Term
| Gene Expression Profiling of Radiation-induced Tumorigenic Mammary Epithelial Cells |
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Definition
Forensic Toxiciology-poison
Clinical Toxicology- ER setting
Environmental Toxicology
Ecotoxicology- Toxcity to animals rather than humans
Developmental Toxicology
Teratology- birth defects
Reproductive Toxicology- what makes humans sterile |
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Definition
| Anthropogenic origin- Man made |
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Term
| Fate of Toxicants in the Body |
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Definition
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Term
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Definition
Degradation and elimination of a chemical can decrease the magnitude and duration of a chemical exposure.
The half life is the time it takes to remove half of the chemical from the bloodstream. |
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Term
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Definition
Frequency of administration
Dose
Recovery Time
-The longer the half life it will stay in the body longer.
-The shorter half life will be excreted early. |
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Term
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Definition
| the passage of a drug from its site of administration into the circulation |
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Term
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Definition
| Anything that goes outside the intestine |
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Term
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Definition
| Anything that goes through the intestine |
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Term
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Definition
IV
Inhalation
IP
SC
IM
Intradermal
Oral
Dermal |
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Term
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Definition
The proportion of the drug in a dosage form available to the body
i.v injection gives 100% bioavailability b/c everything is given at the same time |
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Term
| Factors affecting oral availability |
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Definition
Disintegration of dosage form-how quickly does it break apart
Dissolution of particles
Chemical stability of drug- how well the drug hold up on the shelf or pH
Stability of drug to enzymes
Motility and mixing in GI tract
Presence and type of food- Carbs, Fat
Passage across GI tract wall
Blood flow to GI tract
Gastric emptying time- Metabolism
FORMULATION |
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Term
| Tablets and Oral bioavailability |
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Definition
dissociation is the rate limiting step (how quickly it breaks apart)
drugs are often better as salts than acids/bases |
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Term
| Ways to increase surface area on Small Intestine |
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Definition
| Villi, microvilli, and folds of kirkring |
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Term
| Spectrum of Undesired effects |
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Definition
Allergic Reactions
Idiosyncratic reactions-new drug in system
Immediate versus delayed toxicity
Reversible versus irreversible toxics effects
Reversible- able to fix itself
Local versus systemic toxicity
Tolerance- Give the same does response goes down |
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Term
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Definition
2+3=5
When teo drugs are added and the response increases |
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Term
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Definition
| when two compounds mix they exhibit a large response |
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Term
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Definition
| when one compound has no response until it is mixed with another and the response is drastic |
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Term
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Definition
| one compound decreases the reactivity of another compound |
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Term
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Definition
Functional
Opposite effects on the same physiologic function
2 compounds acting on different receptors elicit opposing responses
Chemical
Effect is from a chemical reaction, not receptor mediated
Ex: Chelators of metals
Dispositional
Interferes with the ADME of the compound
Receptor
Blockers
Two objects cannot occupy the same space at the same time |
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Term
| graded dose response curve |
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Definition
A DR increase in the severity of a response at the individual level.
If the # of mortalities at each dose is reduced by the # in each previous dose, we get a mortality frequency distribution.
Quantal DRs usually exhibit a normal or gaussian distribution.
Biological variation causes the differences in sensitivity.
Animals at the low end: Hypersusceptable
Animals at the high end: Resistant |
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Term
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Definition
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Term
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Definition
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Term
| Assumptions made in DR relationships |
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Definition
The response is due to the chemical administered.
Common in epidemiologic studies where there is an association btwn a response and one or more exposures.
The magnitude of the response is related to the dose.
There is a molecular target site w which the chemical interacts.
Response is related to chemical [] at the site.
The chemical [] at the site is related to the dose.
The is a means of measuring and expressing the toxicity.
For most compounds, there is a family DR relationships w varying pertinence to the animal’s health.
An endpoint should be chosen that is relevant to the toxic effects
Outright toxicity or mechanistic indicators (biomarkers) |
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Term
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Definition
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Term
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Definition
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Term
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Definition
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Term
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Definition
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Term
| WHat does it mean when the ED, TD, LD, TI lines are really close? |
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Definition
| THe more toxic the drug is |
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Term
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Definition
The response is due to the chemical administered.
Common in epidemiologic studies where there is an association btwn a response and one or more exposures.
The magnitude of the response is related to the dose.
There is a molecular target site w which the chemical interacts.
Response is related to chemical [] at the site.
The chemical [] at the site is related to the dose.
The is a means of measuring and expressing the toxicity.
For most compounds, there is a family DR relationships w varying pertinence to the animal’s health.
An endpoint should be chosen that is relevant to the toxic effects
Outright toxicity or mechanistic indicators (biomarkers) |
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Term
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Definition
Non-nutritional toxicants impart beneficial or stimulatory effects at low doses, but adverse effects at higher doses.
