Drug Metabolism and Excretion Flashcards
The inhibition can be the result of formation of a metabolite that:
1.
OR
2.
(1) covalently binds to the enzyme (suicide inhibition) resulting in destruction of the enzyme OR
(2) forms a tight complex with the enzyme inhibiting its further activity
Potential for drug-drug interactions if presence of second ligand results in ___ or ____ of transport of first drug.
-Many inducers and inhibitors of ____ have corresponding effects on these p-glycoprotein transporters.
induction or competitive inhibition
CYP450
Infant exposure to maternal drugs can be limited by desynchronizing breastfeeding and peak milk drug concentrations as follows:
- Breastfeed at end of dosing interval
- or administer drug immediately after nursing
3 Administer a dose prior to infant’s longest sleep time - Shorter nursing periods–> fat [and thus drug] content of milk increases during feeding period
what is the operative enzyme in conjugation rxns and what is the product like?
transferases
Product often (but not always) highly water-soluble and readily excreted–> N-acetylation can be exception
what is the most common pathway of chemical transformation?
oxidation
how much do drugs cross into breast milk?
The resulting infant plasma level for most drugs is substantially below a therapeutic level (less than 5% of maternal plasma levels).
-Only small numbers of adverse reactions from drugs passing into breast milk have been reported - infant deaths are extremely uncommon
what diet and nutritional factors influence drug metabolism
- High protein : carbohydrate ratio in diet stimulates mixed function oxidase (CYP).
- Malnutrition dramatically changes drug metabolism in a complex manner (generally decreases); inducers may present in charbroiled food.
what is the most common outcome of drug metabolism
- inactivating-detoxifying process forming readily excreted and pharmacologically inactive metabolites (95%)
- metabolism of an active drug to an inactive or less active compound
how does rifampin effect OCPs?
rate in=unchanged
rate out=
- clearance increased
- decreased Cp for OC—> unplanned pregnancy
when does the onset of inhibitory effects occur?
within hours
*more often in phase I enzymes than phase II
The duration of action for most drugs would be extremely_____ if terminated by renal excretion only (excreted at rate of _____ as it would take ___ for elimination of drug from the body
prolonged
urine formation [∼ 1 ml/min] as it would take days to weeks for elimination of drug from body
how does age effect phase I and phase II metabolism?
phase I- decreases w/ age (1/3)
phase II- no effect
is genetic polymorphism significant in Phase I or phase II metabolism?
BOTH
Accounts for drug “taste” noted after IV administration
saliva excretion
what are examples of inducers?
- cigarette/marijuanna smoke
- air pollutants
- industrial chemicals
- DDT
- numerous drugs
Pulmonary excretion is seen with what? via what?
gases, alcohols, and volatile substances (simple diffusion)
*Parent drug is usually cleared without metabolism
How does erythromyocin affect lipitor
Rate in= unchanged
rate out=
- lipitor clearance decreased
- increased CP for lipitor= increased risk of myopathy
P-glycoproteins act primarily to move drugs ___ of the cell - effect varies with location:
GI tract-
Liver-kidney-
Blood-brain barrier-
out
- GI tract: DECREASE oral ABSORPTION of drugs
- Liver-Kidney: ENHANCE biliary and renal EXCRETION/ELIMINATION of drugs
- Blood-brain barrier: LIMITS DISTRIBUTION of drugs to the brain
responsible for multidrug resistance in cancer cells and in numerous bacteria
P-glycoprotein transporter
aka: MDR1 gene
responsible for cancer chemotherapy-induced hair loss
hair excretion
Drug clearance by glomerular filtration occurs at rate of ___
120 ml/min
type of phase II conjugation rxns
- glucuronidation
- N-acetylation (form amide bond formation via N-acetyltransferase)
- glutathione conjugation
- sulfate conjugation (results in strong acid w/ pKa ~1)
- methylation
what are the phenotypes of PM in caucasians and asians
- 5-10% of Caucasians are CYP2D6 PMs
- about 20% of Asians are CYP2C19 PMs
what oxidation reactions are catalyzed by CYP450 (aka CYP450 dependent)
- Aromatic hydroxylations
- Aliphatic hydroxylations
- Epoxidation
- Oxidative Dealkylation (O-, N-, S-)
- S-Oxidation
- Deamination
- Desulfuration
- Dechlorination
some products of N-acetylation are ____.
ex.
less water soluble
ex. certain sulfonamides
what determines if a patient is an ultra-rapid (UM) metabolizer or a poor metabolizer (PM)
-varies in enzymatic activity
PM= total absence of enzyme
what is the Amplichip CYP450 Test?
