Flashcards in Pharm: ADME 2 Deck (90):
What are the principal metabolism reactions of Phase I metabolism?
What are the principal metabolism reactions of Phase II metabolism?
-glutathione (GSH) conjugation
What is the enzymatic nature of Phase I and Phase II metabolism reactions?
Phase I = CYPs
Phase II = (1) UGTs; (2) STs; (3) Other; (4) NATs and GSTs; (5) TPMTs (important in DNA-modifying drugs)
What is the role of CYP450 in Phase I metabolism?
huge - it's the main catalyst of Phase I oxidation reactions
What are the major P450 isozymes?
17 CYP450 gene families are recognized and contain many different isoforms; most important to know and love are CYP3A4, CYP3A5, CYP2C, CYP2D6
What factors affect drug metabolism?
- species difference
- sex (hormones)
- disease (esp. in liver)
- drug-induced induction
- drug-induced inhibition
What is genetic polymorphism and how does it relate to metabolism?
variations in DNA sequence between individuals in a population that affect rates and extents of metabolism
What factors affect renal and hepatic drug elimination?
- drug's MW
- volatility (inahaltion)
- lipid solubility (reabsorbed)
- volume of distribution
- protein binding
- excretion mechanism
- rate of metabolism
- blood flow
- disease states
What are the processes of renal and hepatic drug elimination?
-renal = process of absorption and secretion in the nephron for excretion in the urine
-hepatic = drug metabolites secreted along with bile acid/salts into intestinal tracts for excretion in the feces
The elimination and removal of drugs from the body is mediated by the processes of metabolism and excretion, which, in general, contribute to setting the _______ by controlling the _______.
duration of action; rate of termination
What is biotransformation?
term reflecting the chemical modification of xenobiotics by endogenous enzymes
What is metabolism?
refers exclusively to normal anabolic and catabolic reactions but is often used to refer to the chemical transformation of both endogenous and exogenous agents
What is inactivation, or detoxification?
the conversion of active compounds into less active (or less toxic) compounds through reactions
Which conditions favors drug excretion:
- more polar vs. less polar?
- more lipid soluble vs. less lipid soluble?
more polar, less lipid soluble favors excretion
Although catabolic reactions can inactivate or detoxify agents, they can also catalyze conversion of ____ to ____.
prodrugs to their active forms
All biotransformation reactions are ____ in nature.
For biotransformation reactions, the reaction rate is proportional to the level of ____ at saturating substrate concentrations.
For biotransformation reactions, when a substrate is limiting, the reaction rate is proportional to the level of ____.
For biotransformation reactions, when is the maximum rate achieved?
when the enzyme is saturated
If a phase I metabolite is sufficiently polar, what will happen to it?
will be readily excreted in the urine
True or False: Resulting phase I metabolites are not very reactive and carry no potential for toxicity.
False - resulting phase I metabolites are often HIGHLY reactive (free radicals) and potentially TOXIC.
Describe the nature of Phase II reactions.
covalent modifications made to the parent compound, or the reactive product of a phase I reaction, generally make the new compound inactive and readily excreted
Name the 2 main sites of biotransformation.
Biotransformation takes place predominantly in which organ?
Liver. Always the liver.
Aside from the liver, a significant capacity for metabolic activity exists within what 3 organs?
1. GI tract
*Bonus: brain - for having metabolic enzymes thought to play a role in the etiology of several neurodegenerative disorders and responses to environmental toxins
Where (cellular location) are most drug metabolizing enzymes found?
primarily: ER and cytosol
also: mitochondria, nuclear envelope, and plasma membrane
What is a microsome and microsomal enzyme?
- following homogenization & differential centrifugation, the ER fragments into microvesicles called microsomes
- drug metabolizing enzymes associated with this fraction are called microsomal enzymes
Where do most Phase I reactions take place?
Where do most Phase II reactions take place?