Example: Ethanol |
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Term
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Definition
| relationship between the the dose of a drug and the therapeutic effect. It refers to the drug's strength. A drug is considered potent when a small amount of the drug achieves the intended effect. |
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Term
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Definition
| ability of a drug to produce the desired therapeutic effect. Efficacy means that the drug is effective |
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Term
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Definition
To understand
how a toxicant enters a cell/tissue
Distribution
how it interacts with target molecules
What is the response
how the organism deal with the insult
Methods of detoxification |
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Term
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Definition
Step 1- Delivery:from the site of exposure to the target
Step 2a- Reaction of the toxicant with the target molecule
Step 2b- Alteration of biological environment
Step 3- Cellular dysfunction, injury
Step 4- Inappropriate repair or adaptation |
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Term
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Definition
chemical species that reacts
with the endogenous target molecule or critically
alters the biological environment, initiating structural
and /or functional alteration that result in toxicity.
Toxicity depends on the [ ] (dose) of the ultimate toxicant at
the target site.
Parent compound
Metabolites of parent compounds
Reactive oxygen or nitrogen species
Endogenous molecules |
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Term
| Influencing factors for absorption |
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Definition
Rate: concentration, SA, microcirculatiocon, solubility
Epithelial barriers |
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Term
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Definition
Usually for chemicals absorbed from GI tract
first pass through liver
AKA: First-pass elimination
AKA : First-pass effect |
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Term
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Definition
Endothelium porosity
Specialized transport
Reversible intracellular binding |
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Term
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Definition
Plasma proteins
Special barriers
Storage sites
Non-target binding
export |
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Term
| Porosity of the capillary endothelium |
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Definition
in the hepatic sinusoids
in the renal peritubular capillaries |
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Term
| Specialized transport across the plasma membrane |
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Definition
ion channels
protein transporters
endocytosis: toxicant-protein complex
membrane recycling |
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Term
| Accumulation in cell organelles (lysosomes and mitochondria) |
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Definition
amphipathic xenobiotics with a protonable amino group
and lipophilic character |
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Term
| Reversible intracellular binding |
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Definition
organic and inorganic cations and PAH bind /release to
melanin (polyanionic aromatic polymer) |
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Term
| Mechanisms opposing distribution to a target |
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Definition
Binding to plasma protein
DDT and TCDD are bound to high M.W. protein
or lipoprotein
Specialized barriers (for hydrophilic toxicants)
blood-brain barrier
reproductive cells
Distribution to storage sites (where they do not exert effects)
Association with intracellular binding proteins
metallothionein
Export from cells by ATP dependent transports
multidrug-resistance protein (P-glycoprotein)
in brain cappilary endothelial cell, oocyte
stem cell, and tumor cell |
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Term
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Definition
Kidney and Liver
Filtration
Acitve Transport
Hydrophilicity vs hydrophobicity
Reabsorption
Diffusion
pH and weak acids and bases |
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Term
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Definition
Hydrophilic, ionized chemicals
Renal glomeruli-hydrostatically filter
Proximal renal tubular cells-active transport
Hepatocyte
Nonvolatile, highly lipophilic chemicals
Excretion by the mammary gland
Excretion in bile salts
Intestinal excretion
Volatile, nonreactive toxicant
Pulmonary capillaries into the alveoli |
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Term
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Definition
Renal tubule
diffusion-lipid solubility, ionization (pH)
carriers and transporters-
Ex: peptide transporter sulfate transporter
Ex: phosphate transporter (arsenate)
Intestinal mucosa
Secretion by salivary glands and exocrine pancreas
Lipid solubility |
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Term
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Definition
Biotransformation that results in harmful product.
AKA: Metabolic activation
AKA: Bioactivation |
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Term
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Definition
1. Electrophiles
molecules containing an electron-deficient atom with
partial or full positive charge
insertion of an oxygen atom
conjugated double bonds are formed
Heterolytic bond cleavage, C-O
2. Free radials
accept an electron from reductases
losing an electron and form free radical by peroxidase
(CCl4 CCl3. , HO., Fenton reaction)
3. Nucleophiles (relatively uncommon)
HCN from amygdalin, CO
4. Redox-active reactants |
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Term
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Definition
Biotransformation that eliminates the toxicant
Or prevents its formation
Mechanisms:
Toxicant w/out functional groups: 2 phases of metabolism that increase molecular polarity (see Ch6)
Nucleophiles and electrophiles
Free radicals: SOD & Catalase
Protein toxins: protesases, antibodies
No functional groups
1st add a functional group (OH,COO) by CYP450
2nd then conjugation
Nucleophiles
Conjugation at the nucleophilic functional group (OH, SH)
Electrophiles (Metal ion, etc)
Conjugated with glutathione
specific mechanism:
epoxide hydrolase-epoxidediols, arene dihydrodiols
alcohol dehydrogenase |
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Term
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Definition
Tripeptide:
Glutamate-Cysteine-Glycine
Thiol groups are reducing agents
5mM (IC) |
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Term
Tripeptide:
Glutamate-Cysteine-Glycine
Thiol groups are reducing agents
5mM (IC) |
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Definition
Require Zn2+ and Cu+ (in Euk)
Commercially available purified from the bovine erythrocytes |
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Term
| Free radicals are detox’d by: |
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Definition
superoxide dismutase (SOD)
Requires NADPH
Glutathione
-tocopherol (Vitamin E= anitoxidant)
ascorbic acid (Vitamin A=antioxidant)
glutathione
Protein are detox’d by proteases. |
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Term
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Definition
Toxicants may overwhelm detoxication process
exhaustion of the detoxication enzymes
consumption of the cosubstrates
depletion of cellular antioxidants
Toxicant inactivates a detoxicating enzyme
ONOO-incapacitates SOD
Some conjugation reactions reversed
Sometimes detoxication generates potentially harmful
byproducts
ex. glutathione thiyl radical (GS.)
