Flashcards in Biotransformation, Pharmacogenomics & Drug Trials Deck (53):
What is the general strategy for eliminating compounds via Biotransformation?
Changing one substance into more polar, and sometimes larger, derivatives
Polar and water soluble products are more readily excreted by the kidneys
Most metabolic products are less pharmacodynamically active than the parent drug
Acetyl salicylic acid (aspirin) -> acetic acid + salicylate is an example of what type of Biotransformation?
Diazepam -> oxazepam is an example of what type of Biotransformation?
Active compound -> active compound
L-dopa -> dopamine is an example of what type of Biotransformation?
- this is an example of a pro-drug which is an inactive drug that undergoes Biotransformation to become an active drug
**mostly occurs in the liver at some point between absorption into the general circulation and renal elimination
Explain the first-pass effect
Process by which oral drugs undergo extensive Biotransformation after absorption prior to entering circulation
**drugs administered parenterally do not undergo first-pass biotransformation
**The first-pass effect greatly limits the bioavailability of Somme drugs such that alternative routes of administration must be explored
What drug is a prime example of a first-pass effect drug?
- oral bioavailability is roughly 25%
- parenteral administration is preferred
As a general rule, what is the result/goal of phase I vs phase II reactions?
Phase I rxns result in the biological inactivation of the drug
Phase II rxns produce a metabolite with improved water solubility and increased molecular weight to enhance elimination
Explain phase I drug metabolism enzymes
- convert the parent drug to a more polar metabolite by introducing or unmasking a functional group
- oxidation, reduction, and hydrolysis rxns are most common
- phase I reactions are catabolic
- phase I products can be more reactive and sometimes more toxic than the parent drug
Explain phase II drug metabolism enzymes
- form a conjugate of the substrate from the phase I reaction
- conjugation with endogenous substrates such as glucuronic acid, sulfuric acid, acetic acid, or AA to improve water solubility and increase molecular weight
- phase II reactions are anabolic
The typical order of drug metabolism is phase I followed by phase II reactions but not always. What drug is the common exception?
Isoniazid (used to treat TB)
T/F: products of phase I drug metabolism reactions are generally more reactive and may be more toxic than the parent drugg
List the 3 common enzymes used in phase I drug metabolism reactions
Flavin-containing monooxygenases (FMO)
Epoxide hydrolases (mEH, sEH)
Where are phase I drug metabolism enzymes located?
In lipophilic ER membranes of the liver and other tissues
List the 5 phase II drug metabolism enzymes
TPMT: thiopurine methyltransferase
List the genetic factors the affect drug biotransformation
Polymorphism in xenobiotic-metabolizing enzymes
Pharmacogenetic differences in enzyme expression levels
List the non-genetic factors that effect the biotransformation of drugs
Age and sex
Liver size and function
Nutritional and environmental factors
List the well characterized drug inducers
- phenytoin (anticonvulsant)
- chronic ethanol (CYP2E1)
- Benzo[a]pyrene (tobacco smoke)
- Rifampin (anti-TB)
- phenobarbital and other barbiturates (used for sedation and anesthesia)
- St. John’s Wort
**These will all speed up the clearance of the drug so you will need a higher dose of the drug to get the same effect
T/F: Men have more CYP450 than women
False! Women have more CYP450 than men
How does grapefruit juice affect the clearance of a drug?
It increases the clearance time, therefore acting as an inhibitor to clearance
What is the effect of administering allopurinol and mercaptopurine together?
Allopurinol is used to treat gout and mercaptopurine is an immunosuppressive agent that utilizes xanthine oxidase that is inhibited by allopuriol, therefore causing inhibition of clearance.
Coadministration of the 2 prolongs duration of mercaptopurine action and enhances its chemotherapeutic and toxic effects
T/F: doses of mercaptopurine must be increased in pts receiving allopurinol
False! They must be reduced!
Explain acetaminophen-induced hepatotoxicity
- 95% of acetaminophen undergoes glucuronidation and sulfation with 5% biotransformed via CYP450s 2E1 & 3A4
- when acetaminophen intake exceeds therapeutic dose, hepatic GSH is depleted faster than regenerated causing toxic metabolites to accumulate resulting in hepatotoxicity
What is the function of CYP2D6?
Metabolizes basic drugs like beta blockers, antidepressants, antipsychotics and opioid analgesics
What is the most common nonfunction CYP2D6 allele and what population is it nearly absent in?
Nearly absent in Asians
What is the function of CYP2C19?
- metabolizes acidic drugs like proton pump inhibitors, antidepressants, antiepileptics and antiplatelet drugs
What is the most common nonfunctional CYP2C19 allele and which population is it most common in?
