In this file you will find several links that will take you to individual
clinical studies that were conducted relative to the
the CYP 2D6
factor. Why are these studies relevant to you? Let us explain:
Response to drugs can vary between individuals and between different ethnic
populations. The biological variables
(age, gender, disease and
genetics), along with cultural and environmental factors which contribute to
these variations are taken into account in these clinical studies.
Individuals vary in their ability to metabolize (detoxification & elimination), drugs due to polymorphism (genetic variance), of certain enzymes. Genetic polymorphism of drug metabolizing enzymes (DME), can lead to severe toxicity or therapeutic failure. The most widely studied of the genetic polymorphisms are those involving cytochrome P450 2D6 (CYP2D6), and (CYP2C19). Of these two, the CYP2D6 is responsible for metabolizing antidepressants and antipsychotic drugs, amongst others.
The population can be classified into three phenotypes (signifying how an individual metabolizes a certain drug). Extensive Metabolism (EM) of a drug is characteristic of the normal population. Poor Metabolism (PM), is asssociated with the accumulation of specific drug substrates, and is typically an autosomol rcessive trait requiring mutation and/or deletion of the gene, while the third class comprises individuals with Ultraextensive Metabolism (UEM), resulting in increased drug metabolism, and is an autosomol dominant trait arising from gene amplification.
For some classes of therapeutic agents (drugs), including the antidepressants/SSRIs, there is good evidence that genetic polymorphisms of drug metabolizing enzymes (in these cases, the CYP 2D6 enzyme), plays a significant role in adverse effects of the therapeutic agent, and even in an increased risk of exposure-linked cancer.
Thus, determination of these genetic polymorphisms are of clinical vale in predicting adverse or inadequate response to the antidepressants/SSRIs, and in predicting increased risk of other disease.
There is a relatively simple test to determine which class or phenotype an individual falls into. What is interesting to note is that most individuals are never tested to determine if they are EMs, PMs or UEMs.... We'd like to know why. If a PM is given a high dose of an SSRI such as Prozac, it is likely that the proper metabolism of this therapeutic agent will not take place. Thus, the drug can build to toxic levels.... Do you understand the significance of this?
Here now are the individual studies drawn exclusively from PubMed: In order to more easily access the study, cut the reference beginning with "http, and ending with Abstract" and paste it into your browser's "location" window. Press enter, and the study will come up.
Inhibition
by fluoxetine of cytochrome P450 2D6 activity.
Otton SV, Wu D, Joffe
RT, Cheung SW, Sellers EM.
Drug
interactions with newer antidepressants: role of human cytochromes P450.
Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI.
Choreiform
syndrome associated with fluoxetine treatment in a patient with deficient CYP2D6
activity.
Marchioni E, Perucca E, Soragna D, Bo P, Malaspina A,
Ferrandi D, Albergati A, Savoldi, F.
Cytochrome
P450 enzymes: interpretation of their interactions with selective serotonin
reuptake inhibitors. Part II.
Harvey AT, Preskorn SH.
"It's
the genes, stupid". Molecular bases and clinical consequences of genetic
cytochrome P450 2D6 polymorphism.
Kroemer HK, Eichelbaum M.
The
effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6
(CYP2D6) activity in human liver microsomes.
Crewe HK, Lennard MS,
Tucker GT, Woods FR, Haddock RE.
Newer
antidepressants and the cytochrome P450 system.
Nemeroff CB, DeVane
CL, Pollock BG.
Identification
of the human cytochromes p450 responsible for in vitro formation of R- and
S-norfluoxetine.
Ring BJ, Eckstein JA, Gillespie JS, Binkley SN,
VandenBranden M, Wrighton SA.
(Department of Drug Disposition, Lilly
Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.) ring_barbara_j@lilly.com
Cytochrome
P450 enzymes: interpretation of their interactions with selective serotonin
reuptake inhibitors. Part I.
Harvey AT, Preskorn SH.
Recent
advances: the cytochrome P450 enzymes.
Slaughter RL, Edwards DJ.
Cytochrome
P450: genetic polymorphism and drug interactions.
Belpaire FM,
Bogaert MG.
Genetically
determined adverse drug reactions involving metabolism.
Lennard
MS. (Drug Saf 1993 Jul;9(1):60-77)
Genetic
polymorphism of CYP2A6 in the German population.
Bourian M, Gullsten
H, Legrum W.
Interpatient
variability: genetic predisposition and other genetic factors.
West
WL, Knight EM, Pradhan S, Hinds TS.
Molecular
basis for differences in susceptibility to toxicants: introduction.
Boobis AR.
Genetic
differences in drug disposition. Populations
and genetic polymorphisms. [Individualization
of drug therapy and pharmacogenetics]. Pharmacogenetics:
role in modifying drug dosage regimens. Chapter
18. Cytochrome P450 CYP2D6. Pharmacogenetic
phenotyping and genotyping. Present status and future potential.
Polymorphism
of cytochrome P-450 in humans. Pharmacogenetics:
a laboratory tool for optimizing therapeutic efficiency. Cytochrome
P450 enzyme system: genetic polymorphisms and impact on clinical
pharmacology. [The
importance of examining genetic polymorphism of drug oxidation in
psychiatry]. Polymorphic
drug oxidation in humans. Clinical
importance of genetic polymorphism of drug oxidation. Certain individuals have a metabolic deficiency in the
metabolism of debrisoquin, sparteine, Update:
genetic polymorphism of drug metabolizing enzymes in humans. [Role
of pharmacogenetics in psychopharmacotherapy]. [Pharmacogenetics
of antidepressant metabolism. Value of the debrisoquin test]. Debrisoquine
hydroxylation in a Polish population. Antidepressants
and drug-metabolizing enzymes--expert group report. Recent
developments in hepatic drug oxidation. Implications for clinical
pharmacokinetics. Pharmacogenetics
and psychopharmacotherapy. [Individualization
of drug therapy and pharmacogenetics]. The
influence of ethnicity and antidepressant pharmacogenetics in the treatment of
depression. Pharmacogenetics
of antidepressants: clinical aspects. Pharmacogenetics
and drug metabolism of newer antidepressant agents. Drug
interactions with newer antidepressants: role of human cytochromes P450.
