Clinical Trials, Biotransformation, Pharmacogenomics Flashcards
A ____ is an inactive drug that undergoes biotransformation to become an active drug. This mostly occurs in the ____ at some point between absorption and general circulation
Prodrug; liver
As a general rule:
_____ reactions result in biological inactivation of the drug and are catabolic
_____ reactions produce a metabolite with improved water solubility and increased molecular weight (enhances elimination); anabolic
Phase I
Phase II
Phase I enzymes are located in the lipophilic ____membranes of the liver and other tissues
ER
What are some well characterized inducers of CYP450 enzymes?
Phenytoin (anticonvulsant) Phenobarbital Chronic ethanol (CYP2E1) Aromatic hydrocarbons (benzoapyrene) - tobacco Rifampin (anti-Tb) St. Johns wort
Well known inhibitor of CYP450
Grapefruit juice (consumption can irreversibly inhibit intestinal CYP3A4)
Mercaptopurine (coadministration with allopurinol prolongs the duration of mercaptopurine action and enhances its chemotherapeutic and toxic effects)
How can acetaminophen lead to hepatotoxicity
When acetaminophen intake exceeds therapeutic doses: glucuronidation and sulfation pathways are saturated and P450 pathways become increasingly important
Over time, hepatic GSH is depleted faster than it is regenerated. Toxic metabolites accumulate resulting in hepatotoxicity
Alcohol consumption has similar effect
Most common disease-producing enzyme defect of humans
G6PD deficiency
Ryanodine receptor mutations may cause a reaction to inhalational anesthetics and succinylcholine having what effect?
Elevation of calcium in sarcoplasm of muscle leads to muscle rigidity, elevation of body temp, and rhabdomyelosis
[malignant hypothermia]
What type of test usually involves 2 species, 2 routes, determines the no-effect dose and the maximum tolerated dose
Acute toxicity
What type of test involves 3 doses and 2 species, allowing 2 weeks to 3 months of testing before clinical trial in order to determine biochemical and physiologic effects
Subacute or subchronic toxicity test
What type of test involves rodent and nonrodent species for at least 6 months and is required when a drug is intended to be used in humans for prolonged periods?
Can this be run concurrently with clinical trials?
Chronic toxicity; usually run concurrently with clinical trials
Describe testing for carcinogenic potential
2 years, 2 species; required when drug is intended to be used in humans for prolonged periods; determines gross and histologic pathology
Describe testing for mutagenic potential
Test effects on genetic stability and mutations in bacteria (ames test) or mammalian cells in culture; dominant lethal tesst and clastogenicity in mice
Describe testing for investigative toxicology
Determine sequence of mechanisms of toxic action. Discover genes, proteins, paths involved; develop new methods for assessing toxicity
Most abundantly expressed CYP450 enzyme, involved in metabolism of about 50% of clinically used drugs
CYP3A4
Individuals with genetic defects in pseudocholinesterase can metabolize ____ at 50% the rate as normal individuals
Succinylcholine
Individuals with the AR ____ ____ phenotype have a decrease in N-acetyltransferase levels in the liver
What is the result?
Slow acetylator
As a result, isoniazid, hydralazine, caffeine, and other amines are metabolized at slower rates which can lead to hepatotoxicity
For drugs whose biotransformation is flow-limited, cardiac disease may cause specific drug levels to rise
What are some drugs in which this is the case?
Atenolol and propranalol
Isoniazid
Lidocaine
Morphine
Verapamil
Enzyme responsible for O-demethylation conversion of codeine into morphine to produce desired analgesic effect
Thus polymorphisms in this gene cause pt to experience insufficient pain relief, due to higher systemic concentrations of morphine
CYP2D6
[involved in metabolism of up to 1/4 of all drugs used clinically, including predominantly basic compounds such as beta blockers, antidepressants, antipsychotics, and opioid analgesics]
Enzyme responsible for conversion of clopidogrel to the active thiol metabolite responsible for antiplatelet activity
Thus when polymorphisms are present = decrease active metabolite formation and consequently reduce drug antiplatelet activity
CYP2C19
[known to preferentially metabolize acidic drugs including PPIs, antidepressants, antiepileptics, and antiplatelet drugs)
Complete or partial deficiency of this enzyme can lead to dramatically reduced clearance of 5-FU, increased levels of toxic metabolites 5-FUMP and 5-FdUMP, and consequently an increased risk for severe dose-dependent fluoropyrimidine-based chemo
DPD, encoded by DPYD gene
[RL step in pyrimidine catabolism and major elimination route for fluoropyrimidine chemotherapy]
This is a phase I enzyme
Phase II enzyme that when deficient can lead to increased risk of severe life-threatening toxicities — neutropenia, and diarrhea — due to decreased clearance of SN-38 (cytotoxic metabolite of irinotecan chemotherapeutic agent)
UGT1A1
Enzyme involved in phase II metabolism of azathioprine, 6-MP, and 6-TG such that polymorphisms may increase risk of exposure to cytotoxic 6-TGN metabolites and thiopurine-related toxicities
TPMT
Individuals with _____ enzyme deficiency receiving rasburicase therapy are at greatly increased risk for severe hemolytic anemia and methemoglobinemia
G6PD