glutathione disulfide (GSSG) |
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Term
| Types of reactions with target molecules |
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Definition
Noncovalent binding
Hydrogen bond, ionic bond
ex. Interaction of toxicants with receptors, ion channels,
and some enzymes
Covalent binding
covalent adduct formation
Hydrogen abstraction
R-SH, RSOH
Electron transfer
enzymatic reactions |
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Term
| Outcomes/ Effects on Targets |
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Definition
Dysfunction (by mimicking ligands)
Enzymes: active site, conformational change
Neurotransmitters
Ion Transporters
DNA: template interference for replication/transcription
Destruction:
Cross-linking of proteins
Fragmentation: proteins and nucleic acids
Neoantigen formation |
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Term
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Definition
Definition: Interruption of cellular coordinated activity involving “long term” and “short term” cell programs.
Regulatory networks
Gene expression
Transcription
Signal Transduction
Signal Production |
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Term
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Definition
Ongoing cell activity of specialized cells
Interference with 2nd messengers
Electrically excitable cells (neurons, muscle)
Dysregulation of transcription
Promoter region of the gene
Transcription factors (TFs)
altering the regulatory region of the genes
direct chemical interaction
FYI Ex: thalidomide/Gcbox methylation of cytosine |
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Term
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Definition
Toxic alteration of cellular maintenance
Impairment of internal cellular maintenance:
mechanism of cell death
1. Ca accumulation (Table 3-3)
2. ATP depletion (Table 3-2)
3. ROS/RNS generation |
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Term
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Definition
Depletion of energy reserve
ATP consumption by the Ca2+ -ATPase
eliminate the excess Ca2+
ER needs Ca2+
IC Ca2+ causes the ER to leak Ca2+
Na+/Ca2+ pump gets activated
Dissipates mitochondrial membrane potential
Cell can’t make ATP because it shuts down mitochondria
2. Dysfunction of microfilaments
dissociation of actin filaments from anchor proteins
membrane blebbing
Rupture
3. Activation of hydrolytic enzymes
calpains (protesases)
phospholipases (↑ IC FFAs)
Ca2+ -Mg2+ dependent endonuclease
4. Generation of ROS and RNS
inactivate dehydrogenases in
TCA ↑activity of e-
transport O2●- radical |
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Term
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Definition
Proteins
Thiol Group re-oxidated (NADPH dependent)
Heat shock proteins aid in protein denaturation
Damaged proteins are refolded or Ub.
Lysosomes also aid in proteolysis and elimination of damaged proteins.
Lipids
Also NADPH dependent
Proteins
Thiol Group re-oxidated (NADPH dependent)
Heat shock proteins aid in protein denaturation
Damaged proteins are refolded or Ub.
Lysosomes also aid in proteolysis and elimination of damaged proteins.
Lipids
Also NADPH dependent |
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Term
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Definition
Apoptosis: an active deletion of damaged cells
Proliferation: regeneration of tissue, replacing cells
Side reactions to tissue injury |
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Term
| Cellular repair: A strategy in peripheral neurons |
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Definition
Macrophages 1- remove debris
2- produce cytokine and growth factors- aid in the removal of cells
Schwann cells- proliferate & transdifferentiate from myelinating operation mode into a growth-supporting mode
synthesis of cell adhension molecules (N-CAM)
Elaborating ECM protein for base
membrane construction
Producing neurotrophic factors and their receptors
Comigrating with the regrowing axon, physically guide
and chemically lure the axon to reinnervate the target cell |
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Term
| Proliferation : Regeneration of tissue |
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Definition
Replacement of lost cells by mitosis.