Most common in Asians
What CYP2C19 allele has increased function and what population is this most common in?
Rare in Asians but more frequent in Europeans and Africans
**increased fnx of this allele cant make up for a nonfunctional allele, so 17 with a nonfunctional allele would be IM phenotype
What is the function of Uridine 5’-Diphosphoglucuronosyl transferase 1 (UGT1A1)?
- conjugates glucuronic acid onto small lipophilic molecules
What is Gilbert’s syndrome?
- UGT1A1*28 allele decreased function polymorphism due to extra TA repeat in proximal promoter region
- affected pts may have 60-70% increased levels of circulating unconjugated bilirubin due to decreased UGT1A1 activity
What are pts with Gilbert’s syndrome at an increased risk for?
Adverse drug rxns with UGT1A1 drug substrates due to reduced biliary elimination
What is the function of Thiopurine-S-methyltransferase (TPMT)?
Covalently attaches a methyl group to an aromatic and heterocyclic sulfhydryl compounds and is responsible for pharmacologic deactivation of thiopurine drugs
Following exposure to what substances does G6PD activity increase to meet NADPH demands and prevent hemoglobin from oxidation?
Certain therapeutic drugs (sulfamethoxazole)
What is the function of the organic anion transporter (OATP1B1)?
Located in sinusoidal membrane (facing blood) of hepatocytes and is responsible fore the hepatic uptake of mainly weakly acidic drugs and endogenous compounds
Pts with decreased function of ______________ need lower dose of simvastatin to avoid myopathies
What is the function of BCRP (breast cancer resistant protein)?
It is an efflux ABC transporter located on epithelial cells of the kidney, liver, intestine and BBB
What population commonly has a low frequency variant of BCRP and what is this associated with?
Most common in Asian populations
Associated with changes in response to allopurinol (xanthine oxidase inhibitor) and rosuvastatin and toxicity to various anticancer drugs
What is the function of CYP2C9?
Phase I drug metabolizing enzyme that acts primarily on acidic drugs including S-warfarin, NSAIDs and phenytoin
Explain the characteristics of the CYP2C9*3 allele
AA change to Leu on interior of enzyme resulting in decreased affinity and decreased warfarin metabolism
Explain the characteristics of the CYP2C9*2 allele
AA change to cys on outer surface of enzyme impairing interaction with P450 oxidoreductase and leads to decreased warfarin metabolism
What is the effect of decreased VKORC1 expression?
Excessive anticoagulation with standard warfarin dose
What is the effect of decreased CYP2C9 function?
Increased risk of bleeding
Differentiate between minimum lethal dose (LDmin) and median lethal dose (LD50)
LDmin = smallest dose that is observed to kill any experimental animal under defined set of conditions
LD50 = dose that kills ~50% of animals
Explain phase 0 trials
- microdoses to human volunteers
- minimal preclinical safety testing
- can help find suitable drug candidates when in vitro & lab animal models are unreliable
- minimal cost
Explain phase I trials
- usually 1st stage of drug testing in humans
- n = 25-50 healthy volunteers
- Q = is it safe? Pharmacokinetics?
- open label
**If drug produces significant toxicity as in AIDs and cancer then diseased pts are used
Explain phase 2 trials
- single blind
- n = 100-200
- Q = does it work in pts?
- drug failure typically occurs during this phase when the drug is discovered to be toxic or not efficacious at approximate doses
Explain phase 3 trials
- crossover and double blind
- n= >1,000
- Q = does it work?
- goal = determine benefit-risk ratio
- most expensive phase
Explain phase 4 trials
- after approval to market the drug
- no fixed duration
- post-marketing surveillance
- can discover rare drug-induced effects or toxicities
What is an IND?
- submission of the IND is the means by which investigators technically obtain permission from the IDA to proceed with drug distribution
- each IND must contain precliniccal data from animal pharmacology and toxicology studies, manufacturing info, clinical protocols, investigator info
How do inhalational anesthetics and succinylcholine cause malignant hyperthermia?
Cause elevation of calcium in the sarcoplasm of muscle leads to muscle rigidity, elevation of body temp, rhabdomyolysis
What population most commonly has G6PD deficiency?
African american males
When is a new drug application submitted?
After phase 3 clinical trial is completed -> usually about 8-9 years after lead compound
Differentiate between endpoint and surrogate endpoint
Endpoint = measured to assess a drugs effect (ex. BP is the endpoint for testing an antihypertensive agent)
Surrogate endpoint = an outcome of therapy that predicts the real goal of therapy without being that goal (ex. Reduction. In tumor size as a surrogate for survival)