Biotransformation, clinical trials, etc. Flashcards
biotransformation
enzymatically-driven process whereby a substance is changed from one chemical to another by a chemical reaction; chemical modification of lipophilic, unionized, large compounds to terminate their actions and facilitate elimination
Prodrug
inactive drug that undergoes biotransformation to become an active drug
Sites of biotransformation
liver, kidneys, GI tract, lungs, skin, kidneys; enzymes in ER, mitochondria, cytosol, lysosomes, plasma membrane
First-pass effect
process by which drugs are absorbed in the small intestine and transported to the liver via the hepatic portal system, undergo extensive metabolism
Phase I reactions result in…
biological inactivation
Phase II reactions result in…
improved water solubility and increased molecular weight
What functional groups may be added to a drug to increase it’s polarity?
-OH, -NH2, -SH, -COOH, -O
Most common phase I reactions
oxidation, reduction, hydrolysis
Phase I reactions are carried out by what types of enzymes?
CYP450s, Flavin-containing monooxygenases, epoxide hydrolases
Conjugation of drugs is dependent on which endogenous substrates
glucuronic acid, sulfuric acid, acetic acid, amino acid
Five most important CYP450s
CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A4
How do P450s carry out their oxidation of substrates?
use O2 and H derived from NADPH
Biotransformation is dependent on what factors?
drug-drug interactions, age, sex, circadian rhythm, body temp, liver size and function, environment, genetics
A genetic defect in pseudocholinesterase causes what?
succinylcholine metabolism at 50% the rate of normal individuals
Slow acetylator phenotype results in…
decrease in N-acetyltransferase levels in the liver
What drugs may be metabolized more slowly as a result of the slow acetylator phenotype?
isoniazid, hydralazine, caffeine
Well-characterized enzyme inducers
phenytoin, chronic ethanol, benzo[a]pyrene, rifampin, phenobarbital and other barbituates
Grape juice effect on enzyme inhibition
Irreversibly inhibits intestinal CYP3A4, inhibits bioavailability of antihypertensives, immunosuppressant, antidepressants, antihistamines, and statins
Clinical use of allopurinol
gout, inhibits xanthine oxidase
Clinical use of mercaptopurine
immunosuppressive agent used for CA treatment; xanthine oxidase is an important enzyme for biotransformation
Interaction that can occur between mercaptopurine and allopurinol
coadministration prolongs the duration of mercaptopurine action and enhances it’s toxic effects
Speed of drug biotransformation throughout life time
slow in neonate, increases rapidly in postnatal period, heterogenous in elderly
What developmental issues may male the fetus or neonate more susceptible to drug toxicity?
Poorly developed blood brain barrier, weak biotransforming activity, immature excretion mechanisms
What are the most important factors to consider for decreased drug metabolism in the elderly?
Liver and kidney disease
Examples of drug levels that may rise due to cardiac disease and lower rates of elimination
beta blockers, isoniazid, lidocaine, morphine, verapamil
Examples of important detoxifying substrates
glutathione, glucuronic acid, sulfate
Pharmacogenetics
study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, 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
polymorphism
variation in DNA sequence
Single nucleotide polymorphism
base pair substitutions that occur in the genome
CYP2D6
involved in phase I biotransformation, highly polymorphic
Enzyme responsible for O-demethylation conversion of codeine into morphine
CYP2D6
Individuals with polymorphisms in CYP2D6 may experience what kinds of side effects when taking codeine
drowsiness, respiratory depression, insufficient pain relief
CYP2C19 metabolizes what drugs?
acidic; proton pump inhibitors, antidepressants, antiepileptics, antiplatelet
Clopidogrel clinical use
antiplatelet prodrug indicated to prevent atherothrombotic events
How is clopidogrel metabolized?
85% by hepatic esterases, 15% by CYP2C19
Carriers of CYP2C19 polymorphisms that take clopidogrel are at increased risk for…
adverse cardiovascular events
Uridine 5’-Diphosphoglucuronosyl Transferase 1 (UGT1A1)
conjugates glucuronic acid into small lipophilic molecules that can be excreted into bile
Irinotecan clinical use
topoisomerase I inhibitor, first-line chemotherapy
Irinotecan biotransformation
hydrolyzed by hepatic carboxylesterase enzymes to cytotoxic metabolite; SN-38 is the active metabolite
SN-38 is inactivated by what enzyme?
