The Impact Of Pharmacogenetics On Pharmacokinetics I
Much of the attention afforded to pharmacogenetics has aimed at pharmacokinetics
. This should not come as a surprise given that the drug levels can be measured and correlated to clinical response with ease. Therefore, the genetic factors were first found to impact drug response at the level of drug metabolizing enzymes.
Today, it is clearly manifested that majority of the drug metabolizing enzymes are expressed in genetically-divergent forms with modified operational properties. Among the earliest models of a genetically-ascertained difference in drug reaction is the prolonged apnoea that follows application of suxamethonium chloride in certain people.
This was due to the inheritance of a divergent form of plasma esterase, and butyrylcholinesterase-the atypical cholinesterase. Nevertheless, since 1950s, studies on N-acetylation of isoniazid-a drug widely prescribed to treat tuberculosis-resulted in the primary systematic characterization of genetic polymorphism in drug metabolizeing enzymes.
A population could be categorized between slow and rapid acetylators. Consequently, differences in responses to several drugs metabolized by acetylation were manifested to be linked to N-acetylation status of each patient.
But, the quantity of drugs metabolized foremost by acetylation is few. Majority of the drugs are metabolized by enzymes known as cytochrome P450 or CYPs. The capability of clinical impact of pharmacogenetically-ascertained differences in the activity of drug-metabolizing enzymes and on a drug response is optimally exemplified by genetic polymorphism of CYP2D6.
In the middle of 1970s, studies have shown that any population may be divided between two CYP2D6 drug-metabolizing phenotypes, namely the extensive metabolizers (EM) and poor metabolizers (PM), depending on their capacity to mediate CYP2D6-dependent hydroxylation of anti-hypersensitive drug debrisoquine, which is now obsolete.
The said polymorphism is a result of autosomal recessive inheritance of alleles at a single locus on chromosome 22. The pharmacokinetic effects of polymorphism in CYP2D6 are that relative to Ems, the PMs have greater exposure to the parent drug, and minimal exposure to the metabolites produced by such enzyme.
On the other hand, the ultra-rapid metabolizers-individuals with gene amplification and having multiple copies of gene responsible for metabolic capacity-are exposed to high concentrations of swiftly gathering metabolites, achieve only low plasma levels of the parent drug.
In retrospective candidate gene association studies have demonstrated that the PM genotype is linked with a raised risks of a few ADRs to drugs that are fundamentally cleared by CYP2D6-mediated metabolism, and being at risk of having no effect when the therapeutic effect of a drug is intervened by its CYP2D6-produced metabolite.
For instance, because the PMs are unable to perform the metabolic activation of the pro-analgesic drug codeine to morphine, they cannot obtain sufficient analgesic effectiveness from codeine. On the contrary, the UM patients cannot respond to traditional doses of drugs metabolized by CYP2D6 when the therapeutic actions dwells in the parent drug, and often needs 'megadoses' of the drug concerned such as the anti-depressant nortriptyline, or the perhexiline which is an antianginal drug.
Also, the UM patients are at risk of toxicity of codeine to morphine among these individuals who are predisposed to morphine toxicity. Applying knowledge of Pharmacogenetics to pharmacokinetics will reduce the negative incidences of certain drugs in individuals as far as absorption, distribution, metabolism and elimination are concerned.
by: Charles Godbout
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