ch 8 Pharmacogenomics
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| What Is Pharmacogenomics? | Pharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression with a drug’s efficacy or toxicity.
In other words, drugs and drug combinations are optimized for each individual’s unique genetic makeup.
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| Physiology Review | Although humans share 99.9.% of DNA sequence, the less than 0.1% difference is about 3 million nucleotides/Of the 0.1% difference, over 80% will be single nucleotide polymorphisms (SNPs). An SNP is a single base substitution of one nucleotide with another/An example of an SNP is individual “A” has a sequence GAACCT, while individual “B” has a sequence GAGCCT, the polymorphism is a A/G.
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| Review: CYP 450 | Cytochrome P450 (CYP) enzymes are involved in about 75% of drug metabolism and bioactivation in the liver.
Some CYPs metabolize only one (or a very few) drug(s), while others may metabolize multiple drugs.
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| Review: CYP 450 | Genes provide the coding for CYP enzymes, and the enzymes themselves are designated w/ abbr CYP, followed by Arabic numeral indicating gene family, a capital letter indicating the subfamily, and another numeral for the ind gene.
•For example, CYP 2E1 is the gene that encodes the enzyme CYP 2E1, one of the enzymes involved in acetaminophen metabolism.
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| Role of P-Glycoprotein (P-gp) | P-gp: membrane-bound transport system responsible for drug transport across cell membranes/P-gp, an efflux pump expressed along the gastrointestinal tract, limits the permeability of many drugs and thus affects their absorption and bioavailability/A number of drugs inhibit or activate both CYP 450 and P-gp at the same time (e.g., grapefruit juice)
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| Pharmacodynamic Differences | How does a person’s genetic makeup affect CYP enzyme function & pharmacodynamic differences? /What other factors besides genetic coding contribute to pharmacodynamic differences?
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| CYP 450 in Clinical Practice | Clinical knowledge of substrates, inhibitors, and inducers for each CYP 450 family assists clinicians in predicting potential drug-drug interactions /The CYP 3A subfamily is responsible for over 50% of drug metabolism
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| CYP 450 in Clinical Practice | Race, gender, environmental factors, and drugs may alter the gene expression of individual CYP 450 families and subfamilies/40% of Asians display drug polymorphism/There is no specific clinical test to estimate sensitivity or activity of CYP 450
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| Inhibitors vs. Inducers of CYP 450 | What are the clinical implications when substrates inhibit CYP 450 enzymes? /An inhibitor may decrease the metabolism of substrates and generally lead to an increased drug effect
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| Inhibitors vs. Inducers of CYP 450 | What are the clinical implications when substrates induce CYP 450 enzymes?/An inducer may increase the metabolism of substrates and generally lead to a decreased drug effect
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| CYP 450 in Clinical Practice | CYP families 1 through 3 have the least affinity for substrates and have the widest genetic variability /They are responsible for 78% to 80% of phase I metabolism-drug interactions in clinically used drugs/Variations or polymorphisms in genetic codes for these CYP enzymes have tremendous clinical importance
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| Variations in Phenotypes Affect Speed of Metabolism | Poor metabolizers: homozygous for lack of a working enzyme
Intermediate metabolizers: heterogenous for one working wild-type allele and one mutant-allele /Extensive metabolizers: homozygous
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| Variations in Phenotypes Affect Speed of Metabolism | Have two normally functioning alleles /Ultra-rapid metabolizers: heterozygous for more than one functioning copy of a certain enzyme
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| Variation of Alleles | Slow metabolizers: homozygous, have two copies of alleles that cause slow metabolism because they lack the working enzymes
/Fast metabolizers: homozygous, have two copies of alleles that cause fast metabolism because they have working enzymes; heterozygous one allele may have more than one copy for making working enzymes
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| Clinical Implications of Pharmacogenomics | Pharmacogenetic testing before prescribing: Cetuximab/Trastuzumab/Maraviroc/Dasatinib
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| Clinical Implications of Pharmacogenomics | Warfarin/Variants in VCORC1 may lead to resistance./Label updated by the U.S. Food and Drug Administration (FDA) to include recommended starting doses depending on the VKORC polymorphism profile./Carbamazepine
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| Clinical Implications of Pharmacogenomics | FDA labeled recommending testing for the HLA-B*1502 allele in patients with Asian ancestry before initiating carbamazepine therapy due to high risk of developing carbamazepine-induced Stevens-Johnson syndrome or toxic epidermal necrolysis.
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