Cytochrome P 2D6 (CYP2D6) is an enzyme that in humans is encoded by the CYP2D6 Hence, for drugs that are metabolized by CYP2D6 (that is, are CYP2D6 substrates), certain individuals will eliminate these drugs quickly ( ultrarapid. Cytochrome P enzymes can be inhibited or induced by drugs, resulting metabolizers of drugs dependent on CYP2D6, which metabolizes. The enzyme CYP2D6 affects the metabolism of many drugs, and its effect is altered by genetic variability.
by CYP2D6 enzymes: Drugs metabolized
A potential conclusion of this study is that a lower CYP2D6 activity seems to confer some degree of protection against methamphetamine dependence Otani et al. PM subjects appeared to be more sensitive to the slope of plasma methamphetamine concentrations in several measurements of subjective effects.
The data suggest that brain methamphetamine concentrations in the absence of differences in plasma concentrations are higher in PM subjects or that they have a steeper concentration-response relationship Sellers and Tyndale, Methamphetamine use may induce the following physical effects: It may cause rhabdomyolysis which has been associated with mortality. In a series of 18 autopsies genetic susceptibility to rhabdomyolysis was examined.
Mutations of the following genes were studied: The conclusion was that there was no obvious relationship between the genetic mutations observed in this study and rhabdomyolysis Matsusue et al. Neuropsychological alterations seen in many methamphetamine users are often unrelated to its lifetime consumption or length of abstinence. In a series of 52 methamphetamine users the contribution of CYP2D6 polymorphism to variability observed in long-term effects was studied.
Apparently, a more efficient metabolic disposition of methamphetamine is associated with a poorer cognitive performance. It has also been suggested that metabolism may generate metabolic species involved in the underlying mechanism of neurotoxicity Cherner et al. The administration of inhibitors of CYP2D6 activity can influence the metabolism of methamphetamine, and methamphetamine can inhibit the metabolism of CYP2D6 substrates.
The number of published drug-interaction studies with this class of substances is very scarce. Previous administration of bupropion, a known CYP2D6 inhibitor, produces a large increase of methamphetamine concentrations, and a reduction in amphetamine ones. The pharmacological effects of methamphetamine cardiovascular and euphoria-like ones were decreased by bupropion Newton et al. Antiretroviral drugs ritonavir, a known CYP2D6 inhibitor have been reported to be the main cause of life-threatening interactions with methamphetamine Hales et al.
The involvement of CYP2D6 polymorphism in the metabolic clearance of both MDMA and methamphetamine leads to the speculation that it should have an impact on acute and long-term drug toxicity and drug taking behavior.
Concerning acute effects, those subject carriers of alleles with a reduced functionality are at higher risk, for both MDMA and methamphetamine, of experiencing heightened pharmacological effects. Moreover, in combination with some environmental factors this may lead to acute toxicity episodes including death. Irrespective of the initial dose, the following one results in the MBI of MDMA and phenocopying to the PM phenotype thus diluting the variability incorporated by the genetic polymorphism and, consequently, putting all subjects at risk of acute effects.
Concerning the relevance of CYP2D6 polymorphism on drug abuse, preliminary data from methamphetamine suggest that an increased CYP2D6 functionality may lead to an increased abuse of the substance. An observation that is more relevant for methamphetamine, with a higher abuse liability, than MDMA. Regarding neurotoxicity, only in the case of MDMA may a metabolic bioactivation be involved in long-term neurotoxic effects. Theoretically those subject carriers of CYP2D6 functional alleles including those carriers of duplications and with a low COMT activity should be the most efficient in generating metabolic neurotoxic species and, consequently, the most vulnerable to neurotoxicity.
Thus, in possible future reports on other substances it would not be surprising to find that the CYP2D6 polymorphism has a strong role in the clinical outcome of drug users. The difficulty in performing controlled clinical studies with drug users stratified as a function of drug metabolizing polymorphisms, limits the evaluation of their clinical impact.