After injury, intracellular signaling turns on:
Activation of protein kinase and TF
Immediately early genes-transcription factors and cytokine-like secreted protein
Delayed early genes-antiapoptotic protein
Cell cycle accelerators (cyclin D)
Cell cycle decelerators (p53, p21)
Mediators of tissue repair and side reactions
Replacement of the extracellular matrix
Proteins, glycosamineoglycans, glycoprotein and proteoglycan glycoconjugates
Matrix metalloproteinase |
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Term
| Side Reactions to Tissue Injury |
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Definition
Inflammation
Cells and mediators
tissue damage resident M secreting cytokines endothelial cells and fibroblasts release mediator
Alteration of the microcirculation
Accumulation of inflammatory cells (leukocyte)
Chemoattractant
ICAM on endothelial cells
Production of ROS and NOS
M and leukocytes |
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Term
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Definition
1. Adaptation by decreasing delivery to the target
-Induction of ferritin and metallothionein
-Induction of detoxication
2. Adaptation by decreasing the target density or responsiveness
-induction of opioid tolerance
3. Adaptation by increasing repair
-induction of enzymes repairing oxidized proteins (Fig 3-23)
-induction of chaperones repairing misfolded proteins
heatshock response, ER stress response
-induction of enzymes repairing DNA (p53)
-adaptive increase in tissue repair (NF-κB) |
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Term
| Toxicity resulting from dysrepair |
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Definition
Tissue Necrosis
Fibrosis-excessive disposition of an extracellular
matrix of abnormal composition
Carcinogenesis
Failure of DNA repair: mutation, the initiating event in carcinogenesis
Failure of apoptosis:promotion of mutation and clonal growth
Failue to terminate proliferation:promotion of mutation, protooncogene overexpression, and clonal growth
Nongenotoxic carcinogens:promotors of mitosis and inhibitors of apoptosis |
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Term
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Definition
The disposition of a xenobiotic is defined as the composition actions of its absorption, distribution, biotransformation and elimination.
Pharmaco- or Toxico- Kinetics: the quantitative characterization of xenobiotic disposition.
Simply: what the drug does to the body
Dynamics: what the body does to the drug (metabolism and excretion)
Dose makes the poison, but dose does not determine toxicity. Based on LD50
Target organ (or target tissue): site where chemical interacts
Different systems are subject to different concentrations. |
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Term
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Definition
Compound must rapidly and readily distribute between the plasma and other body tissues.
Only Vd matters
Elimination must be Zero-Order
Ex: aminoglycosides |
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Term
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Definition
Compound slowly equilibrates with tissues.
Assume:
Mixing occurs between the two compartments
Mixing is instaneous within a given compartment
Ex: Vancomycin |
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Term
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Definition
Passive Transport
Simple Diffusion
Small hydrophilic: Paracellular diffusion
Lipophilic: diffuse bilayer
Filtration
Porous membrane
Special Transport
Active Transport
Facilitated Diffusion
Additional Transport Processes |
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Term
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Definition
Gases and Vapors
Aerosols and Particles
VOCs: safe or not?
Diffusion will occur from blood-tissue until equilibrium is reached. |
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Term
| Absorption of by the Skin |
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Definition
Impermeable (multiple layers)
Influenced by:
Hydration, Vehicle and Species
Stratum Coneum: uppermost layer of epidermis- Most important
Keratinized
Not nucleated (biologically inactive)
All compounds transverse by passive diffusion,no active transporters |
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Term
| Special Routes of Administration |
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Definition
Intraperitoneal (rapidly absorbed)
Primarily through the liver: First pass effect
Subcutaneous (Slow)_under the skin
Intramuscular (Slow)
Intravenous (direct) |
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Term
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Definition
< permeable than other sites in the body
Capillary endothelial cells of CNS are tightly joined
Cells have ATP dependent transporter multi-drug resistant protein
Cells surrounded by glial cell processes
Protein [] in the interstitial fluid of CNS is lower than that in other body fluids |
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Term
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Definition
Two determinates:
Lipid solubility
Higher lipophilicity = better absorbed
Ionization
Higher ionization = less absorption |
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Term
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Definition
Functions of the Placenta
Protection
Provide nutrition
Exchange of blood gases |
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Term
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Definition
Toxicants are removed from the systemic circulation by biotransformation, excretion, and storage at various sites in the body.
