3. DSA Biotransformation, Pharmacogenomics, and Clinical Trials Flashcards
What is the enzymatically driven process whereby a substance is changed from one chemical to another?
Drug biotransformation
The strategy for eliminating compounds is biotransformation into more polar and larger derivatives. The polar and water soluble products are excreted via?
more readily via the kidney
Inactivation can be seen due to biotransformation, such as aspiring being made into acetic acid and salicylate. What are the other two consequences that can occur?
Active compound to Active compound
Actication: L dopa to Dopamine = Prodrug
What is an inactive drug that undergoes biotransformation to become and active drug? Where does this commonly occur?
prodrug
Occurs in the liver between absorption into the general circulation and renal elimnation
Xenobiotics absorbed from the SI are transported to the liver via portal system. What is the process by which oral drugs undergo extensive biotransformation after absorption prior to entering circulation?
First Pass effect (not parenterally administered drugs)
First pass effect can be bad, since the drugs are being processed before being able to enter circulation, limiting the bioavailibility of some drugs. What is an alternative route to go around the first pass effect?
Give a drug parenterally
ex: morphine oral bioavailbility is 25%
What are the two phases of biotransformation?
- Reactions which result in inactivation of a drug
2. Reactions produce metabolite with improved water solubility and increased molecular weight to enhance elimination
Phase 1 involves enzymes to convert the drug to a more polar metabolite via oxidation, reduction and hydrolysis. Phase 1 products are catabolic and the products can be?
more reactive and more toxic than the parent drug
Phase 2 involves enzymes that form a conjugate of the substrate. Conjugation improves water solubility and inc. molecular weight. Phase 2 reactions are?
anabolic (building)
NOTE: isoniazid does not follow Phase 1 to Phase 2
All of phase 1 reactions are carried out by mixed function oxidases MFOs or monooxegenases, including what 3?
CYP450
Flavin containing monooxygenases FMO
Epoxide Hydrolases
Where does phase one of biotrasnformation occur?
in lipophilic ER membranes of the liver
What is the main clinical relevance of biotransformation?
Rate and efficiency differs between individuals, so it may affect drug dose and frequency of administration among individuals
There are genetic and nongenetic factors influencing biotransformation (BT), what are two of each?
Genetic: mutation in xenobiotic metabolizing enzymes, pharmacogenetic differences in E expression levels
Nongenetic: age,sex,circadiam rhythm, drug-drug interactions
Enzyme induction can occur via rifampin, st john’s wort, enzyme inhibition can occur via grapefruit juice. What are two other non genetic factors that can affect BT?
Age (dec. hepatic blood flow=dec ability to break down)
Disease states such as liver/cardiac disease
Acetaminophen-induced hepatotoxicity… when an adult takes too much, the glucuronidation and sulfation pathways are saturated forcing liver to use P450… leading to?
toxic metabolites when GSH is depleted d/t using other pathway
What is the study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy and toxicity at the genomic level?
Pharmacogenetics
What is the study of the entire genome to assess multigenetic determinants of drug resopnse?
Pharmacogenomics
What is the variation in the rate at which the body absorbs, transports, metabolized, or excretes a drug/metabolite?
Pharmacokinetics
What is the allelic variation in a drug’s downstream targets such as receptors, enzymes, or metabolic pathways?
Pharmacodynamics
Polymorphisms in CYP450 in phase 1 reactions can result in?
absent, decreased or increased enzyme activity
What is the most common disease-producing enzyme defect of humans, which is needed to regenerate glutathione from its oxidized form? (pharmacodynamic response variation)
Glucose-6-phosphate dehydrogenase deficiency (can lead to hemolytic anemia d/t lack of glutathione which protects cells from oxidative damage)
Ryanodine receptor mutation and malignant hyperthermia are examples of variations in?
pharmacodynamic response
Clinical trials include 4 phases and are often designed to compare?
one form of therapy to another experimental form
In vitro studies to animal testing for efficacy selectivity mechanism. To clinical testing:
Phase 1: 20-100subjects, is it safe, pharmacokinetics?
Phase 2: 100-200 subs, does it work in patients?
Phase 3: 1000-6000, does it work double blind
Phase 4?
posmarketing surveillnace (10 years later!)
What is the purpose of IRB (institutional review board)?
to assure that appropriate steps are taken to protect the rights, safety, and welfare of humans participating as subjects in the research