What is oxidation?
addition of oxygen and removal of hydrogen
Common oxidation reactions include the conversion of the following:
- alkyl group --> ____
- aromatic ring --> ____
- alkyl group --> alcohol
- aromatic ring --> phenol
What generates the sulfoxide or nitroxide derivatives of parent compounds?
oxidation at S or N, respectively
Where (subcellularly) do most oxidation reactions occur?
What is reduction?
addition of H or removal of O
Reactions that convert azo (-N=N-) or nitro (-NO2) groups to primary amines (-NH2) are what type of reactions?
What is hydrolysis?
addition of water with breakdown of a molecule
Hydrolysis is performed in blood plasma and liver by what enzyme?
Esters are converted by esterases to what?
esters --> alcohol and acid
What do Phase I reactions do to the parent compound?
- convert the parent drug to an inactive metabolite by introducing or unmasking a functional group
- modify or increase activity of the drug/prodrug
What do Phase II reactions do to the parent compound?
- covalent addition of a functional group
What is glucuronidation, what catalyzes it, and where does it occur?
the main conjugation (phase II) reaction in the body; catalyzed by UDP-glucoronyl transferases (UGTs); occurs in the liver
What two compounds are commonly conjugated with glucuronide?
aliphatic alcohols and phenols; hydroxylated metabolites can also be conjugated (ex: morphine)
What is acylation, what catalyzes it, and where does it occur?
common phase II reaction, esp. acetylation by the acetyl group
Nicotinic acid is conjugated by ____ in a common phase II reaction.
Sulfoxidation is a Phase II conjugation reaction and common with what two compounds?
morphine and paracetamol
Morphine cab be conjugated by what two processes?
glucuronidation and sulfoxidation
What Phase III conjugation reaction leads to a mercapturic acid metabolist?
glutathione (GSH) conjugation
Glutathione is a tripeptide consisting of what?
In most cases, the resultant metabolite after Phase II reactions is more ____ soluble and less ____ soluble. An exception is that acetlyated metabolites are often ____ water soluble.
MORE water soluble; LESS lipid soluble *(think Way more Water; Less Lipid)
EXCEPTION: acetlyated metabolites are often LESS water soluble (favoring reabsorption)
What properties of metabolites result in less drug reabsorption from the kidney?
higher water solubility and lower lipid solubility; the better to excrete them with, my dear.
On a subcellular level, Phase I reactions tend to occur in the ____ fraction, while Phase II reactions tend to occur in the ____ fraction.
microsomal; cytosolic (or non-microsomal)
What enzyme family is the major catalyst of Phase I drug biotransformation?
the cytochrome P450 monooxygenase enzyme family
Where (subcellularly) are CYPs located?
in the ER membrane; located in numerous tissue but highest concentration is in hepatocytes
True or false: CYP enzymes have narrow and specific substrate specificity.
False - they have wide and overlapping substrate specificity
CYPs are ___-containing ER membrane proteins.
Why are CYPs also referred to as the mixed function oxidase system?
because they have wide and overlapping substrate specificity and are non-specific
Which CYPs encode the the enzymes involved in the majority of biotransformations?
CYP1, 2, and 3
What are the tope 4 busiest CYPs?
1st&2nd place = CYP3A4 and CYP3A5 - these guys are involved in metabolizing about 50% of drugs
3rd&4th place = CYP2C and CYP2D6 are also involved in metabolism of many drugs
What effect does the CYP3A subfamily have on many drugs during absorption from the GI tract?
decreases the bioavailability of many orally absorbed drugs
What does the CYP complex consist of?
CYP450 enzyme and the CYP450 reductase
What is the energy source for CYP450 catalyzed reactions?
(no ATP here!)
Describe the catalysis process of CYP450 and a drug.
1. drug binds oxidized form of CYP450
2. the CYP reductase reduces the CYP450 complex
4. addition of O2 molecule oxidizes the drug--CYP complex
5. oxidized drug and H2O released
6. oxidized CYP restarts the cycle
Many drugs can cause an increase over time in liver enzyme activity; what effect does this have?
can increase the metabolic rate of the same or other drugs, which can result in dose escalation for chronic administration of a drug; ex; phenobarbital - will induce itself and others
Is induction generally a reversible or irreversible process?