Excretion: the removal of xenobiotics from the blood and their return to the external environment via urine, feces, or exhalation. |
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Term
| Factors Influencing Metabolism |
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Definition
Age
Nutrition
Time of Day/Season
Immune Health
Hormonal
Pregnancy
Gender
Disease
Genetic |
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Term
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Definition
hydrolysis
reduction
oxidation
These reactions introduce functional group (—OH, —NH2, —SH, or —COOH)
Usually result in a small increase of hydrophilic properties |
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Term
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Definition
glucuronation,
sulfation,
acetylation,
methylation,
conjugation with glutathione,
conjugation with aminoacids (glycine, taurine, glutamic acid)
Phase II results in the marked increase of hydrophilic properties of xenobiotic. |
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Term
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Definition
Biotransformation by liver or gut enzymes before compound reaches systemic circulation
Results in lower systemic bioavailability of parent compound
Examples: isoniazid, propanolol |
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Term
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Definition
Microsomal enzyme ranking first among Phase I enzymes with respect to catalytic versatility and substrate number
Heme-containing proteins
Complex formed between Fe2+ and CO
Overall reaction proceeds by catalytic cycle:
** R+O2+NADPH RO+H2O+NADP+ |
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Term
| Cytochrome P450 reactions |
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Definition
Converts Amines to hydroxylamines
Cleavage of esters
Cleavage of functional group, with O incorporated into leaving group
Dehydrogenation
Abstraction of 2 H’s with formation of C=C
Activation of APAP to hepatotoxic NAPQI |
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Term
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Definition
Gene family, subfamily names based on amino acid sequences
27 families
300+ variants
60+ different chemical rxns catalyzed
Variation in levels, activity due to:
Genetic polymorphism
Environmental factors: inducers, inhibitors, disease
Multiple P450’s can catalyze same reaction (lowest Km is predominant)
A single P450 can catalyze multiple pathways |
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Term
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Definition
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Term
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Definition
Carboxyesterases & peptidases
hydrolysis of esters
ex: valacyclovir, midodrine
hydrolysis of peptide bonds
ex: insulin (peptide)
Epoxide hydrolase
H2O added to expoxides
ex: carbamazepine
Cholinesterases
Decreased activity potentiates organophosphate toxicity
Serine esterase Inhibitors are protective
Ex: Pyridostigmine |
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Term
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Definition
Azo reduction
N=N to 2 -NH2 groups
ex: prontosil to sulfanilamide
Nitro reduction
N=O to one -NH2 group
Quinone reduction
Cytosolic flavoprotein NAD(P)H quinone oxidoreductase
two-electron reduction, no oxidative stress
Flavoprotein P450-reductase
one-electron reduction, produces superoxide ions
metabolic activation of paraquat, doxorubicin
Dehalogenation
Reductive (H replaces X)
Enhances CCl4 toxicity by forming free radicals
Oxidative (X and H replaced with =O)
Dehydrodechlorination (2 X’s removed, form C=C)
DDT to DDE
Disulfide reduction
First step in disulfiram metabolism
Sulfoxide reduction
NSAID prodrug Sulindac converted to active sulfide moiety |
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Term
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Definition
Alcohol dehydrogenase
Alcohols to aldehydes
Genetic polymorphism
Asians metabolize alcohol rapidly “flushers”
Inhibited by ranitidine, cimetidine, aspirin
Aldehyde dehydrogenase
Aldehydes to carboxylic acids
Inhibited by disulfiram |
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Term
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Definition
Monoamine oxidase
Deamination reactions
Haloperidol, tryptophan are substrates
Activates 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) to neurotoxic toxic metabolite, resulting in Parkinsonian-like symptoms
MPTP is formed from MPPP synthesis
Flavin-containing mono-oxygenases (FMOs)
Generally results in detoxification
Microsomal enzymes
Substrates: nicotine, cimetidine, chlopromazine, imipramine
Repressed rather than induced by phenobarbital |
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Term
| Metabolic activation by P450 |
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Definition
Formation of toxic species
Dechlorination of chloroform to phosgene
Dehydrogenation and subsequent epoxidation of urethane (CYP2E1)
Formation of pharmacologically active species
Cyclophosphamide to electrophilic aziridinum species (CYP3A4, CYP2B6) |
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Term
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Definition
Drug-drug interactions due to reduced rate of biotransformation
Competitive
S and I compete for active site
Mechanism-based
Irreversible; covalent binding to active site |
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Term
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Definition
Increased rate of biotransformation due to new protein synthesis
Must give inducers for several days for effect
Drug-drug interactions
Possible sub-therapeutic plasma [ ] s
Ex: co-administration of rifampin and oral contraceptives is contraindicated
Some drugs induce, inhibit same enzyme
Ex: ethanol (CYP2E1) |
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Term
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Definition
1A: Caffeine, APAP, smoking & cruciferous vegtables
3A: St. John’s Wort (2D6 & 1A2)
2E1: Ethanol |
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Term
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Definition
Conjugation does not always result in less toxicity or inactivation
Morphine-6-glucuronide is pharmacologically active
N-acetyl procainamide is pharmacologically active
Of 52 active metabolites in a 1985 review, only two were conjugates and those were acetylated products (Sutfin and Jusko, in Drug Metabolism and Disposition: Considerations in Clinical Pharmacology, Wilkinson and Rawlins, ed. MTP Press, Boston, 1985).
