Intro Drug Biotransformation, Pharmacogenomics, And Clinical Drug Trials-lecture + CIS-Kruse Flashcards
Acetylsalicylic acid (aspirin) –> acetic acid + salicylate
This is an example of ___
Inactivation
Diazepam –> Oxazepam
This is an example of ___
Active compound –> active compound
-biotransformation into another active compound
L-dopa –> dopamine
This is an example of ___
Activation
-prodrug- an inactive drug that undergoes biotransformation to become an active drug (L-dopa in an inactive or pro-drug)
Where does biotransformation mostly occur?
In the liver at some point between absorption into the general circulation and renal elimination
__ is the process by which oral drugs undergo extensive biotransformation after absorption prior to entering circulation
1st pass effect
Drugs administered parenterally do not undergo 1st pass biotransformation
The 1st pass effect greatly limits the bioavailability of some drugs such that alternative routes of administration must be explored. List a classic example of this
Morphine
Ora bioavailability is roughly 25% so parenteral administration is preferred
As a general rule:
__ result in the biological inactivation of the drug
___ produce a metabolite with improved water solubility and increased molecular weight (enhances elimination)
Phase 1 rxns
Phase 2 rxns
__ consist of enzymes that convert the parent drug to a more polar metabolite
Phase 1 rxns
- catabolic
- phase 1 products can be more reactive and sometimes more toxic than the parent drug
___ consist of enzymes that form a conjugate of the substrate
Phase 2 rxns
- conjugation with endogenous substrates to improve water solubility and increase MW
- anabolic
Phase 1 is usually followed by phase 2. List an exception to this:
Isoniazid –> used for TB tx, acetylated 1st by N-acetyltransferase
What types of rxns comprise phase 1 rxns?
Oxidations, reductions, and hydrolysis
-products are generally more reactive and may be more toxic than the parent drug
Where are phase 1 enzymes located?
In lipophilic ER membranes of the liver (and other tissues)
List some well-characterized enzyme-inducers:
Phenobarbital, chronic ethanol (higher CYP450 2E1), benzo[a]pyrene (tobacco smoke), rifampin, st johns wort
List some well-characterized enzyme inhibitors:
Grapefruit juice
Compound in juice that inhibits CYP450 enzymes, that will then effect steady state dose of drug you are taking
List ways in which acetaminophen is normally metabolized:
95% glucuronidation and sulfation
5% P450-dependent GSH conjugation
Describe glucuronidation and sulfation pathways in acetaminophen toxicity:
They are saturated and P450 pathways become increasingly important. Over time, hepatic GSH is depleted faster than is regenerated and toxic metabolites accumulate resulting in hepatotoxicity
__ is the study of differences in drug response d/t allelic variation in genes affecting drug metabolism, efficacy, and toxicity at the genomic level
Pharmacogenetics
__ is the study of the entire genome to assess multigenetic determinants of drug response
Pharmacogenomics
___ is a variation in the DNA sequence that is present at an allele frequency of 1% or greater in a population
Polymorphism
Describe drug-response variability & genetics in relation to pharmacokinetics:
Variation in the rate at which the body absorbs, transports, metabolizes, or excretes a drug/metabolites
Describe drug response variability & genetics as it relates to pharmacodynamics:
Allelic variation in a drugs downstream targets, such as receptors, enzymes, or metabolic pathways
Polymorphisms in CYP450s can result in absent, decreased, or increased enzyme activity. Describe poor metabolizers vs ultrafast metabolizers:
Poor metabolizers are at risk for accumulation of toxic drug levels
Ultrafast metabolizers are at risk for being undertreated with inadequate doses
this enzyme deficiency is the most common disease-producing enzyme defect of humans. Deficiencies cause oxidative damage that leads to hemolytic anemia in the presence of oxidants
Glucose-6-phosphate DH deficiency
What happens with adminstration of succinylcholine in an individual with a polymorphism in butyrcholinesterase?
Succinylcholine is a fast acting paralytic. A pt with this polymorphism will take longer to come out of a paralytic state
Lead compounds are associated with what type of study?
In vitro
What is the transition period for an investigational new drug?
Between animal testing and clinical testing
__ is the maximum dose at which a specified toxic effect is not seen
No-effect dose
__ is the smallest dose that is observed to kill any experimental animal under a defined set of conditions
Minimum lethal dose (LDmin)
__ is the dose that kills approximately 50% of the animals
Medial lethal dose (LD50)
__ is measured to assess a drug’s effect (e.g., BP for testing an antihypertensive agent
Endpoint
The general strategy for eliminating compounds involves biotransformation into ___ derivatives
More polar, and sometimes larger
-polar and water-soluble products are more readily excreted by the kidneys