[The
importance of examining genetic polymorphism of drug oxidation in
psychiatry]. Genetically
determined adverse drug reactions involving metabolism. Drug
interactions--friend or foe? We hope to add to this list of studies as they become available.
May DG.
Weber WW.
[Article
in Japanese] Yamamoto I, Azuma J.
Mah JT, Wong JY, Lee EJ.
Wolf CR, Smith G.
Gonzalez FJ, Idle JR.
Guengerich FP.
Linder MW,
Prough RA, Valdes R Jr.
van der Weide J, Steijns LS.
**By the use of
genotyping or phenotyping methods every individual can be classified as either a
poor,
an intermediate, an extensive or an ultrarapid
metabolizer. If this could be performed prior to drug
therapy, the knowledge could be applied to drug selection and dose adjustment in
order to reach
therapeutic serum drug levels.
[Article in Polish]
Beszlej JA, Kiejna A.
Eichelbaum M.
**As a consequence of
impaired metabolism of these drugs, toxicity and
therapeutic failure are observed in the PMs. With
regard
to molecular mechanisms, studies with microsomes from human liver provide
evidence that
in the PM phenotype a cytochrome P-450
isozyme is either missing or functionally inadequate.
Edeki T.
**Department of Medicine, Meharry Medical College,
Nashville, Tennessee 37208, USA.
dextromethorphan,
and more than 80 other clinically important drugs. Examples of such drugs
include tricyclic antidepressants, neuroleptics,
selective serotonin reuptake inhibitors,
beta-adrenoceptor blockers, and antiarrhythmics. CYP2D6, the enzyme responsible
for the
metabolism of these drugs, is polymorphically
distributed in different populations. Studies in different
ethnic groups in particular demonstrate significant
variation. CYP2D6 deficiency has important
therapeutic
consequences, such as increased side effects when medications that are
substrates of
this enzyme are prescribed for such
individuals. To optimize drug therapy, physicians should
therefore determine the metabolic capacity of their patients.
Tanaka
E.
**Patients who are poor metabolizers (PMs), extensive metabolizers (EMs)
and ultrarapid metabolizers (URMs)
can be identified.
Having such information will help in determining the appropriate dosage of
certain
drugs when treating patients with an inherited
abnormality of a drug-metabolizing enzyme.
[Article in French] Gram LF.
**Genetic polymorphism
related to certain P450 isozymes, in particular the sparteine/debrisoquine
oxygenase, is the dominant cause of interindividual
variation in elimination of several drugs.
The
sparteine/debrisoquine oxidation
polymorphism affects two
major classes of drugs in psychopharmacology, the antidepressants and
the neuroleptics, and this is the best example of
clinical relevance of pharmacogenetic
polymorphism.
Routine use of phenotyping thus should be considered for psychiatry departments
[Article in French] Baumann P. (Encephale 1986 Jul-Aug;12(4):143-8)
**The drug
monitoring of antidepressants in blood plasma has revealed considerable
interindividual
differences in steady-state levels. For
some compounds recent results strongly suggest that this
phenomenon finds an explanation in genetic differences in the metabolism of the
drugs by
monooxygenases (cytochrome P-450) in the
liver.....It is predicted that pharmacogenetic tests will
find their place in psychopharmacotherapy, especially for subjects candidates
for a long-term treatment
or susceptible to suffer from
side effects.
Kunicki PK, Sitkiewicz D,
Pawlik A, Bielicka-Sulzyc V, Borowiecka E, Gawronska-Szklarz
B. Sterna R,
Matsumoto H, Radziwon-Zaleska M.
**Nine persons (5.8%) with MR > 12.6
were classified as poor metabolisers (gene frequency 0.242)
which is in substantial agreement with the data reported
for other Caucasian populations.
Meyer UA, Amrein
R, Balant LP, Bertilsson L, Eichelbaum M, Guentert TW, Henauer S,
Jackson P,
Laux G, Mikkelsen H, Peck C, Pollock BG, Priest R, Sjoqvist F, Delini-Stula A.
Brosen K. (Clin Pharmacokinet 1990
Mar;18(3):220-39)
Poolsup N, Li Wan Po A, Knight TL.
[Article
in Japanese] Yamamoto I, Azuma J.
Jann MW, Cohen LJ.
Bertilsson L, Dahl ML, Tybring
G.
DeVane CL.
Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI.
[Article in Polish] Beszlej
JA, Kiejna A.
Lennard MS.
Jefferson JW. (J Clin Psychiatry
1998;59 Suppl 4:37-47)
**An explosion of knowledge about interactions of
drugs with other drugs and with foods threatens to
inundate clinicians. This review provides a better understanding of the
cytochrome P450 system
with a focus on those enzymes most
involved in drug metabolism. Emphasis is placed on
antidepressant medications, how they are metabolized by the P450 system, and how
they alter the
metabolism of other drugs. The role of
antidepressants in precipitating the serotonin syndrome is
also discussed.
The
Avenging Angel