Week 1: Drug Metabolism Flashcards
What is the biotransformation of a drug?
Enzyme-catalyzed chemical transformation, and more than one pathway may be involved
What is first pass metabolism?
Metabolism in the intestinal mucosa or liver, which occurs before (some) orally administered drugs reach systemic circulation
If drugs are substantially metabolized before reaching systemic circulation, they have been exposed to the “first pass effect”
What is entero-hepatic recycling? What effect does it have on the half-life of a drug?
The continuing cycle of biliary secretion and intestinal reabsorption. This can prolong the half-life of a drug and create a delayed second peak in [drug].
What are the consequences of drug metabolism? Are drugs ever given in an inactive form?
Active drug –> Inactive metabolite
Active drug –> Active metabolite
Inactive drug (prodrug) –> Active metabolite
Active drug –> Toxic metabolite
Inactive drugs (prodrugs) can be given to delay activity in the body
What are the sites of first-pass metabolism?
The liver and GI tract
What are common intracellular sites of drug-metabolizing enzymes?
SER
Mitochondria
Cytosol
Lysosomes
Nuclear envelope
Plasma membrane
What are Phase I reactions?
Oxication (microsomal, P450-mediated, and nonmicrosomal, non P450-mediated)
Reduction
Hydrolysis
What are Phase II reactions?
Conjugation reactions
What enzymes are involved in Phase I microsomal oxidation?
Cytochrome P450, a Mixed Function Oxidase System (MFO) which is found in the liver, intestinal mucosa, lung, kidney, and skin (SER is primary source)
also flavin mono-oxygenase (FMO3)
What are the isozymes of Cytochrome P450?
CYP1A2
CYP2B6
CYP2C8, CYP2C9, CYP2C19
CYP2D6
CYP2E1
CYP3A
What are the general characteristics of P450s?
Small differences in AA sequences lead to important differences in metabolism. They also have genetic variability in expression.
They are inhibited by commonly used drugs, and also are inducible, with the exception (possibly) of CYP2D6, by things like foods, cigarette smoke, etc.
What are the three key elements that influence CYP enzymes?
Substrates, which are drugs that the enzyme can metabolize
Inhibitors, ususally drugs meant as substrates for other pathways that can inhibit a separate CYP enzyme
Inducers, usually food, environmental elements (cigarette smoke), or other drugs that can activate a different CYP enzyme
What CYP enzymes differ in their amounts across different groups? What is the average % difference in amount, and in what populations?
CYP2C9 - absent in 1% of Caucasians
CYP2C19 - absent in 20-30% of Asians, and 3-5% of Caucasians
CYP2D6 - absent in 7% of Caucasians, hyperactive in 30% of East Africans, hyperactive in up to 10% of Western Europeans
What is the significance of the tizanidine-fluvoxamine interaction? What enzyme is involved?
CYP1A2 is involved in the metabolism of tizanidine. Fluvoxamine acts as a potent inhibitor of CYP1A2. When tizanidine was given alone (open circles), [tizanidine] is much lower. When given with fluvoxamine, however, CYP1A2 was inhibited, so [tizanidine] was 12x higher.
Open circles are fluvoxamine alone, closed are with tizanidine (see graph)
What is the function of tizanidine?
It decreases blood pressure by decreasing systolic & diastolic pressure as well as heart rate. It also causes sedation.
Fluvoxamine alone is in open circles, with tizanidine is in closed circles
What enzyme processes codeine, and how does it conduct this process chemically? What is notable about it?
CYP2D6. It is absent in 7% of Caucasians, and is hyperactive in 30% of East Africans and 10% of Western Europeans. It converts codeine to morphine, which is an analgesic. Those with polymorphisms do not get the benefit from CYP2D6.
CYP2D6 is responsible for the O-demethylation of codeine to morphine.
What can happen to individuals who metabolize codeine too rapidly?
CYP2D6 overactivity in East Africans (30%) and Western Europeans (10%) can lead to codeine intoxication, with blood levels of morphine 20-80x higher than expected.
How can you test the phenotype of CYP2D6 to determine if the pt has multiple copies/high amounts of the gene/protein?
Administering dextromethorphan (a nontoxic cough suppressant) and analyzing its rate of metabolism.
Why shouldn’t new mothers breastfeed babies if they are taking codeine?
The metabolite of CYP2D6, morphine, which is converted from codeine, will end up in breastmilk and be transferred to the baby, causing toxic concentrations of morphine to build up in the babies’ system
Why is it important to ask a patient if they are taking supplements, in addition to prescription drugs?
Some supplements, like St. John’s Wort, are inducers of CYP enzymes (CYP3A, in this case) and can increase the mebatolism of drugs like indinavir, an HIV treatment (see graph for reference)
What are nonmicrosomal oxidations that can occur in drugs?
Alcohol dehydrogenase
Aldehyde dehydrogenase
Purine oxid.
Monoamine oxid.
If someone had methanol (or ethylene glycol) poisoning, why would you give ethanol as a treatment?
Ethanol competes with alcohol dehydrogenase, blocking at least some of it’s activity in converting methanol to formaldehyde.
How do you block purine oxidation?
Hypoxanthine oxidation to uric acid via xanthine oxidase can be blocked by our good friend, allopurinol.
What can block monoamine oxidase? What do they do?
Since monoamine oxidase (MAO) degrades serotonin, MAO inhibitors can be given as antidepressants
What enzymes mediate hydrolysis reactions?
Esterases in plasma, liver and other tissues
Amidases in liver and gut flora
What endogenous substrates can drugs be conjugated to?
Glucuronic acid
Acetic acid
Glutathione
Sulfuric acid
Methyl groups
What enzyme conjugates glucuronide?