UGT1A1
Thiopurine S-Methyltransferase (TPMT)
attaches a methyl group onto aromatic and heterocyclic sulfhydryl compounds
Clinical uses of Azathioprine and 6-MP
treating immunologic disorders
Clinical uses of 6-MP and 6-TG
anticancer agents
Enzyme responsible for activation of 6-MP and 6-TG
HGPRTase
Enzymes responsible for inactivation of 6-MP and 6-TG
xanthine oxidase and TPMT
Glucose 6-phosphate dehydrogenase
first and rate-limiting step in pentose phosphate pathway, supplies NADPH in the body
Source of NADPH and reduced glutathione in RBCs
G6PD
What may cause an increase in G6PD activity in RBC?
decreased NADPH caused by infection, fava beans, and therapeutic drugs
G6PD deficiency is associated with increased risk for what
RBC destruction and hemolysis
Rasburicase clinical use
management of high uric acid levels in CA patients receiving chemotherapy
How does rasburicase alleviate the uric acid burden caused by tumor-lysing treatments?
converting uric acid to allantoin
Individuals taking rasburicase with a G6PD deficiency are at increased risk for what?
severe hemolytic anemia and methemoglobinemia
OATP1B1 transporter
responsible for hepatic uptake of mainly weak acid drugs and endogenous compounds such as statins, methotrexate, and bilirubin
HMG-CoA reductase inhibitors
statin, widely used to reduce serum lipids to prevent CV events
OATP1B1 genetic alteration that may cause simvastatin toxicity
rs4149056 in SLCO1B1
Two genes that effect warfarin
CYP2C9 and VKORC1
Drugs that CYP2C9 acts on
acidic drugs - warfarin, phenytoin, NSAIDs
CYP2C9 alleles commonly seen in European populations
CYP2C9*2 and *3
CYP2C9 alleles commonly seen in African populations
CYP2C9*5, *6, *8, and *11
Vitamin K epoxide reductase complex subunit 1
key enzyme in vitamin K recycling and important target for warfarin
Vitamin K is essential for activation of what cofactors?
II, VII, IX, and X; protein C and protein S
Important consequences of VKORC1 polymorphism
increased sensitivity to warfarin
When was the Food, Drug, and Cosmetic Act passed?
1938
Six approaches to drug discovery and development
- ID or elucidation of new target
- Rational drug design of new drug based on understanding of mechanisms and structures
- Chemical modification of a known molecule
- Screening for biologic activity of large numbers of natural products
- Biotech and using genes to produce proteins and peptides
- Combos of drugs known to obtain additive or synergistic effects
Lead Compound
chemical compound that has pharmacological or biological activity, whose chemical structure is used as a starting point to improve potency, selectivity, or pharmacokinetic parameters
Goals of in vitro and in vivo drug tests
ID potential human toxicities, design tests to define toxic mechanisms, predict specific and most relevant toxicities to be monitored
No-effect dose
maximum dose at which a specified toxic effect is not seen
Minimum lethal dose
smallest dose observed to kill any experimental animal under a defined set of conditions
Median lethal dose
dose that kills approx. 50% of animals
Purpose of clinical trials
test safety and efficacy of new drugs in humans
Crossover design
patients receiving each therapy in sequence so that patients serve as their own controls
Placebo effect
inert medicine or ineffective therapy alters a patient’s symptoms in some way
Single-blind design
only health professionals know ID of treatment
Double-blind design
patient nor health professional know therapy ID
Purpose of IRB
to assure appropriate steps are taken to protect rights, safety and welfare of humans participating in research
Phase 0 clinical trial
subpharmacological doses of drug are administered to volunteers
What kind of data may a phase 0 clinical trial provide?
early pharmacokinetic data on humans
Phase I clinical trial
first stage of drug testing in humans
Purpose of phase I clinical trial
observe whether or not there are significant differences between human and animal responses
Number of participants in phase I clinical trials
25-50
Phase II clinical trial
single-blind design with 100-200 patients
Data detected and recorded in phase II trials
efficacy, dosing requirements, toxicities
Phase II clinical trial goals
establish drug safety and efficacy in a larger group of patients (300-3,000)
New Drug Application
application submitted by manufacturer of a drug to FDA for license to market drug
Phase IV clinical trials
post marketing study to continue to monitor the safety of the drug