Can analyze blood-derived DNA and detect genetic polymorphisms in the activity of CYP2D6 and CYP2C19.
-These are two CYP isozymes that account for 25% of drug metabolism, including many antidepressants, antipsychotics, and opioid analgesics
Some enzyme systems are not well developed at birth that ultimately affect drug metabolism. Ex?
deficient glucuronidation in neonates can lead to “gray baby syndrome” after chloramphenicol administration
- After about 2 weeks of life both phase I and phase II enzymes begin to mature, but at variable rates.
what non-hepatic disease states influence drug metabolism
With hyperthyroidism
- pituitary insufficiency
- tumors, diabetes
- infectious diseases, or
- inflammatory disorders
- a reduction in drug metabolism rates has been observed
Potential for drug interactions:
-2nd drug results in competitive inhibition of transport of 1st drug results in _____
-2nd drug induces p-glycoprotein enhancing transport of 1st drug (e.g., rifampin and St. John’s wort) results in
increased potential for toxicity with 1st drug
lessening of therapeutic effect of 1st drug
what is phase I in biotransformation/ drug metabolism?
- Usually inserts or unmasks a functional group on the drug [-OH, -NH2, -SH] that renders the molecule more water-soluble –> the molecule can then undergo conjugation in a Phase II reaction.
- Phase I reactions include: Oxidation, reduction, hydrolysis
explain enterhepatic cycling
Drugs and drug metabolites with molecular weights higher than 300 may be excreted via the bile, stored in the gallbladder, delivered to the intestines by the bile duct, and then reabsorbed into the circulation where it can return to the liver by way of the superior mesenteric and portal veins.
Hydrolysis of some glucuronides by intestinal bacterial enzymes (β-glucuronidase) results in ___-
formation of free drug
what are the enzymes in phase I and Phase II metabolism
Phase I- CYP450, Esterases-Amidases Reductases
Phase II- transferase
when can you typically see the effect of induction?
*Generally requires 48-72 hrs to see onset of effect
Induction by one agent may increase the clearance of other drugs. The resulting drug interactions may have clinical implications such as ___ or ___
- reduced therapeutic effect of drug whose elimination is accelerated or
- increased toxicity via a toxic metabolite.
Clinical implications of resulting drug interactions from induction include:
- Reduced therapeutic effect if inactivation reaction is accelerated
- Increased toxicity if activation reaction is accelerated
- Increased toxicity if toxic metabolite is produced
what is the formula for maintenance dose
MD/frequency= CPss X clearance
how do you increase elimination?
- increase size (via phase 2)
- decrease ionization (via phase 2)
- decrease lipid solubility (via phase 1-2)
how are lipid soluble compounds and high protein binding compound levels in breast milk
-Lipid soluble compounds → generally increased milk concentration
High protein binding → decreased milk concentration
where are esterase and amidase enzymes typically found (used in phase I hydrolysis rxns)
Esterase-Extremely reactive enzymes found in plasma, liver, other sites
(reach adult values w/in 1st month)
Amidases- primarily in liver and in gut flora
Many drugs (usually of high molecular weight) are EXCRETED into ___, but these are usually ____ from the small intestine and then elminated in the ___, rather than the feces
bile
reabsorbed from SI
urine
what is an example of a drug that induces the metabolism of another to toxic metabolics
ethanol induces CYP2E1 that metabolizes acetaminophen to a hepatotoxic metabolite.
