Biotransformation, Pharmacogenomics and Clinical Drug Trials Flashcards
What is the general strategy for eliminating compounds?
Biotransform it into a more polar, and sometimes larger, derivatives.
First-pass effect
Phenomenon where oral drugs undergo extensive biotransformation after absorption prior to entering circulation. It limits the bioavailability of some drugs, so other routes of administration might be preferred (ex: morphine is better parenterally).
Drugs administered parenterally do not undergo first-pass biotransformation.
Phase 1 vs. Phase 2 reactions
Phase 1 - biologically inactivate the drug by making it more polar. Phase 1 rxns are catabolic. Sometimes the metabolistes can be more toxic than parent drug.
Phase 2 - make the drug more water soluble (conjugate) and increase its molecular weight (easier for elimination). Phase 2 rxns are anabolic.
What 3 kinds of reactions occur in phase 1?
What enzymes accomplish these reactions?
Where do these reactions occur generally?
Oxidation, reduction and hydrolysis.
CYP450s, FMO, Epoxide hydrolases.
The enzymes are in lipophilic ER membranes in the liver.
5 most important CYP450s
CYP3A4** CYP1A2 CYP2A6 CYP2D6 CYP2E1
Phase 2 enzymes (5)
UGT - UDP-glucuronosyltransferase GST - glutathione-S-transferase NAT - N-acetyltransferase TPMT - thiopurine methyltransferase SULT - sulfotransferase
Genetic factors involved in the clinical relevance of biotransformation
Polymorphisms in xenobiotic-metabolizing enzymes
Differences in enzyme expression levels
Non-genetic factors involved in clinical relevance of biotransformation
Drug-drug interactions Age and sex Circadian rhythm Body temp. Liver size/fxn Nutritional/environmental factors
For an adult dose of 1.2 g/day, what percentage of what 2 enzymes are responsible for biotransformation?
95% glucuronidation and sulfation
5% p450-dependent GSH conjugation
What 3 things occur when acetaminophen intake exceeds therapeutic doses?
Glucuronidation and sulfation pathways are saturated and the p450 pathway becomes more important.
Over time, hepatic GSH is depleted faster than it is regenerated.
Toxic metabolites accumulate -> hepatotoxicity.
What are risks for pts. that are poor metabolizers of xenobiotics?
What are risks for pts. that are ultrafast metabolizers of xenobiotics?
Poor metabolizers are at risk for accumulation of toxic drug levels.
Ultrafast metabolizers are at risk for being undertreated w/ inadequate doses.
Glucose-6-phosphate dehydrogenase deficiency (4)
Most common dz-producing ezyme defect in humans.
More than 400 variants described.
G6PD makes NADPH, which regenerates reduced glutathione from its oxidizes form. Reduced glutathione protects against oxidative damage.
G6PD deficiency -> oxidative damage that can lead to hemolytic anemia in the presence of oxidants.
Ryanodine receptor mutations can lead to malignant hyperthermia when what meds are given?
How does it occur?
Inhalational anesthetics, succinylcholine.
Elevates Ca++ levels in the sarcoplasm of muscle leads to muscle rigidity, elevation of body temp. and rhabdomyolysis.
What 2 kind of polymorphisms may exist in Warfarin?
Polymoprhisms in biotransforming enzymes.
Polymorphisms in drug targets.
4 phases of drug development and clinical trials
- Is it safe PKs? (20-100 subjects)
- Does it work in pts.? (100-200 subjects)
- Does it work double-blind? (1000-6000 subjects)
- Postmarketing surveillance.
