and its metabolites, 5-hydroxylansoprazole and lansoprazole sulfone, were monitored up to 24 hours after the dosing. During placebo administration, there was a significant difference in the area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) of lansoprazole between CYP2C19 genotypes. Fluvoxamine treatment increased AUC(0-infinity) of lansoprazole by 3.8-fold (P < .01) in homozygous EMs and by 2.5-fold (P < .05) in heterozygous EMs, whereas no difference in any pharmacokinetic parameters was found in PMs. There was a significant difference in the fluvoxamine-mediated percentage increase in the AUC(0-infinity) of lansoprazole between CYP2C19 genotypes. The present study indicates that there are significant drug interactions between lansoprazole and fluvoxamine in EMs. CYP2C19 is predominantly involved in lansoprazole metabolism in EMs.

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