GLIMPSE ON PHARMACOGENOMICS

From DawaSpace.

Pharmacogenomics is the study of how differences in genetic factors in different individuals affect their response to drugs. It was commonly understood that our genetic factors play a role in how we respond to drugs, but the fact that the variations in genetic factors among individual could affect how we respond to drugs was yet to be established. The Pharmacogenetics field began when certain individual who had genetic variation in enzyme responsible for metabolizing drugs experienced abnormally severe drug reaction.

The sequencing of human genome has contributed a lot to the development of this study. In 1957 the geneticist   Arno Motulsky Published an article that highlighted the evidence that the antimalaria drug primaquine and the muscle relaxant suxamethonium chloride, possessed the adverse drug reactions that were heritable and linked to deficit in specific enzymes.

Below are the scenarios in which Pharmacogenomics study is evident and applicable

Abacavir hypersensitivity reactions

Abacavir is a nucleoside reverse transcriptase Inhibitor , a anti-retroviral drug indicated for the treatment of human immune deficiency virus (HIV) infections, abacavir is used as the part of multi drug combination in Highly active Anti Retro viral therapy (HAART), data shows that 5% of patients on abacavir experience severe hypersensitivity reaction to the drug, it has been established that the reactions experienced by these patients is due to variations on the gene HLA -B in which patient experiencing these reactions possessed HLA -B*57:01.The signs and symptoms of abacavir hypersensitivity reaction includes rashes ,fever, nausea, vomiting ,diarrhea, abdominal pain , Malaise, dyspnea, cough and Pharyngitis ,it is now recommended that the newly HIV diagnosed patient be tested for HLA-B gene to establish whether or not they will be suitable candidate for abacavir.

Thiopurines toxicity

The drugs in thiopurine group includes azathioprine, mercaptopurines, and thioguanine, these drugs are clinically indicated in treatment of certain types of leukemia, auto immune disorder, and inflammatory bowel diseases. Thiopurines methyl transferases (TPMT) is the enzyme responsible for metabolism of these drugs. Certain individual have deficiency in thiopurine methyl transferase enzymes due to gene mutation, it is approximated that 1 in 300 individuals possess this deficient. The Presence of fewer enzyme responsible for metabolizing these drugs expose the patient to toxic effect of these drug even when given under normal dose, because a significant amount of dose remains unchanged in the system.

Fluoropyrimidines adverse drug reactions

The drugs found in this group include 5-Flouro uracil and its oral pro drug Capecitabine, these drug are mainly used in treatment of solid tumors such as head and neck , gastrointestinal and breast cancer. The major cause of fluoropyridines toxicity is the deficiency of the enzyme Dihydropyridine dehydrogenase (DPD), The enzyme dihydropyridine dehydrogenase is responsible for breaking down the frouropyrimidine, (5-FU and capecitabine). The DPD deficiency is caused by variants in the dihydropyridine dehydrogenase (DPYD) gene, which are associated with an increased risk of severe, specific side effects in carriers. About 30% of 5-Fu toxicity is linked to deficiency of DPD enzyme however other factors also plays a role in toxicity of this drug.

Irinotecan toxicity

Irinotecan is an antineoplastic drug clinically indicated for treatment of various form of neoplasm which includes ,metastatic colorectal cancer, non-small cell lung cancer and Ovarian cancer .This drug has the potential of causing severe side effects which ranges from severe diarrhea  to  neutropenia, some patients taking irinotecan experience severe and life threatening side effects when compared to other  patients ,this is the result of genetic differences that exists in enzymes responsible for metabolism of this drug, irinotecan being a pro drug is metabolized into the active form SN-38  by the enzyme carboxylesterases 1 and 2 ,the active metabolite SN-38 is responsible for the majority therapeutic actions of the drug also its toxicity is related to this metabolite. Some individual’s posses’ genes that cause reduced or total loss of function to the enzyme responsible for inactivation of this metabolite, the metabolite SN-38 remains active for long time in these individuals leading to severe adverse effects.

Warfarin Toxicity  

Warfarin is one of the earliest known oral anticoagulants that function as vitamin K antagonist. Metabolism of warfarin occurs through CYP2C9 enzymes, Vitamin K epoxide reductase complex subunit 1 (VKORC1), encoded by the VKORC1 gene is the target of anticoagulant warfarin and a key enzyme in the vitamin K recycling .The pharmacologic action of warfarin is mediated through inactivation of VKORC1, and since the discovery of the VKORC1 gene in 2004, numerous studies have indicated that individuals with decreased VKORC1 expression,  are at increased risk for excessive anticoagulation following standard warfarin dosages. Furthermore, warfarin is administered as a racemic mixture of R- and S-warfarin, and patients with reduced-function CYP2C9 genotypes are at increased risk for bleeding due to decreased metabolic clearance of the more potent S-warfarin enantiomer. It is predicted that gene-based dosing may help optimize warfarin therapy management and minimize risks for adverse drug reactions



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