Biotransformation and Pharmacogenomics (Kruse) Flashcards
What is drug biotransformation?
it is the enzymatically driven process whereby a substance is changed from one chemical to another (to become more polar, possibly larger) as these are more easily excreted
can be anabolic or catabolic
Most metabolic products are less pharmacodynamically active than the parent drug
What are the three main consequences of biotransformation?
inactivation
active compound to active compound
activation
What is an example of drug inactivation?
What is an example of drug active compound to active compound?
What is an example of drug activation?
Acetylsalicylic acid to acetic acid and salicylate
Diazepam to oxazepam
L-dopa to dopamine (prodrug to active drug)
Where does biotransformation occur?
Mostly occurs in the liver at some point between absorption into the general circulation and renal elimination
What is the first pass effect?
the process by which oral drugs undergo extensive biotransformation after absorption prior to entering circulation
Note: Drugs administered parenterally do not undergo first-pass biotransformation
How does the first pass effect change bioavailability?
the first pass effect greatly limits bioavailability of some drugs such that alternative routes of administration must be explored
ex: morphine, with oral bioavailability of 25% so that parenteral administration is preferred
What are the results of Phase I reactions?
What are the results of Phase II reactions?
results in the biological inactivation of the drug
produce a metabolite with improved water solubility and increased molecular weight (enhances elimination)
What sort of reactions occurs in Phase I?
enzymes that convert the parent drug to a more polar metabolite by unmasking or introducing a functional group
Most common: Oxidation, Reduction, Hydrolysis
These reactions are catabolic and their products can be more reactive/toxic than parent drug
What sort of reactions occurs in Phase II reactions?
Conjugation occurs with endogenous substrates (glucoronic acid, sulfuric acid, acetic acid, amino acid) to improve water solubility and increase molecular weight
These reactions are anabolic
typically occur after Phase I (except in Isoniazid for TB tx)
Phase I reactions are carried out by MFOs-what are some examples?
Cytochrome P450s
Flavin-containing monooxygenases
Epoxide hydrolases
These enzymes are located in lipophilic ER membranes of the liver and other tissues
What is the main key enzyme in phase I reactions?
What are the main key enzymes in phase II reactions?
CYP3A4 (and other CYPs)
UGT=UDP-glucuronosyltransferase
GST-glutathione S transferase
NAT-N-acetyltransferase
TPMT-thiopurine methyltransferase
SULT-sulfotransferase
What are some individual factors that effect biotransformation?
differences in the rate of metabolism and elimination
genetic factors like polymorphisms in CYPs and pharmacogenetic differences in enzyme expression levels
non-genetic factors like drug interactions, age/sex, circadian rhythm, body temp, liver size and function, nutritional and env. factors
Genetic differences can effect the biotransformation of these two compounds
Succinylcholine
slow acetylator phenotype for N-acetyltranferase enzyme
What are some CYP inducers?
phenobarbital
chronic ethanol use
aromatic hydrocarbons (benzo-a-pyrene) in tobacco smoke
rifamplin
St. John’s wort
What are some CYP inhibitors?
grapefruit juice
inhibitors can be reversible and irreversible
How can age affect biotransformation?
How do disease states affect biotransformation?
liver function and blood flow decrease with increasing age
liver disease and cardiac disease can disrupt drug biotransformation
Discuss acetaminophen-induced hepatotoxicity
for an adult dose of 1.2g/d, 95% will undergo glucuronidation and sulfation and 5% will undergo P450-dependent GSH conjugation
when acetaminophen intake exceeds therapeutic doses glucuronidation and sulfation pathways are saturated and P450 pathway becomes more important. Hepatic GSH gets depleted faster than is regenerated
Toxic metabolites accumulate resulting in hepatotoxicity
How does ETOH consumption effect acetaminophen biotransformation?
I *think* alcohol and tylenol together use up the glucuronidation and sulfation enzymes faster such that GSH has to be used and can cause hepatic damage more quickly.
Can occur at smaller doses of tylenol/ETOH (doesn’t nec. need to be a tylenol overdose or a ton of booze)
Basic Vocab (It’s an LO, so I’m including it)
Pharmacogenetics
Pharmacogenomics
Allele
Polymorphism
SNPs
Pharmacogenetics: study of different drug response to allelic variation in genes affecting drug metabolism, efficacy and toxicity at genomic level
Pharmacogenomics: study of entire genome to assess multigenetic determinants of drug response
Allele: one of two or more alternative forms of a gene that arise by mutation and are found at same locus (CYP2D6*3 is variant for CYP2D6)
Polymorphism: variation in DNA sequence that is present at an allele frequency of 1% or greater in pop.
SNP: base pair substitution that occur in genome
Genetics can effect dose-response in what two ways?
by variations in pharmacokinetics and pharmacodynamics
Polymorphisms in CYP450s can cause what?
absent, decreased or increased enzyme activity
poor/slow metabolizers are at risk for toxic accumulation
Ultrafast metabolizers are at risk for being undertreated
What are some common polymorphisms in Phase II reaction enzymes?
UDP glycosyltransferase and campothetcin
N-acetyltransferase and isoniazid
butyryl cholinesterase and succhinylcholine
How does glucose-6-phosphate dehydrogenase deficiency affect the pharmacodynamic response?
most common disease-producing enxyme defect in humans
normally, G6PD produces NADPH which regenerates glutathione to protect cells from oxidative damage
inG6PD def. oxidative damage leads to hemolytic anemia in the presence of oxidants
How do ryanodine receptor mutations cause malignant hyperthermia?
inhalation anesthetics, succinylcholine given during surgery cause an elevation in CA in the sarcoplasm of muscle leading to muscle rigidity, elevation of body temp and rhabdomyolysis