What are the 3 characteristics of induction?
(described in terms of time from initial administration)
1. onset is 3-12hrs
2. peak is 1-5 days
3. persists for 5-12 days
What is drug-induced inhibition?
when drugs can inhibit the metabolism of other drugs, often by competitively inhibiting the metabolic enzyme(s)
What are 5 mechanisms of metabolic inhibition?
1. competitive substrate binding
2. inactivation by forming tight complex with the heme
3. depletion of cofactors (more common in Phase II)
4. enzyme inhibitors
5. increased degradation
Drug-induced inhibition of metabolic enzymes results in what?
accumulation of that drugs or other drugs metabolized by the same enzymes
Pharmacogenetics is what?
the genetic basis for difference among the population in drug responses (therapeutic or toxic)
What is Pharmacogenomics?
application of genomic information toward discovery/development of novel specific drugs; such drugs may be targeted for selective use among specific patient populations
How do genetic polymorphisms translate into difference in individuals' response to drugs?
the DNA variations translate to structural protein differences; structural differences, when important for a drug's effect(s), means different responses to drugs
In terms of pharmacogenomics, how are genotypic vs. phenotypic polymorphisms observed?
genotypic polymorphisms observed only by sequencing DNA; phenotypic polymorphisms observed by an individual's response to a drug
What are frequency distribution patterns used for?
for characterizing phenotypic variations in a population
Describe the frequency distribution pattern for a monogenic trait versus a polygenic trait.
monogenic = 2-3 discreet population distributions
polygenic = one broad population distribution (curve)
What are the 3 common mechanisms by which genetic variations can control metabolism?
1. complete loss of activity
2. reduced catalytic activity
3. enhanced catalytic activity
Routes of drug excretion include:
- renal --> urine
- liver/intestines --> feces
- lungs - major route for inhaled agents
- sweat/saliva - minor
- breast milk
What three major process relevant to drug elimination occur in the kidney?
1. glomerular filtration
2. tubular secretion
3. tubular reabsorption
What happens in the loop of Henle in a nephron?
reabsorption of water
How is the glomerular filtration rate measured clinically?
measuring creatinine - indicates the renal clearance of cretinine
Glomerular filtration is a ____ and ____ process.
passive and nonsaturable
True or false: in the glomerulus low molecular weight compounds--including ions, glucose, and proteins--are filtered out of the blood and into the urine.
false - in the glomerulus low molecular weight compounds--including ions, glucose, and PEPTIDES--are filtered out of the blood and into the urine. PROTEINS are too big.
Why would a drug NOT be filtered out of the blood in the glomerulus?
if it is bound tightly to a large molecule such as plasma protein, or haas been incorporated into RBCs
What is considered a normal amount of urine output in one day?
In the proximal tubule there is ____ of water and ____ of weak electrolytes.
reabsorption of water; active secretion of electrolytes
Nonionized, lipid soluble forms of weak acids and bases can be ____ in the distal tubules.
reabsorbed (*because the membrane is readily permeable to lipids, lipids are extensively reabsorbed)
Reabsorption of weak electrolytes is passive and therefore depends on what?
pH of the urine - acidification of urine will facilitate excretion of basic compounds, while alkalization will facilitate excretion of acidic compounds
What is renal clearance?
a measure of renal excretion of drugs; calculated as part of total body clearance for a particular drug
If renal clearance is at, above, or below 120 ml/min, what does each measure indicate?
At 120=the drug is being filtered, but neither secreted nor absorbed.
Below 120=drug being reabsorbed
Above 120=drug being secreted
What is enterohepatic cycling?
when drugs are metabolized in liver (conjugated) and sent to the intestine for excretion, but then undergo hydrolysis and are returned to the liver; this phenomenon can prolong the presence and effects of a drug by reducing its elimination rate