Biotransformation, Pharmacogenomics, and Clinical Drug Trials Flashcards
What drugs do not undergo first-pass biotransformation?
Drugs given via parenteral routes of administration
Why is parenteral administration preferred for morphine?
Because oral bioavailability is roughly 25%
How can normal GI flora increase bioavailability of certain drugs such as estrogen used in contraception?
By increasing enterohepatic cycling of metabolites
What does phase I of biotransformation result in?
Phase II?
1) Biological inactivation of the drug by making it more polar
2) Produce a more hydrophilic metabolite with increased molecular weight to aid elimination
How do phase I products compare to the parent drug?
They are more reactive and may be more toxic
Where are Phase I enzymes located?
ER membranes of liver
Conjugation in phase II occurs at what rate compared to phase I reactions?
Significantly faster than phase I reactions
Which phase of biotransformation is catabolic?
Which is anabolic?
1) Phase I
2) Phase II
What are the key enzymes of phase I reactions?
CYP450
Which CYP450 is the most abundantly expressed and is involved in the metabolism of about half of clinically used drugs?
CYP3A4
P450s use molecular oxygen (O2) and H+, derived from what cofactor in order to carry out the oxidation of substrates?
NADPH
What is the most common enzyme of phase II reactions?
UGT
Individuals with genetic defects to what enzyme can only metabolize succinylcholine at 50% the rate as normal individuals?
Pseudocholinesterase
Individuals with slow acetylator phenotype have a decrease in levels of what enzyme, rather than a mutated form of the enzyme, in the liver?
N-acetyltransferase
As a result of slow acetylator phenotype, what are metabolized at slower rates and can lead to hepatotoxicity (hepatitis)?
1) Isoniazid (used to treat tuberculosis)
2) Hydralazine (used to treat hypertension)
3) Caffeine
Phenytoin (anticonvulsant), Chronic ethanol (CYP2E1), Benzo[a]pyrene (tobacco smoke), Rifampin (antituberculosis), and Phenobarbital all have what effect on CYP450?
Inducers
What effect does consumption of grapefruit juice with drugs taken orally cause?
Irreversibly inhibit intestinal CYP3A4 and alters the oral bioavailability of many classes of drugs
What effect does the coadministration of allopurinol with mercaptopurine have?
Prolongs the duration of mercaptopurine action and enhances its chemotherapeutic and toxic effects
How do the hepatic enzyme activity involved in drug biotransformation differ in age?
Low in the neonate, increases rapidly in the postnatal period, and is variable in elderly populations
Premature infants have decreased activity of what biotransformation step?
Conjugation
Hyperbilirubinemia in the newborn is due to the immature hepatic metabolic pathways, where newborns are unable to conjugate bilirubin with?
Because what enzyme is low?
What is a concern when levels become dangerously high?
1) UDP glucuronic acid
2) UDP glucuronosyl-transferase levels
3) Bilirubin-induced encephalopathy
What does it mean for drugs whose biotransformation is flow-limited?
Disease to what organ may cause specific drug levels to rise such as atenolol and propranolol, isoniazid, lidocaine, morphine, and verapamil?
1) The rate of elimination is dependent upon the rate of blood flow supplying the drug to the liver
2) Cardiac disease
When endogenous detoxifying cosubstrates such as glutathione, glucuronic acid, and sulfate are limited what occurs?
Organ toxicity or carcinogenesis
When acetaminophen intake exceeds therapeutic doses what pathways become saturated?
What enzyme is depleted faster than is regenerated?
Toxic metabolites accumulate resulting in what condition?
1) Glucuronidation and sulfation pathways
2) GSH
3) Hepatotoxicity
Variation in the DNA sequence that is present at an allele frequency of 1% or greater in a population is known as?
Polymorphism
Base-pair substitutions that occur in the genome describes what term?
Single nucleotide polymorphisms (SNPs)
The phase I enzyme responsible for the O-demethylation conversion of codeine into morphine is?
CYP2D6
CYP450 polymorphisms can cause phase I enzymes to become poor metabolizers which leads to an increased risk for?
Ones that are ultrafast metabolizers are at risk for?
1) Accumulation of toxic drug levels
2) Being undertreated
Genetic polymorphisms in what phase I gene causes a decrease in active metabolite formation and consequently reduce drug’s antiplatelet activity in response to clopidogrel?
CYP2C19
Inactivation of the metabolite SN-38 of the drug Irinotecan which causes increased risk for neutropenia and diarrhea, occurs via what phase II polymorphic enzyme?
UGT1A1
6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are important anticancer agents that may be inactivated by what polymorphic phase II enzyme?
TPMT
Individuals with G6PD deficiency receiving Rasburicase therapy are at greatly increased risk for severe hemolytic anemia and methemoglobinemia because?
G6PD is an important source for glutathione which is needed to reduce Rasburicase highly reactive oxidant, Hydrogen peroxide
Individuals are recommended to receive a lower simvastatin dose or an alternative statin due to what transporter dysfunction?
Reduced OATP1B1 function (at least one non functional allele)
What is a phase I drug-metabolizing enzyme that acts primarily on acidic drugs including S-warfarin, phenytoin, and NSAIDs?