UDP glucuronyl transferase (UGT)
What enzyme conjugates acetyl groups?
Acetyl transferase
What enzyme conjugates glutathione?
Glutathione S-transferases
What enzyme conjugates sulfur groups?
Sulfotransferases
What enzymes mediate methylation?
Methyltransferases
What effect do transporters have on pharmacokinetics?
They transport drugs and other substances in and out of cells
They may control absorption, distribution and elimination
They may work in concert with metabolizing enzymes
The may be involved in drug interactions
What is a key transporter that is located in the apical membrane of may key tissues? What tissues are these?
The P-glycoprotein (P-gp, a Multi-Drug Resistance [MDR1] protein) is located in the membranes of intestine, liver, kidney and BBB tissues
It prevents entry and toxicity of compounds into the blood, brain, etc.
What P450 analog interacts with/is co-expressed with P-gp?
P-glycoprotein is co-expressed with CYP3A4, an intracellular enzyme that is induced by St. John’s wort, rifampin and ritonavir. This enzyme helps mediate P-gp activity and prevents too much of a drug or toxin from entering the blood.
What effects does the inhibition of drug metabolism have?
It can result in toxicity (active –> toxic) or therapeutic failure (prodrug –> active).
It will most likely inhibit Phase I pathways.
Drugs with common pathways might interact, although not all inhibitors are substrates for a drug’s given processing enzyme. Some may be allosteric-esque inhibitors that affect the enzyme outside of it’s direct interaction with a drug.
There are also food-drug interactions and tobacco-drug interactions that can inhibit a drug’s effect.
What are the consequences of induction of drug metabolism?
Can result in toxicity and therapeutic failure (as with indinavir and St. John’s wort). Other drugs can induce drug metabolism, as can herbal supplements and environmental factors.
What are some endogenous influences on drug metabolism?
Pharmacogenetics (i.e. an individual’s genetic makeup that may/may not allow them to produce enzymes for drug metabolism)
Disease - liver disease and heart failure
Aging - pediatric (Phase I/II slower/absent in neonates) and geriatric (highly extracted drugs, primarly Phase I reactions)
Sex - CYP3A differences in males and females
What is pharmacogenomics?
Study of all the genes that determine drug behavior
What is pharmacogenetics?
The study of inherited differences in drug metabolism and response
What are genetic polymorphisms? What is a SNP?
Differences in DNA sequences that occur naturally in a population with a frequency of >1%
Single Nucleotide Polymorphism (SNP) is a polymorphism where alleles differ by a replacement of a single nucleotide in the DNA sequence
How can you examine the pharmacogenetics of an individual? Why is this useful?
There are rapid microarray tests that allow for the genomics of an individual to be assessed for CYP450-related genes, for example. This can allow individuals to be put on doseages that are relevant to their enzymatic processivity, and decrease the likelihood of being put on a drug that will become toxic due to metabolic issues with a genetic deficiency or excess.
What is the effect of 6-mercaptopurine in bone marrow? What kind of drug is it, and how does it relate to TPMT?
It is an immunosuppressant cancer drug that causes a decrease in bone marrow activity, resulting in decreased RBC, WBC and platelet count. Those who are deficient in thiopurol methyltransferase (TPMT), the enzyme that metabolizes 6MP, require decreased 6MP doses to prevent toxicity.
What is thioridazine and what enzyme processes it? What issues can arize from its use?
It a mood disorder treatment processed by the P450 analog CYP2D6. However, it has a VERY serious side effect of prolonging the QTc interval (heart muscle de/repolarization), and causing arrythmias and sudden death!
What does Warfarin do, what enzyme processes it, and what are genetic issues that arise from it’s use?
Warfarin is a anticoagulant that is metabolized by S-CYP2C9. However,genetic variants are associated with a DECREASED requirement for Warfarin, and if given in normal doses in these ptscan cause internal bleeding.
What is Abacavir used to treat, and what pharmacogenetic issues are associated with it?
Used to treat HIV-1 infection, and HLA-B*5701 gene is associated with potentially fatal hypersensitivity reactions
What is Carbamazepine used to treat, and what are some potential pharmacogenetic side effects of it?
Used to treat seizures, mania/bipolar disease, and neuropathic pain. HLA-B*1502 gene is associated with a severe skin reaction called Stevens Johnson Syndrome (SJS), especially in Han Chinese populations
What is Valproic acid used to treat, and what are the associated pharmacogenetics of it?
Used to treat seizures, and POLG gene mutations (neurometabolic syndromes) cause increased risk of valproic acid-induced liver failure.
What is epigenetics?
Changes in gene expression caused by DNA modifications, without changes in the actual DNA sequence. These changes occur due to…
DNA methylation
Histone modification
RNA activity
What is the difference between pharmacogenetics and epigenetics?
Epigenetics is the difference in phenotypic expression of certain genes due to DNA modification, i.e. the differential expression of certain proteins.
Pharmacogenetics is the differential expression of certain enzymes that relate to drug metabolism, and is, in a way, a subset of epigenetics (i.e. polymorphisms in certain genes, which are actual changes to DNA)
What is epigenetics associated with?
Cancer
Mental retardation
Autoimmune disease
Neuropsychiactric disease
How have drug targets been used in combination with epigenetics?
Analysis of the presence of cancer-causing DNMTs (DNA methyltransferases) and HDACs (histone deacetylases) can be used to assess if drugs that treat overactivity of either are needed. For example, if tumor suppressor genes are methylated, drugs like Azacitidine and Decitabine can be used to treat cancers caused by their methylation.
What aspects of drug metabolism play a role in the framework for pharmacology?
Mechanism of action
Elimination
Pharmacogenetics
Drug interactions
Adverse drug reactions