what are examples of Metabolism of inactive compound (Prodrug) to active ingredient (designed)
Omeprazole –> a Sulfenamide
Enalapril –> Enalaprilat
Valacyclovir –> Acyclovir
What are examples of metabolism of active drug to more active compound
Codeine–> morphine
Hydrocodone–> hydromorphone
**inducer (increase the liver metabolism)
what is the role of gluthione-S-transferase
- limited role in drug metabolism, but are extremely important in detoxification of carcinogens, pollutants, toxic metabolites (ie. acetaminophen)
in conjugation (phase II), drug or drug metabolite is ______ provided by a coenzyme
coupled (conjugated) to endogenous biochemical unit (highly reactive)
*therefore limited supply and reaction is more easily saturable than phase I reactions
clinically relevant inducers
- ethanol*
- St. John’s Wort*
- Tobacco Smoke (not nicotine)*
- Rifampin
- phenobarbital
- phenytoin
- carbamazepine
*available w/o prescription
what hepatic disease states influence drug metabolism by requiring dose adjustments or avoidance
- Cirrhosis, hepatitis, fatty liver disease, etc.,
- can affect drug metabolism. REDUCTION IN METABOLISM is often seen, but the effect depends on the disease and its severity, the drug, and on the specific biotransformation
therapeutic consequences of induction
- Maximal effects of enzyme induction usually seen in 7-10 days and require similar time to dissipate.
- Production of pharmacokinetic tolerance: induction by a drug of its own metabolism
- Induction by one agent may increase the clearance of other drugs.
- One drug may induce the metabolism of another to toxic metabolites;
what can you change urinary pH with?
NH4Cl / ascorbic acid (acidify) or NaHCO3 (alkalinize)
Drugs that can affect milk synthesis, secretion, and / or ejection through effects on prolactin (PRL)and / or oxytocin release include:
- dopamine receptor agonists (decrease PRL release)
- antagonists (increase PRL release)
- ethanol (decrease oxytocin release)
why do we see a decrease in phase I CYP450 with aging that ultimately influences drug metabolism
-decreased liver mass or decreased blood flow to liver
how does postnatal development vary in CYP450?
- early neonatal levels generally 50-75% of adult; although
- some drugs are metabolized faster in neonates (theophylline, phenytoin, phenobarbital) in neonates
Diffusion of weak acids and bases is dependent upon _____
urine pH (non-ionized form only will diffuse across membrane)
*Can change urinary pH with NH4Cl / ascorbic acid (acidify) or NaHCO3 (alkalinize)
describe the nomenclature for CYP1A2:
CYP (human origin),
1 (isoform family),
A (subfamily),
2 (individual gene product)
what are detoxifying polymorphisms and what is their clinical effect
- PMs - CYP2D6 → increased antipsychotic drug toxicity
2. UMs - CYP2D6 → nonresponse to antidepressants reported
what is the richest source of cytochrome P450
liver smooth ER
*aka microsomal enzymes
what are P-glycoproteins and where are they found
- Present in renal brush border membranes, bile canaliculi, astrocyte foot processes in brain microvessels, GI tract
- play a role in elimination of xenobiotics, including drugs/movement of drugs throughout the body
what is the clinical relevance of genetic polymorphisms of CYP?
-depends on whether metabolism is detoxifying or activating and whether polymorphism results in increased (UM-ultra metabolizer) or decreased (PM-poor metabolizer) enzyme activity
what groups are conjugated with glucuronide molecules:
aliphatic -OH, aromatic -OH, -COOH, -NH, and -SH.
Recent evidence has suggested that individual differences in response to the anticoagulant effects of warfarin may be based on genetic variations to:
- Enzyme that warfarin targets (vitamin K reductase [VKORC1])
- Enzyme that metabolizes warfarin (CYP2C9)
**Lab tests to detect these variations are available, but guidelines for their clinical use are still being developed
Most is known about induction of ____ enzymes, but some forms of phase II enzymes (___) are also inducible
CYP450
UGT
The inhibitor can be an inhibitor without being a substrate (important determinant: _____)
relative concentrations and affinities of the inhibitor and the substrate whose metabolism is inhibited
how do enterhepatic cycling effect drug emlination and half life?
reduces the elimination of drug and prolongs its half-life and duration of action in the body
what is active tubular secretion and at what rate do the secreted drugs clear at occur?
- drugs are transported from directly from blood into urine
- Actively secreted drugs can be cleared at rate of 120-600 ml/min.
what are the main enzymes that participate in Phase II metabolism
NATs (N-acetyl transferase)
GSTs (glutathione S-transferase)
UGTs (UDP Glucuronyl transferases)
what type of drug can bypass phase I and phase 2 biotransformation and become an excreted product?
one that is highly water soluble
active tubular secretion occurs with drugs that are stronger acids and bases in the proximal tubule via secretory mechanisms that are saturable (i.e., fixed capacity). Examples of drug substrates for transporter:
- Acids: ____
- Bases: ___
Acids: Penicillins, salicylate, diuretics (thiazides, acetazolamide, ethacrynic acid)
Bases: Morphine, catecholamines (DA, NE, EPI), histamine, hexamethonium, tolazoline
Glucuronyl transferases properties
- They are inducible, but not to the extent of CYP 450 enzymes
- adult levels of activity are reached by 3-4 y/o
- Conjugates are generally highly water-soluble and, therefore, readily excreted in the urine.