In summary, the genetic polymorphism of CYP2D6 and co-administration of CYP2D6 inhibitors may have less impact on the risk of acute toxicity than previously thought, whereas the role of metabolism by other cytochrome P enzymes and renal excretion assumes greater importance with regard to systemic exposure to unchanged drug.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
National Center for Biotechnology Information , U. Journal List Front Genet v. Published online Nov Author information Article notes Copyright and License information Disclaimer. This article was submitted to Frontiers in Pharmacogenetics and Pharmacogenomics, a specialty of Frontiers in Genetics. Received Sep 4; Accepted Oct This is an open-access article distributed under the terms of the Creative Commons Attribution License , which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
This article has been cited by other articles in PMC. Abstract In vitro human studies show that the metabolism of most amphetamine-like psychostimulants is regulated by the polymorphic cytochrome P isozyme CYP2D6. Introduction Amphetamine-type stimulants ATS make up a group of substances comprised of synthetic stimulants including amphetamine, methamphetamine, methcathinone, and ecstasy-group substances [e. Specifically, it was postulated that: Subjects carrying genotypes which lead to enzymatic functional phenotypes should display an increased risk of drug abuse proportionate to their genotype homozygous vs.
Subjects carrying genotypes which lead to enzymatic functional phenotypes should display an increased risk of neurotoxicity proportionate to their genotype and absolute level of enzyme activity if the underlying mechanism is unrelated to a metabolic bioactivation. Subjects carrying genotypes which lead to non-functional enzyme should experience greater risk of toxicity to a drug which is not metabolically inactivated, and might be less likely to acquire drug-taking behavior.
Open in a separate window. MDMA pharmacology and metabolic disposition MDMA is a psychostimulant drug that displays effects related to amphetamine-type drugs plus a number of distinctive ones closeness to others, facilitation to interpersonal relationship, and empathy that have been named by some authors as entactogen properties. Methamphetamine pharmacology and metabolic disposition Methamphetamine is an indirect sympathomimetic agent, similar in structure to amphetamine.
Methamphetamine drug—drug interaction The administration of inhibitors of CYP2D6 activity can influence the metabolism of methamphetamine, and methamphetamine can inhibit the metabolism of CYP2D6 substrates. Concluding remarks The involvement of CYP2D6 polymorphism in the metabolic clearance of both MDMA and methamphetamine leads to the speculation that it should have an impact on acute and long-term drug toxicity and drug taking behavior.
Conflict of interest statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Involvement of CYP2D6 in the in vitro metabolism of amphetamine, two N-alkylamphetamines and their 4-methoxylated derivatives. Xenobiotica 29 , — Substrate specific metabolism by polymorphic cytochrome P 2D6 alleles.
In Vitro 19 , — Genetic association studies of methamphetamine use disorders: Cytochrome PD6 extensive metabolizers are more vulnerable to methamphetamine-associated neurocognitive impairment: Inhibitory metabolite complex formation of methylenedioxymethamphetamine with rat and human cytochrome P Particular involvement of CYP 2D.
Neurotoxicity of MDMA ecstasy: Human pharmacology of MDMA: Lancet , Pharmacological interaction between 3, 4-methylenedioxymethamphetamine ecstasy and paroxetine: Repeated doses administration of MDMA in humans: CYP2D6 deficiency, a factor in ecstasy related deaths? Possible fatal interaction between protease inhibitors and methamphetamine. Fatal interaction between ritonavir and MDMA.
Lancet , — [ PubMed ] Henry J. Lancet , — Mechanism-based inactivation of CYP2D6 by methylenedioxy methamphetamine. Serotonergic neurotoxic metabolites of ecstasy identified in rat brain.
Oxidation of methamphetamine and methylenedioxymethamphetamine by CYP2D6. Differential time course of cytochrome P 2D6 enzyme inhibition by fluoxetine, sertraline, and paroxetine in healthy volunteers. Genetic analysis of the rhabdomyolysis-associated genes in forensic autopsy cases of methamphetamine abusers. Tokyo 13 , 7—11 Investigations on the human hepatic cytochrome P isozymes involved in the metabolism of 3, 4-methylenedioxy-amphetamine MDA and benzodioxolyl-butanamine BDB enantiomers.
Stereoselective differences in the cytochrome Pdependent dealkylation and demethylenation of N-methyl-benzodioxolyl-butanamine MBDB, Eden enantiomers. These subjects often have alleles with duplicate, or in some cases, amplified functional CYP2D6 genes, causing an excessive amount of CYP2D6 enzyme to be expressed.