Conjugated metabolites that are pharmacologically active are not often successfully developed into drugs. There are many examples of active Phase I metabolites that become drugs. (A. Fura, Drug Discovery Today, 2006). |
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Term
| Phase II: Glucuronidation |
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Definition
Major Phase II pathway in mammals
UDP-glucuronyltransferase forms O-, N-, S-, C- glucuronides
six forms in human liver
Adds: UDP-glucuronic acid
Inducers: phenobarbital, cigarette smoking
Substrates include dextrophan, methadone, morphine, p-nitrophenol, valproic acid, NSAIDS, bilirubin, steroid hormones
Crigler-Nijar syndrome (severe):
inactive enzyme
severe hyperbilirubinemia
inducers have no effect
Gilbert’s syndrome (mild):
reduced enzyme activity
mild hyperbilirubinemia
phenobarbital increases rate of bilirubin glucuronidation to normal
Patients can glucuronidate p-nitrophenol, morphine, chloroamphenicol |
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Term
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Definition
Sulfation is a high affinity, low capacity pathway
Glucuronidation is low affinity, high capacity
Capacity limited by low PAPS levels
Acetaminophen undergoes both sulfation and glucuronidation
At low doses sulfation predominates
At high doses, glucuronidation predominates
Aryl sulfatases in gut microflora remove sulfate groups; enterohepatic recycling
Usually decreases pharmacologic/toxic activity
Activation to carcinogen if conjugate is chemically unstable
Sulfates of hydroxylamines are unstable (2-AAF) |
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Term
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Definition
Common, minor pathway which generally decreases water solubility
Methyltransferases
Cofactor: S-adenosylmethionine (SAM)
Substrates include phenols, catechols, amines, heavy metals (Hg, As, Se)
Several types of MTs in h tissues
Genetic polymorphism in thiopurine metabolism
high activity allele, increased toxicity
low activity allele, decreased efficacy
Methylation masks func groups from other conjugation |
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Term
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Definition
Major route of biotransformation for aromatic amines, hydrazines
Generally decreases water solubility
N-acetyltransferase (NAT)
Cofactor is AcetylCoenzyme A
Humans express two forms
Substrates include sulfanilamide, isoniazid
Rapid and slow acetylators
Various mutations result in decreased enzyme activity or stability
Incidence of slow acetylators
70% in Middle Eastern populations; 50% in Caucasians; 25% in Asians
Drug toxicities in slow acetylators
nerve damage from dapsone; bladder cancer in cigarette smokers due to increased levels of hydroxylamines |
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Term
| Phase II: Amino Acid Conjugation |
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Definition
Alternative to glucuronidation
Two principle pathways
-COOH group of substrate conjugated with -NH2 of glycine, serine, glutamine, requiring CoA activation
Ex: conjugation of benzoic acid with glycine to form hippuric acid
Aromatic -NH2 or NHOH conjugated with -COOH of serine, proline, requiring ATP activation
Substrates: bile acids, NSAIDs
Species specificity in amino acid acceptors
mammals: glycine (benzoic acid)
birds: ornithine (benzoic acid)
dogs, cats, taurine (bile acids)
nonhuman primates: glutamine
Metabolic activation
Serine or proline N-esters of hydroxylamines are unstable & degrade to reactive electrophiles |
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Term
| Phase II:Glutathione Conjugation |
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Definition
Enormous array of substrates
Glutathione-S-transferase catalyzes conjugation with glutathione
Glutathione is tripeptide of glycine, cysteine, glutamic acid
Inhibitor: Buthione-S-sulfoxine
Two types of reactions with glutathione
Displacement of halogen, sulfate, sulfonate, phospho, nitro group
Glutathione added to activated double bond or strained ring system
Glutathione substrates
Hydrophobic, containing electrophilic atom
Can react with glutathione nonenzymatically
Conjugation of N-acetylbenzoquinoneimine
activated metabolite of _____________
O-demethylation of organophosphates
Activation of trinitroglycerin
Products are oxidized glutathione (GSSG), dinitroglycerin, NO (vasodilator)
Reduction of hydroperoxides
Prostaglandin metabolism |
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Term
| In vitro guidance: assumptions |
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Definition
Circulating concentrations of parent drug and/or active metabolites are effectors of drug actions
Clearance is principle regulator of drug concentration-cleared not metabolized
Large differences in blood levels can occur because of individual differences |
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Term
| In vitro guidance: techniques/approaches |
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Definition
Identify a drug’s major metabolic pathways
Anticipate drug interactions
Recommended methods
Human liver microsomes
rCYP450s expressed in various cell lines
Intact liver systems (reperfusion models)
Effects of specific inhibitors
Effects of antibodies on metabolism
Guidance focuses on P450 enzymes
Other hepatic enzymes not as well-characterized
GI drug metabolism is discussed
Metabolism studies in animals (preclinical phase) should be conducted early in drug development
Correlation between in vitro and in vivo studies
Should use in vitro concentrations that approximate in vivo plasma concentrations
Should be used in combination with in vivo studies
Ex: a mass balance study may show that metabolism makes small contribution to elimination pathways
Can rule out a particular pathway
If in vitro studies suggest a potential interaction, should consider investigation in vivo
***When a difference arises between in vivo and in vitro findings, IN VIVO should take precedence*** |
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Term
| Clinical Phase of Drug Development |
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Definition
Phase 0: Pharmacodynamics & Pharmacokinetics- Preclinical work
Phase 1: Screening for safety-the drug is given to healthy individuals
Phase 2: Establishing the testing protocol-Giving it to the sick patients and regulate doses
Phase 3: Final testing-on clinical research level and hospitals giving new trial drugs
Phase 4: Post-approval studies-
Phase 5:
IND- investigation new drug |
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Term
| Phases of clinical trials |
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Definition
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Term
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Definition
When a drug enters the body, the body immediately begins to work on the drug. ADME
what the body does to the drug |
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Term
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Definition
The drug also works on the body, an interaction to which the concept of a drug R is responsible for the selectivity of drug action and for the quantitative relationship between drug and effect.