- Some high MW glucuronide conjugates are excreted in the bile and then via the feces.
enzyme-catalyzed chemical structure transformation of a drug after administration to the patient
biotransformation or drug metabolism
what is the formula for:
rate in = rate out
Dose/frequency= CPss X clearance
clinically relevant inhibitors
- Cimetidine*
- grapefruit juice*
- omeprazole*
- erythromyocin/clarithromycin
- Ketoconazole/azole antifungals
- HIV protease inhibitors
- fluoxetine (and other SSRIs)
*available w/o prescription
what happens if drug excreted in saliva is swallowed?
it will undergo the same fate as if orally administered
A therapeutic consequences of induction includes: Production of pharmacokinetic tolerance: induction by a drug of its own metabolism. Examples include
phenobarbital, meprobamate, carbamazepine.
what are CYP450 independent oxidations
- Amine oxidases: Monoamine oxidase, located in outer membrane of mitochondria. (Important enzyme in neurotransmitter metabolism)
- Dehydrogenations: Alcohol dehydrogenase (hepatic soluble fraction, several different types, full adult activity not reached until 5 years). Also aldehyde dehydrogenase
what are examples of metabolism of a drug to a toxic metabolite
Acetaminophen –> N-Acetyl-benzoquinoneimine (hepatotoxic)
how does age influence drug metabolism
- Perinatal: Some enzyme systems are not well developed at birth
- Neonatal: Variable developmental patterns (lower rates than adults)
- Old age: Decrease in phase I CYP450 with aging (1/3 of patients)
Sulfotransferases occur in _____. Available sulfate of body is used. Sulfate conjugates are __ and ___
soluble fraction of cell
ionized and water-soluble* (acids pka ~1)
characteristics of cytochrome P450
- Substrate must be lipid-soluble, otherwise very low specificity
- Inducibility (increase in enzyme protein and drug metabolizing activity) inhibition
- Postnatal development variable
- many different isozymes (CYP1-2-3 are of primary importance in drug metabolism)
Due to ____, drugs that are lipid-soluble and uncharged would be cleared at rate of urine formation (___ ml/min)
tubular reabsorption
1 ml/min
what are the main enzymes that participate in Phase I metabolism
CYP2C8/9
CYP2D6
CYP2E1
CYP3A4/5
what are types of Phase I reductions?
- Azo reduction: involved in activation of certain sulfoamides
- Nitro reductions: several diff. enzymes (microsomal, soluble, bacteria) *Can produce toxic intermediates (chloramphenicol)
- Carbonyl reduction (methadone)
phase I reactions include:
oxidation, reduction, and hydrolysis
Active reabsorption is particularly important for ___ compounds (glucose, amino acids). Most drugs act by ___ this active transport, rather than ___ it
endogenous
reducing
enhancing
when are drug-drug interactions most obvious
when drugs are given orally (1st pass through liver).
*Metabolic rate may be increased (inducers) or decreased (inhibitors) resulting in a decrease or increase, respectively, in the amount of drug available for action
active tubular secretion occurs when what drugs?
drugs that are stronger acids and bases in the proximal tubule via secretory mechanisms that are saturable (i.e., fixed capacity)
Most drug-drug interactions occur via ___
effects on cytochrome P450 system
*many inhibitors and inducers of specific isozymes of P450 are known
the inhibitor can be a substrate competing for the enzyme (important determinant: ____)
relative concentrations and affinities of the two substrates
Responsible for certain skin reactions to ingested drugs
sweat excretion
what is the coenzyme donor of sulfate?
PAPS
what is the primary organ of drug metabolism?
liver
Others that have enzymes capable of drug metabolizing drugs: intestine [6%], lung [30%], kidney [8%], skin [1%], placenta [5%], and bacteria in intestinal lumen
- Many compounds cause a ___ and/or ___ change in the metabolism of drugs.