The active CYP2D62 variant is especially subject to multiplication 17 18 The identification of gene duplication or amplification could help to avoid therapeutic failure in UMs when CYP2D6 substrates are administered at standard doses. Moreover, it could also be a tool to distinguish between genetically determined high metabolic capacity and low plasma drug concentrations caused by noncompliance. Noncompliance is a serious problem in the treatment of psychiatric patients.
It is a common occurrence, especially in outpatients, and it is not easy to prove. However, in more simple and rapid PCR-based methods for efficient genotyping of UMs were developed 20 In the present study, we have tested the CYP2D6 duplication assay described and evaluated by Lovlie et al. We also investigated the prevalence of ultrarapid drug metabolism caused by CYP2D6 gene duplication in a group of psychiatric inpatients of our hospital.
The blood samples used in this study were collected from a group of anonymous psychiatric patients, all of North European Caucasian origin. This differs somewhat from the original method: We modified these assay conditions to save reaction components, especially DNA polymerase.
In addition, a 5. Amplification of a 3. This PCR assay yields product only in subjects carrying two CYP2D6 gene copies on the same allele, whereas no amplification is seen in individuals without duplicate genes. The results of the long-PCR reactions for four patients are shown in Fig. Patients m51 and m52 have a CYP2D6 gene duplication; patients m46 and m50 do not carry duplicate genes.
In contrast with the other seven cases, this last patient is not an UM, although a gene duplication is demonstrated. It is noteworthy that duplication of the 4 allele is rare and commonly associated with black American and African groups 21 As far as we know, among Caucasians it has been described only once 3.
The findings show that duplication of functional CYP2D6 genes in the patient population studied occurred in 3. This is in agreement with the prevalences described earlier among subjects of Caucasian origin. The set of PCR assays described easily identifies subjects having alleles with duplicate active CYP2D6 genes, which causes ultrafast drug metabolism. The method is reliable. The method has been validated by Lovlie et al.
Individuals of the kb, kb, or kb haplotype, for example, which are indicative for alleles with 3, 4, or 13 CYP2D6 genes, were not included in their study. However, it is conceivable that all allelic variants having more than two CYP2D6 genes have been formed by multiple duplications This requires RFLP analysis as described elsewhere Identification of PMs and UMs is of potential clinical importance, e.
Knowledge of individual metabolic capacity can be helpful to avoid therapeutic failure in UMs or the development of adverse reactions in PMs, because differences in drug disposition could be compensated for by dose adjustment Detection of gene duplication may also be of value in patients not responding properly to generally recommended doses of CYP2D6 substrates to distinguish between high metabolic capacity and bad compliance.
Skip to main content. Other Molecular Diagnostics and Genetics. Steijns , Jan Van Der Weide. Abstract The enzyme debrisoquine 4-hydroxylase CYP2D6 , which metabolizes many widely used drugs, is highly polymorphic.
Materials and Methods subjects The blood samples used in this study were collected from a group of anonymous psychiatric patients, all of North European Caucasian origin. Acknowledgments We thank J. Crunitch for critically reading the manuscript. Eur J Clin Pharmacol ; Dahl ML , Bertilsson L. Genetically variable metabolism of antidepressants and neuroleptic drugs in man. Pharmacogenetics ; 3: Cytochrome P 2D6 variants in a Caucasian population: Am J Hum Genet ; Nomenclature for human CYP2D6 alleles.
Pharmacogenetics ; 6: Hydroxylation polymorphism of debrisoquine and mephenytoin in European population.
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Drugs which are metabolized by CYP2D6 may inhibit or induce the action of the enzyme. Drugs that inhibit CYP2D6 will predictably increase. The fact that this polymorphic enzyme partially regulates metabolic disposition .. In fact, the contribution of CYP2D6 to MDMA metabolism has been of MDMA, and in turn MDMA can inhibit drugs metabolized by CYP2D6. A thorough knowledge of this will lead to a future where tailor-made drugs, suiting an The CYP enzyme, a super family of microsomal drug- metabolizing.