genetics differences affect drug metabolism
TRANSCRIPT
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Genetics differences affect drug
metabolism
Md. Faysal
Batch:13th B
ID:151-29-760
SD:08-08-2017
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Drug Metabolism
Drug metabolism is the process by which the body breaks down and
converts medication into active chemical substances.
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Genetics Variation
Genetics variation is a term used to describe the variation in the DNAsequence in each of our genomes. Individuals of a species have a similarcharacteristic but they are rarely identical, the difference between themcalled genetics variation.
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Some external factors
• Diet
• Climate
• Culture
• Lifestyle
• Language
• Accidents
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Genetic difference and drug metabolism
Genetic factors in human is the main cause for the differences in the rate of
drug metabolism. The difference in the rate of acetylation is one example:
Rapid acetylators have more hepatic acetyl N-transferase than the slow
acetylators.
90% of Asians and Eskimos are rapid acetylators.
Egyptians and Mediterranean are slow acetylators.
The rate of acetylation is clinically important in terms of therapeutic
response and toxicity.
Also, genetic factors affect the rate of oxidation.
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Through genetic testing, the results have given light to individual genetic variants
that can be tailored to the appropriate medication regimen for mental health.
Pharmacogenomics is the study of the relationship between genetic variations
and how your body responds to medications.”
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Mechanism of control of genetic
differences
Changes in amount or activity of the enzymes involved
Changes in amount or nature of natural inhibitors or
activators
Changes in amount or accessibility of co factors
Presence or absence of reversing enzymes.
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Table: Hexobarbitone sleeping time in
various strains of mouseStrain Sleeping time (min)
A/NL 48±4
BALB/cAnN 41±2
C57L/HeN 33±3
C3HFB/HeN 22±3
SWR/HeN 18±4
Swiss (outbred) 43±15
The classical example of strain differences in drug metabolism is that of hexobarbitone metabolismin the mouse (see Table 4.4). There is up to a 2.5-fold difference in sleeping time between one strainof mouse and another and the values for the animals in the inbred groups are close to each otherwhereas the outbred group shows a wide variation in sleeping time. This is clear evidence for agenetic control of drug metabolism.
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Table: Effect of cross breeding on the
inducibility by 3-methylcholantherene in
mice.Strain % Inducible
C57 100
DBA 0
F1 (C57×DBA) 100
F1 ×C57 100
F1×DBA 50
F1×F1 75
This is clear evidence for a genetic control of drug metabolism. The marked strain differences in the mouse
have also been extended to include differences in the induction of drug metabolism .Using two strains of
mouse it was shown that one (strain C57) responds to treatment with 3-methylcholanthrene (3-MC, a
polycyclic hydrocarbon inducer of aryl hydrocarbon hydroxylase) whilst the other (strain DBA) does not.
Cross breeding of the strains (see Table 4.5) has shown that the inheritance of inducibility is an autosomal
dominant (Ahd ) trait and accounted for by the presence of the Ah receptor.
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The distribution of isoniazid acetylation in
the Caucasian population
Isoniazid in the human population exhibits bimodal distribution.
With about half the Caucasian population ‘fast acetylators’ and half
‘slow acetylators’. Family studies show that, ‘slow acetylators’ in
an autosomal recessive trait.
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Conclusion and future directions
Common variation in the coding sequence and/or regulatory regions of genes
encoding drug metabolizing enzymes has explained a great deal of interindividual
variation in response and toxicity with medication . However, drug metabolism is
only one aspect of drug-gene interaction, and common genetic variation in the
sequence encoding drug transporters, drug receptors, target genes and other
pharmacodynamics genes have also been shown to impact toxicity and response to
treatment. Many formerly idiosyncratic adverse drug reactions like,
hypersensitivity reaction, liver injury, and prolongation of the QT interval can now
be at least partially explained by variation in genes .