CYP2C9
Much of the variability in metabolic clearance of CYP2C9 substrates may be accounted for which two well-studied alleles?
These alleles have what effect on CYP2C9 metabolism?
1) CYP2C9*2 and *3
2) Reduced metabolism
What is the target of anticoagulant warfarin and a key enzyme in the vitamin K recycling process?
Vitamin K epoxide reductase complex subunit 1 (VKORC1)
A polymorphism common across all major ethnicities results in reduced expression of VKORC1 in?
The most important consequences of the VKORC1 polymorphism are increased sensitivity to?
1) The liver
2) Warfarin
Polymorphism of what gene cause patients to be at increased risk for excessive anticoagulation following standard warfarin dosages?
Patients with reduced-function of what genotype are at increased risk for bleeding due to decreased metabolic clearance of the more potent S-warfarin enantiomer?
1) VKORC1
2) CYP2C9
How many phases must be conducted before the Food and Drug Administration (FDA) will approve the use of the new therapy (drug, device, or dose) in patients?
Three phases of clinical trials (I-III)
What is defined as a chemical compound that has pharmacological or biological activity and whose chemical structure is used as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters?
Lead compound
The maximum dose at which a specific toxic effect is not seen is known as?
No-effect dose
What is the no-effect dose lower than?
The threshold of harmful effect
What is the smallest dose that is observed to kill any experimental animal under a defined set of conditions?
Minimum lethal dose (LDmin)
What is the dose that kills approximately 50% of the animals?
Median lethal dose (LD50)
For statistical reasons, rare and adverse events that occur in humans are unlikely to be detected in?
Preclinical animal testing
What testing design consists of patients receiving each therapy in sequence so that the patients serve as their own controls?
A crossover design
In what type of study do only the health professionals know the identity of the treatment?
Single-blind study
In what type of study do neither the patient nor the health professional know the identity of the therapy?
Double-blinded study
What phase may be designed to investigate the safety, tolerability, pharmacokinetics, and the organ impact of a single dose of orally administered therapy?
Early clinical trials (phase I)
What phase may be designed to assess the proportion of patients in each treatment group who achieve treatment success after a set length of time?
Phase III trials
What is the application process before clinical trials of what is the means by which investigators technically obtain permission from the FDA to proceed with drug distribution?
Investigational new drug (IND)
Who has the authority to approve, require modifications in (to secure approval), or disapprove research?
Institutional review board (IRB)
Which phase of human clinical trial is a study whereby sub pharmacological doses of prospective drug candidates are administered to human volunteers?
Phase 0 (also termed microdosing)
Which phase clinical trial is conducted in order to determine whether humans and animals show significantly different responses to the investigational drug and to establish the probable limits of the safe clinical dosage range for roughly 25-50 people?
What data is reported?
1) Phase 1
2) Absorption, half-life, and metabolism
In phase I if the drug is expected to produce significant toxicity, as in the case with AIDS and cancer therapy, what type of volunteer patients are sought after?
Volunteers with disease rather than healthy volunteers
Which phase of clinical trial is performed with a larger group of patients that have the target disease to determine its efficacy (100-200 patients)?
It is typically set up in what design?
1) Phase II
2) Single-blind design
What is detected and recorded in phase II of clinical trials?
Efficacy, dosing requirements, and toxicities
Drug failure typically occurs during which phase of clinical trials?
Phase II trials
Which phase of clinical trial is conducted after preliminary studies evaluating the effectiveness, dose, and toxicities of the experimental drug are completed (with successful outcomes) to further establish drug safety and efficacy a large group of patients (300-3,000)?
What designs are often used to minimize errors caused by the placebo effect, variable course of the disease, subject and observer bias, and the presence of other diseases and risk factors?
1) Phase III
2) The crossover and double-blind design
What is defined by the FDA as “an application submitted by the manufacturer of a drug to the FDA (after clinical trials have been completed) for a license to market the drug for a specified indication.”?
New drug application (NDA)
In exceptional situations, the FDA may grant approval of a drug for serious diseases while still in which phase?
For life-threatening diseases, approval may be granted during which phase?
1) Phase III trials
2) Phase II trials
Which phase in clinical trials is a post-marketing study with the purpose to continue to monitor the safety of the new drug under actual conditions of use in large numbers of patients?
Phase IV
The post-marketing feedback provided in phase IV trials are essential for new drugs with side effects that occur with an incidence of?
1 in 10,000 patients
What term is used when both health professionals and patient know whether the drug is experimental or control agent?
Open label
What term is used when at least two regimens are tested simultaneously but patients are assigned to only one therapy?
Parallel trial
What term is used to assess a drug’s intended effect?
Endpoint
What term is used for an outcome of therapy that predicts the real goal of therapy without being that goal?
Surrogate endpoint
An individual with hemolytic anemia most likely has a polymorphism in?
This patient’s hemolysis is most likely due to a reduction in?
1) G6PD
2) NADPH
What happens to a patient with G6PD deficiency that takes sulfamethoxazole?
RBC hemolysis
