Flashcards in Pharmacogenetics Deck (23)
the study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity.
• The key conceptual elements here are that pharmacogenetics typically involves the study of just a few genes and these genes are selected based on a priori knowledge of their role(s) in drug metabolism.
the genomic approach to pharmacogenetics, is concerned with the assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy.
• Instead of analyzing individual genes and their variants according to what is known about how they influence pharmacokinetic and pharmacodynamic pathways, sets of alleles at a large number of polymorphic loci are being identified that distinguish patients who have responded adversely to what was considered a beneficial drug from those who had no adverse response.
the rate at which the body absorbs, transports, metabolizes, or excretes drugs or their metabolites. Genetic Examples: Cytochrome P450, glucuronyltransferase, thiopurine methyltransferase
the response of the drug binding to its targets and downstream targets, such as receptors, enzymes, or metabolic pathways. Genetic Examples: Glucose-6-phosphate dehydrogenase, vitamin K epoxide complex
Put another way, _______ is concerned with whether or how much drug reaches the target(s) and__________ is concerned with what happens when the drug successfully reaches its target (note both phenomenon occur simultaneously).
Pharmacokinetics is broken down further into two basic ways that drugs are metabolized through biotransformations:
• Phase I (simplified): attach a polar group onto the compound to make it more soluble; usually a hydroxylation step
• Phase II (simplified): attach a sugar/acetyl group to detoxify the drug and make it easier to excrete
With regards to CYP2D6, what are the effects of frameshift, splicing, missense, and copy number increases on enzyme activity?
• Frameshift - alter reading frame NO ACTIVITY
• Splicing -skip exons and/or alter reading frame NO ACTIVITY
• Missense - alter protein function usually REDUCED ACTIVITY
• Copy number alleles increased gene copy
3 major phenotypes based on activity levels:
normal, poor (includes null alleles), and ultrarapid/ultrafast.
There are numerous ____ of cytochrome P450. (An_____ is a CYP enzyme variant that derives from one particular gene).
How are the cytochrome P450 genes classified? (3 subgroups, each identified by CYP_ _ _)
Families are numbered - for example CYP2, CYP21.
Subfamilies are identified by a letter, and thus we get CYP3A, CYP2D.
Individual genes are identified by a number, for example CYP2D6.
What enzyme is inhibited by grapefruit juice? Give an example where this might be problematic (drug interaction).
A single 8 oz glass of grapefruit juice can inhibit CYP3A activity for 24-48 hours (largely through intestinal inhibition of CYP3A). Thus grapefruit juice can affect the side-effect profiles of many of the CYP3A substrates shown in the table. For example, drinking grapefruit juice while taking felodipine for hypertension can lead to significant hypotension due to potentiation of the felodipine effect since CYP3A activity is reduced and metabolism/elimination of felodipine is similarly slowed.
Why must cyclosporine dosage be adjusted downwards by 75% when administered in conjunction with the antifungal drug ketoconazole? What mechanism is at play to cause this?
Renal transplant patient who develops a fungal infection: Dosage of the immunosuppressive drug cyclosporine (used in kidney transplants for instance) must be reduced by 75% to avoid toxicity when the antifungal ketoconazole is added to treat a fungal infection. Mechanism- ketoconazole temporarily inhibits CYP3A metabolism which leads to raised levels of cyclosporine which can be neprotoxic.
____ changes codeine to its active form (morphine), while ______ inactivates it.
Why must cyclosporine dosage be increased when given in conjunction with rifampicin (ie for a tuberculosis patient)? What mechanism is at play?
Renal transplant patient who is exposed to tuberculosis and requires rifampin prophylaxis: In this case, the dose of cyclosporine must be increased since rifampin is a CYP3 inducer and leads to more rapid metabolism and elimination of cyclosporine. If you fail to take this into account, the cyclosporine levels will decrease and organ rejection will become a problem.
CYP3A is induced by (1) and inhibited by (2)
Inducers: (rifampicin aka rifampin); Inhibitor (ketoconazole, grapefruit juice)
CYP2D6 substrates (2), inhibitors (3)
(Tricyclic antidepressants, Codeine); (Quinidine, Fluoxetine, Paroxetine)
CYP2C9 substrate (1)
What is the substrate of the NAT (N-acetyltransferase) enzyme, and how might fast/slow rates of acetylation cause adverse side effects?
Isoniazid for tuberculosis (N-Acetyltransferase enzyme). Slow acetylation may lead to higher blood concentrations with chronic administration of the drug, with an increased risk of toxicity. Fast acetylation leads to higher blood levels of the toxic metabolite acetylisoniazid and thus to an increase in toxic reactions
TMPT (substrates 2)
6-mercaptopurine, 6-thioguanine (prodrug is azathoprine, which is converted to many other componds, among which are 6-mercaptopurine and 6-thioguanine)
Activity of _____ is absent in 1/300-1/400 children. Normal doses of ______ (prodrug, name 2 substrates) will be lethal due to _______ in children with childhood leukemia or inflammatory bowel diseases (ie Crohns).
TMPT (Thiopurine methyltransferase); Azathoprine (6-mercaptopurine, 6-thioguanine); immunosupression
G6PD deficiency (2 substrates). What is the deal with it.
(sulfonamide antibiotics, dapsone). X-linked enzyme, G6PD deficient individuals are susceptible to hemolytic anemia after drug exposures (due to oxidative stress). Also known as favism (legumes like the fava bean cause problems).
VKORC1 is associated with what drug?
Warfarin is metabolized primarily via oxidation in the liver by CYP2C9, and exerts its anticoagulant effect by inhibiting the protein vitamin K epoxide reductase complex, subunit 1 (VKORC1). Three single nucleotide polymorphisms (SNPs), two in the CYP2C9 gene and one in the VKORC1 gene, have been found to play key roles in determining the effect of warfarin therapy on coagulation.
Several variant CYP2C9 alleles are associated with reduced enzyme activity and lower clearance rates of warfarin. Patients who carry at least one copy of such a variant allele have reduced metabolism and thus higher drug concentration, and require a lower daily warfarin dose.
A common non-coding variant, -1639G>A, is associated with an increased sensitivity to warfarin (14). The polymorphism occurs in the promoter region of VKORC1 and is thought to alter a transcription factor binding site, leading to lower protein expression.