Genetics differences affect drug

metabolism

Md. Faysal

Batch:13th B

ID:151-29-760

SD:08-08-2017

Drug Metabolism

Drug metabolism is the process by which the body breaks down and

converts medication into active chemical substances.

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.

Some external factors

• Diet

• Climate

• Culture

• Lifestyle

• Language

• Accidents

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.

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.”

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.

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.

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.

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.

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 .