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 Drugs CYP2D6 enzymes: metabolized
As a result, metabolic capacity ranges between individuals from extremely slow to ultrafast 3. The various alleles are classified by the unified nomenclature developed by Daly et al. Treatment with standard recommended doses of the drugs listed above may produce higher steady-state plasma drug concentrations compared with extensive metabolizers, with an increased risk of concentration-dependent side effects and drug toxicity.
On the other hand, when a drug, for example, codeine, requires metabolic activation by CYP2D6, the absence of the enzyme might produce a loss of therapeutic effect. The majority of defective allelic variants of the CYP2D6 gene that, occurring homozygous or heterozygous together, give rise to the PM genotype have now been identified 3 6 7 8 9 10 11 12 By screening for all these null alleles, i.
Identifying PM subjects before starting drug therapy may allow prediction of the adequate dose of CYP2D6 substrates in PMs, to assure therapeutic efficacy with a minimum risk of side effects.
However, it is unnecessary and impractical to carry out routine screening for all known inactivating CYP2D6 mutations. In our psychiatric hospital, we perform PCR-based genotyping for the three most common defect gene variants, i.
We only test for the remaining null alleles if poor metabolism appears present and is not caused by the three allelic variants mentioned above. The other side of the range of metabolic capacity is ultrarapid drug metabolism, a result of excessively high CYP2D6 enzyme activity.
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. British Journal of Clinical Pharmacology. Retrieved 5 February Pharmacology and the Nursing Process. Cytochrome P Drug Interaction Table". Indiana University School of Medicine. Pediatric Clinics of North America.
Retrieved 14 June DNA matters in breast cancer". Journal of Clinical Psychopharmacology. Drug Metabolism and Disposition. German Journal of Psychiatry: Clinical Pharmacology and Therapeutics. The Journal of Clinical Investigation. Journal of Medicinal Chemistry. E; Krantis, A; Budzinski, J. W; Livesey, J; Arnason, J. European Journal of Clinical Pharmacology. Biochemical and Biophysical Research Communications. Wolf CR, Smith G Ding X, Kaminsky LS Annual Review of Pharmacology and Toxicology.
Amphetamine-type stimulants ATS make up a group of substances comprised of synthetic stimulants including amphetamine, methamphetamine, methcathinone, and ecstasy-group substances [e. In vitro human studies show that the metabolism of most psychostimulants belonging to this class of compounds is regulated by the polymorphic cytochrome P isozyme CYP2D6.
The gene CYP2D6 environment drug use, gender, ethnicity… interaction has been evaluated in drug users in order to evaluate: Specifically, it was postulated that:. The present review will examine available clinical data to determine to what extent these postulates have been confirmed. Due to the fact that ATS are a broad class of compounds encompassing a number of substances, and that scant in vivo data from human studies are available for most of them Wu et al.
MDMA ecstasy and methamphetamine. They will serve as archetypes in order to discuss the translation and clinical significance of in vitro to in vivo findings. Both compounds were chosen based on their differential interaction with CYP2D6 and their abuse prevalence in society. CYP2D6 exhibits a marked genetic polymorphism—over 70 alleles www. Subjects with a PM phenotype lack two functional alleles; those with an IM have one reduced-activity allele and one non-functional allele or two reduced-activity alleles; whereas EM individuals have one or two functional alleles; and the UM phenotype is associated with gene duplications of functional alleles, with an increased protein expression Zanger et al.
Both compounds are, therefore, substrates of the same enzyme although the rates by which they are oxidized differ markedly. Simplified scheme of MDMA main metabolic pathways. For a more detailed description, readers are referred to de la Torre et al. Simplified scheme of methamphetamine main metabolic pathways. For a more detailed description, readers are referred to Shima et al. Interaction of amphetamine-like and related psychostimulants with CYP2D6: The east and south—east regions of Asia home to about one-third of the global population, have one of the most strongly established markets for ATS in the world, primarily for methamphetamine UNODC, This almost fold difference in intrinsic clearance for both drugs, depending on the allelic variant considered, is of significance in the interpretation of clinical data.
Findings observed in Caucasian populations with respect to the impact of CYP2D6 polymorphism on drug effects are not always reproduced in Asian ones. This lack of reproducibility is due to the distribution of extreme phenotypes UM and PM in these populations. Another aspect to be considered is the common belief that amongst drug abuser populations genotypes are distributed according to the same patterns as the general population. In the case of CYP2D6, assuming that PM subjects have a higher tendency to accumulate drug in the body, either these subjects discontinue drug consumption or autoregulate it by taking lower doses.
Due to the relatively small size of the populations evaluated in clinical studies in terms of guaranteeing a fair representation of all genotypes , the number of subjects carrying extreme genotypes is usually quite small. In fact, the authors of the present review believe that PM subjects are underrepresented in MDMA and other amphetamine-like compound user populations probably because of the acute effects experienced.
This bias has to be taken into consideration when interpreting clinical data. 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. These actions result from the interaction of MDMA with the membrane transporters involved in neurotransmitter reuptake and vesicular storage systems. The most frequent effects after MDMA administration are euphoria, well-being, happiness, stimulation, increased energy, extroversion, feeling close to others, increased empathy, increased sociability, enhanced mood, and mild perceptual disturbances.
In addition, cardiovascular related somatic symptoms, autonomic effects dry mouth, sweating, tremor, mydriasis tremor, jaw clenching, and restlessness , and moderate derealization have been observed de la Torre et al. MDMA induced acute toxic effects are related to its pharmacologic actions. Hyponatremia is an uncommon complication associated with inappropriate antidiuretic hormone SIADH secretion and excessive water intake.
Fulminant hepatitis and hepatic necrosis have been described Henry et al. Chronic use of MDMA is linked to a progressive neurodegeneration of the serotonergic neurotransmission system Green et al. Two main pathways are involved in MDMA metabolic clearance: This phenomenon is associated with a decrease in the amount of effective enzyme so that recovery of activity depends on its de novo synthesis Liston et al.
In MBI there is a rapid phenocopying to apparent PM status after a single dose of MDMA, which signifies that within 2 h subjects display the PM phenotype after drug intake, irrespective of their original genotype.
Preliminary in vitro studies showing that MDMA was a CYP2D6 substrate raised the possibility that subject carriers of allelic variants leading to the PM phenotype for CYP2D6 might be at increased risk of acute toxicity episodes and higher abuse liability Tucker et al.
A similar observation has been reported for another methylenedioxyamphetamine derivative,3,4-methylenedioxyethylamphetamine MDE Kreth et al. These compounds can easily enter into redox cycling, generating radical oxygen species, which are the underlying mechanism of MDMA neurotoxicity.
CYP2D6 is also the source of a number of drug—amphetamine interactions because it regulates the biotransformation of many therapeutic drugs. Methamphetamine is an indirect sympathomimetic agent, similar in structure to amphetamine. Nevertheless, an added N-methyl group confers increased lipid solubility, allowing for more rapid diffusion into the central nervous system.
Methamphetamine effects derive from their interaction with a number of neurotransmitter systems; primarily with the dopaminergic but also with serotonergic, noradrenergic, and glutamatergic systems. Acute adverse effects including cardiovascular and psychoactive ones are related to an excess of neurotransmitters. As previously explained, long-term methamphetamine induced effects are the result of a neurodegeneration of the dopaminergic system Schep et al. 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:
MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?
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.