-The mechanisms of drug action are the processes of PDs.
what the body does to the drug |
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Term
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Definition
We can generally think of the body as a series of interconnected well-stirred compartments within which the [drug] remains fairly constant.
BUT movement BETWEEN compartments important in determining when and for how long a drug will be present in body. |
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Term
| Partitioning into body fat and other tissues |
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Definition
Fat = a large, nonpolar compartment.
Fat has low blood supply—less than 2% of cardiac output, so drugs are delivered to fat relatively slowly
For practical purposes: partition into body fat important following acute dosing only for a few highly lipid-soluble drugs and environmental contaminants which are poorly metabolized and remain in body for long period of time |
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Term
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Definition
In multi-compartment models the drug distributes at various rates into different tissues
Tissues with the highest blood flow generally equilibrate with the plasma/ blood compartment
The highly perfused tissues along with the blood, make up the ‘central’ compartment
Simultaneously, but at a slower rate, drug is delivered to one or more ‘peripheral’ compartments composed of tissues with similar blood flow and affinity for the drug. |
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Term
| Characteristics of the 2 Compartment Model |
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Definition
Many drugs are characterized by two compartment characteristics (lidocaine, digoxin, gentamicin, etc)
Multicompartment models are not used as much as one compartment models
There are many 1 compartment drugs
Clinically 2 compartment drugs can be treated as one compartment drugs for drug monitoring purposes (gentamicin)
Plasma concentration-time profile cannot be characterized by a single exponential function (Cp=Cp0*e-k*t)
Drug does not distribute into a homogenous volume, and may distribute more slowly into some tissues
Elimination occurs primarily via the liver or kidneys. (these organs are associated with the central compartment)
IV dosage always delivers drug directly into the plasma/central compartment |
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Term
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Definition
| Central Compartment = 1st Compartment |
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Term
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Definition
| Peripheral Compartment = 2nd Compartment |
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Term
| General Grouping of Tissue According to Blood Supply |
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Definition
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Term
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Definition
| A measure for the amount of drug that an organism has really "seen" |
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Term
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Definition
| A measure for the proportion of the dose that reaches the systemic circulation (not the same as exposure) |
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Term
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Definition
| A measure of the elimination of a compound from the blood given as amount cleared/time |
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Term
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Definition
| The fraction of drug not bound to proteins: Compound = fu × Ctotal |
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Term
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Definition
| Time it takes for the organism to decrease the [ ] of the drug by 50% |
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Term
| Volume of Distribution (Vd or Vd) |
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Definition
| A measure of the theoretical volume that a compound distributes to. |
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Term
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Definition
Dose/
Plasma Concentration |
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Term
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Definition
Volume of blood cleared of drug per unit time
Ability of organs of elimination (e.g. kidney, liver) to “clear” drug from the bloodstream.
Volume of fluid which is completely cleared of drug per unit time.
Units are in L/hr or L/hr/kg
Pharmacokinetic term used in determination of maintenance doses.
Volume of blood in a defined region of the body that is cleared of a drug in a unit time.
Vd cleared per time
CL remains constant with changes in blood levels
CL relates infusion rates of SS [ ].
Clearance is a more useful concept in reality than t 1/2 or kel since it takes into account blood flow rate.
Clearance varies with body weight.
Also varies with degree of protein binding |
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Term
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Definition
| constant rate of elimination irrespective of plasma concentration |
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Term
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Definition
| rate of elimination proportional to plasma concentration. Constant Fraction of drug eliminated per unit time. |
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Term
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Definition
Vd is a theoretical Volume and determines the loading dose
Abstract concept
Gives information on how the drug is distributed in the body
CL is a constant and determines the maintenance dose.
CL = k * Vd
CL and Vd are independent variables
k is a dependent variable (% based) |
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Term
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Definition
| Apparent Vd is the theoretical volume that would have to be available for drug to disperse in if the concentration everywhere in the body were the same as that in the plasma or serum, the place where drug concentration sampling generally occurs. |
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Term
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Definition
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Term
| Zero Order Elimination Pharmacokinetics of Ethanol |
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Definition
Ethanol is distributed in total body water.
Mild intoxication at 1 mg/ml in plasma.
