The Impact Of Pharmacogenetics On Pharmacokinetics Ii
In the application of pharmacogenetics on pharmacokinetics
, the genetic factors were first found to influence the drug reaction at drug metabolizine enzymes level. Most of the drug-metabolizing enzymes are expressed in genetically-variant form with changed functional properties.
The prolonged apnoea that follows the administration of suxamethonium chloride in some people is one of the earlier examples of genetically-determined differences in drug response. Also, earlier, we understood the pharmacokinetic effects of polymorphism in CYP2D6, one of the CYP isoforms that metabolize a huge number of drugs utilized clinically.
Moving forward, there are other isoforms included less often such as the CYP1A2, CYP2A6, CYP2B6, CYP2C8 and CYP2E1. Now the genetic polymorphisms are being found not only in CYP isoforms. They are also discovered in other drug-metabolizing enzymes that are significant in developing and clinical usage of medicines.
Besides the pharmacokinetic effects of CYP2D6 polymorphism, there are also clinical effects for extensive metabolizers (EM) and ultra-rapid poor metabolizers (PM) phenotypes of CYP2D6. When a drug is used clinically as a single agent, it is not only the adverse drug reaction and effectiveness of a drug that are influenced by CYP2D6 genotype of a patient.
Some drug-drug interactions can also manifest dramatic inter-genotypic variations. For instance, the CYP2D6 PMs do not illustrate the drug-drug interactions foreseen from in vitro case studies. This is not very surprising because there is no functional CYP2D6 operation than can be restrained.
On the contrary, there are other drug metabolizing enzymes in which CYP2D6 is not inducible. Moreover, even the Ums may fail to show the expected drug-drug interaction. Unlike the PMs and Ems, the Ums have adequately huge functional reserve of CYP2D6 operation that they would need higher doses of the inhibitor to evoke interaction.
the individuals that will exhibit a drug interaction under normal conditions of use are those who have an intermediate or compromised drug metabolizing (IMs) capacity, or those who have inherited CYP2D6 alleles with decreased or modified affinity for CYP2D6 substrates. At the level of the CYP2D6, the expected dependence of drug intervention on the metabolic phenotype has been affirmed for a few substrates of CYP2D6 such as metoprolol, encainide, mexiletine, propafenone, desipramine and codeine.
Besides the acetylation, polymorphisms of other conjugation response like the glucuronidation intervened by UGT are likewise drawing out more attention particularly in oncology. A multi-gene family encodes the UGTs and some human UGT enzymes catalyze the glucuroniation of a several structurally-diverse endogenous and exogenous chemicals.
The genetic difference and single nucleotide polymorphisms within the UGT genes are not uncommon. UGT1A1 and UGT1A9, two of major isoforms of UGT, exhibit wide inter-individual difference in their operations and show genetic polymorphisms that have a relevant pharmacological effect when it comes to the adverse drug reactions.
However, the irinotecan and flavopiridol are metabolized by UGT1A, which is inhibited by tranilast and atazanavir. The retrospective studies that examine the role of UGT1A isoforms in the safety of irinotecan, flavopiridol, tranilast and atazanavir have been most precious in explaining the clinical concerns linked to these drugs.
by: Charles Godbout
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