Types of drugs that are eliminated through renal excretion:
polar compounds or compounds with small molecular volumes
What drug route does not undergo first pass effect
parenteral route administrated drugs: non-oral drugs
Phase I vs Phase II reactions result in?
phase 1 results in biological inactivation of the drug while phase II reactions produce a metabolite with improved water solubility and increased molecular weight.
Phase I reaction types
more common is oxidation, reduction, and hydrolysis
less common includes hydroxylation, epoxidation, dealkylation, deamination, desulfuration, dechlorination
Enzymes that carry out phase I reactions
Cytochrome P450s, Flavin-containing monooxygenases, epoxide hydrolases
where are phase I enzymes located?
phase I products vs parent drug?
phase I enzymes are located in the lipophlic ER membranes of the liver
products are generally more reactive and may be more toxic than the parent drug
Phase II rxns
-characteristics of drug conjugates produced
-conjugation dependent on which endogenous substrates?
-rate of conjugation vs phase I rxns?
-drug conjugates are polar molecules w/ higher molecular weight that are readily excreated and often inactive compared to their precursors
-dependent upon endogenous substrates such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid
-conjugation occurs at faster rates than phase I
Most important CYPs:
-which is the most common?
CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A4
CYP3A4 is the most abundantly expressed
how does a CYP work?
-use molecular oxygen (O2) and H+ derived from what?
-use O2 and H derived from the cofactor reduced nicotinamide adenine dinuleotide phosphate (NADPH) to carry out the oxidation of substrates
Genetic defect in pseudocholiesterase causes?
that individual to metabolize SUCCx at 50% of normal
Slow acetylator phenotype:
-have decrease what levels?
-what types of drugs metabolized slower?
-what populations is this common in?
-AR trait leads to decrease in N-acetyltransferase levels
-isoniazid (TB drug), hydralazine (HTN), caffeine, other amines, metabolized slower and can lead to hepatotoxicity (hepatitis)
-phenotype occurs in about 50% of US population, 83% Frenchies, less common in Asians
phenytoin, chronic ETOH (CYP2E1), aromoatic hydrocarbons like benzo[a]pyrene, rifampin, phenobarbital, other barbituates
newborns have trouble metabolizing hemoglobin why?
immature hepatic metabolic pathways--> newborns unable to conjugate bilirubin with UDP glucuronic acid and bilirubin is unable to be excreted
study of the entire genome to assess multigenetic determinants of drug response
Define Single Nucleotide Polymorphism
variation in DNA sequence that is present at an allele frequency of 1% or greater in a population
-MOA of G6PD
-deficiency leads to?
MOA: G6PD produces NADPH which regenerates glutathione from its oxidized form
-reduced glutathione protects cells against oxidative stress/damage, so without it oxidative damage leads to hemolytic anemia in the presence of oxidants
-what does it do?
-what mutation associated w/ reduced membrane expression?
-pts w/ this defect can suffer from _ induced myopathy
-organic Anion Transporter (OATP1B1) responsible for hepatic uptake of weak acidic drugs
-Val74Ala mutation is associated w/ reduced membrane expression-->reduced trafficking
-pts with this mutation suffer from Simvastatin-induced myopathy
Enzyme responsible for converting codeine to morphine
Enzyme responsible for activation of Clopidogrel
decreased activity of the drug causing increased risk for adverse CV events. specifically the CYP2C19*2 gene
N-acetyltransferase genetic variation:
-causes problems w/ which drug
causes hepatitis w/ isoniazid
-responsible for deactivation of?
responsible for deactivation of thiopurine drugs, 6-mercaptopurine can cause defects in TPMT fxn
-responsible for ?
-mutations lead to?
conjugates glucuronic acid so it can be excreted into bile
UGT1A1-28 mutations lead to increased risk of adverse drug rxns due to reduced biliary elimination
Variations associated w/ altered response to warfarin therapy
-VKORC1 results in increased sensitivity to warfarin/ increased bleeding
-CYP2C9 polymorphism results in decreased metabolic clearance of S-Warfarin leading to increased anticoagulation and bleeding
What is a lead compound?
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, and phamacokinetic parameters.
maximum dose at which a specified toxic effect is not seen, just lower than the threshold of harmful effects
In vitro cell based study vs in vivo
in vitro--> lead compounds tested in mammalian cells to see which proteins the drug binds to and/or which pathways it may inhibit or upregulate
in vivo--> drugs tested in mammalian subjects, animals first and then humans
goals of preclinical testing:
-identify potential human toxicities without human testing
-design tests to further define the toxic mechanisms
-predict the specific and most relevant toxicities to be monitored in clinical trials
Limitations of preclinical testing
-time and cost--> could take 2-6 years
-number of animals used--> cost of mice
-extrapolation of values--> not all toxicities directly translate to humans from animals
-rare and adverse events are unlikely to be detected in preclinical animal testing
Caveats in human testing
-variable natural history and proggression of disease (diseases can increase and decrease in severity over time or spontaneously disappear)
-presence of other diseases and risk factors (other drug use can affect results)
-subject and observer bias
neither the patient nor the physician knows the identity of the therapy the pt is receiving
only the health professional knows the identity of the therapy the pt is receiving
both the patient and health professional know the identity of the therapy the pt is receiving
a study where one group of pts receives only treatment A and the other group of pts receives only treatment B
pts receive each therapy in sequence so that the pts serve as their own controls
Endpoint vs surrogate endpoint
endpoint: the primary outcome measure
surrogate endpoint: an endpoint that may correlate with the "real" endpoint but does not necessarily have a guaranteed relationship.
Phases of clinical trials
phase 0, phase 1
0: subpharmacological doses of prospective drug candidates are administered to human colunteers--> provides early pharmacokinetic data in humans
1: conducted to determine whether humans and animals show different responses to the investigational drug and establish approximate limits on the safe dosage range
phases of clinical trials
performed on large groups (100-200) that have the target disease to determine its efficacy, dosing requriements, and toxicities
phases of clinical trials
only occurs after approval of a drug to go to market
post marketing study to continue to monitor safety and efficacy of the drug
Investigational new drug:
an application that must be approved before the drug is transported across state lines
-must contain preclinical data from animal pharmacology and toxicology studies, manufacturing info, clinical protocols, and investigator info
institutional review board:
-what does it assure
assures appropriate steps are taken to protect the rights, safety, and welfare of humans participating as subjects in the research.
new drug application:
an application filed with the FDA by a manufacturer of a drug for a license to market the drug for a specific indication.