How much should be ingested to reach it
Answer: 43 g or 55 ml of pure ethanol (C*Vd)
Or 137.5 ml of a strong alcoholic drink like bourbon
Ethanol has a constant elimination rate = 10 ml/h
To maintain mild intoxication, at what rate must ethanol be taken now?
10 ml/h of pure ethanol, or 25 ml/h of drink. |
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Term
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Definition
On continuous steady administration of a drug, Cp will rise fast at first then more slowly and reach a plateau, where:
rate of administration = rate of elimination ie. steady state is reached.
Therefore, at SS:
Dose (Rate of Administration) = CL x Cp
Constant blood [ ] caused by equal rates of drug input and elimination. |
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Term
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Definition
Half-life is the time taken for the drug concentration to fall to half its original value
The half-life of elimination of a chemical (and
its residence in the body) depends on its
clearance and its volume of distribution
t1/2 is proportional to Vd
t1/2 is inversely proportional to CL |
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Term
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Definition
| The elimination rate constant (k) is the fraction of drug in the body which is removed per unit time. |
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Term
| If drug has short duration of action |
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Definition
| design drug with larger t ½ and smaller kel |
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Term
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Definition
| design drug with smaller t ½ and larger kel |
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Term
| What is Steady State (SS) ? Why is it important ? |
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Definition
Rate in = Rate Out
Reached in 4–5 half-lives (linear kinetics)
Important when interpreting drug [ ]s in time-dependent manner or assessing clinical response
Steady-state occurs after a drug has been given for approximately five elimination half-lives.
At SS the rate of drug administration equals the rate of elimination and Cp- time curves found after each dose should be approximately superimposable. |
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Term
| Maintenance Dose Calculation (SS Infusion Rate) |
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Definition
Infusion Rate (DIR) for desired SS level (CSS):
DIR = CL * CSS = ke * Vd * CSS
CSS is the target average steady state drug concentration
Maintenance dose (DIR) will be in mg/hr so for total daily dose will need multiplying by 24 |
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Term
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Definition
Therapeutic index = toxic dose/effective dose
This is a measure of a drug’s safety
A large number = a wide margin of safety
A small number = a small margin of safety |
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Term
| FYI: Why Measure Drug Concentrations? |
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Definition
Lack of therapeutic response
Toxic effects evident
Potential for non-compliance
Variability in relationship of dose and concentration
Therapeutic/toxic actions not easily quantified by clinical endpoints |
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Term
| FYI: Potential for Error when using TDM |
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Definition
Assuming patient is at steady-state
Assuming patient is actually taking the drug as prescribed
Assuming patient is receiving drug as prescribed
Not knowing when the [drug] was measured in relation to dose administration
Assuming the patient is static and that changes in condition don’t affect clearance
Not considering drug interactions |
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Term
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Definition
binds many acidic drugs and a few basic drugs
b-globulin and an a1acid glycoprotein have also been found to bind certain basic drugs |
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Term
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Definition
1) free drug concentration
2) the protein concentration
3) affinity for binding sites
% bound: __[bound drug]_________ x 100
[bound drug] + [free drug] |
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Term
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Definition
Renal failure, inflammation, fasting, malnutrition can have effect on plasma protein binding.
Competition from other drugs can also affect % bound. |
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Term
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Definition
Rate = k
C = Co - kt
Constant rate of elimination regardless of Cp
C vs. t graph is LINEAR |
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Term
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Definition
Rate = k C
C = Co e-kt
Rate of elimination proportional to Cp.
Constant fraction of drug eliminated per unit time.
C vs. t graph is NOT linear
Decaying exponential.
Log C vs. t graph is linear |
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Term
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Definition
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Term
| Capacity-Limited Metabolism |
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Definition
Saturation
There are a finite number of drug metabolizing enzymes. If you increase the [ ] of any substrate you will saturate the enzyme.
This is theoretically possible with any drug that is metabolized. However, only a few compounds approach this [ ] within the normal therapeutic range of the drug.
Consequences:
Elimination t1/2 inc w/ inc dose
Cp levels inc disproportionately w/ dose.
SS levels inc dramatically as dosage rate approach Vmax.
Other drugs using the same enzyme ay inhibit capacity-limited drug metabolism.
Changing dose may alter quantitative distribution of metabolites of a drug. |
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Term
| AUC: An Indicator of Bioavailability |
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Definition
Dose is proportional to [drug] in tissues.
[drug], in turn, is proportional to the AUC in a Concentration-decay curve.
Thus, we have k = dose/AUC
Because oral administration is full of barriers, the fraction (F) that is available by entering the general circulation, may not be significant.
Thus, k = (F* dose) / AUC
Dose administered:
F = AUC/Dose |
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Term
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Definition
| Rate of absorption depends, in part, on rate of dissolution (which in turn is dependent on chemical structure, pH, partition coefficient, surface area of absorbing region, etc.) Also first-pass metabolism is a determining factor |
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