- One mechanism underlying the changes is the stimulation of the CYP450 system, resulting in ____ , aka ___
qualitative and/or quantitative
increased drug-metabolizing activity, aka INDUCTION
*compound that causes induction is called an inducer
therapeutic consequences of inhibition
- Inhibition of metabolism can occur as soon as sufficient hepatic concentration is reached (generally within hours),
- Time to effect on steady state plasma concentration dependent on the inhibited drug’s half-life.
- Inhibition by 2nd drug of 1st drug metabolism –> decreased CL of 1st drug –> higher Cp –> increased toxicity
- If an activating metabolic reaction (less common) is inhibited –> reduction in therapeutic effect
what does clearance consist of
liver metabolism (inhibitors and inducers) renal excretion (renal dosing)
Antibiotics that reduce gut bacterial flora can ____ and ____ levels and is a potential mechanism for drug-drug interactions, although exact clinical significance is uncertain
decrease enterohepatic recycling
decrease plasma drug
what is phase 2 in biotransformation/drug metabolism
- Conjugations
- Endogenous substrate (that are high energy and limited in supply) combines with pre-existing or metabolically inserted functional group (via Phase I reaction) on the drug forming a highly polar (water-soluble) conjugate that is readily excreted via the urine.
-Phase II reactions may also precede phase I reactions
what biological factors influence drug metabolism
- diet and nutritional factors
- sex
- age
- genetic factors
- disease states- May require dosage adjustment or drug avoidance
are lipid soluble or water soluble compounds more readily excreted?
more water soluble
*Lipid-soluble compounds are generally converted to more water-soluble (more polar) compounds that are then more readily excreted.
A primary function of drug metabolism is ____
production of a more water soluble metabolite that is less likely to be reabsorbed
*RECALL: cells with tight junctions exist between blood and urine, thus drugs must pass through membranes to be reabsorbed
in N-acetylation (phase II) rxns, the rxn is catalyzed by ____ located in ___
acetyl transferase
hepatic soluble fraction
*Acetylation activity can display marked genetic variation in humans. Example, fast (50%) and slow (50%) acetylators (e.g., metabolism of isoniazid).
how are drugs excreted
- Kidney
- biliary and fecal excretion
- breast milk
- pulmonary excretion
- other: sweat, saliva, hair
when are esterase hydrolyses utilized?
- Commonly utilized in design of pro-drugs (valacyclovir)
- another ex: Procaine metabolized to allergenic PABA
- Clearance rate for highly soluble gases depends on ___
- Clearance rate for poorly soluble gases depends on ____
- Clearance rate for highly soluble gases depends upon respiratory rate
- poorly soluble gases rate (e.g., nitrous oxide) depends upon blood flow
is there induction/inhibition with phase I or phase II metabolism
phase I- significant
phase II- possible but less
The mechanism of induction in many cases is the ____.
This may be accompanied by marked morphological and biochemical changes, including:
increased synthesis of enzyme protein
(1) Increase in liver weight,
(2) Marked proliferation of SER,
(3) Increases in NADPH and cytochrome P-450.
what are acceptors of sulfotranserases
Aromatic -OH, aliphatic -OH, N-OH
*(N-OH-sulfate conjugates of this type may play a role in the toxicity of some N-OH compounds).
does phase I or phase II have saturability?
phase I- minimal
phase II- substantial
Many transformations are catalyzed by ____ and some by ____
membrane-bound enzymes of the smooth endoplasmic reticulum (CYP450 enzymes)
soluble enzymes in the cytosol
what other lipid-soluble chemical structures serve as substrates in addition to drugs for phase I
- organophosphate pesticides
- foods
- bilurubin
- steroid hormones
- thyroid hormones
- fatty acids
why is phase II reactions more easily saturable than phase I reactions?
Limited supply of high energetic reactants renders Phase II reactions more easily saturable (zero order elimination kinetics) than phase I
Clinical effect of drug-drug interactions are dependent on whether metabolic reaction is:
__, __, or __=
- Inactivating-detoxifying – most common (95%)
- Activating (less than 5%)
- Produces a toxic metabolite (WAY less than 1%)
what is enterohepatic recirculation?
Drug may be secreted by liver into bile as drug-conjugate and then reabsorbed via the GI tract as free drug (Hydrolysis by bacterial β-glucuronidase –> free drug in intestine)
*may be source of drug interactions (antibiotics and oral contraceptives).
what are mechanisms of inhibition?
- A compound can inhibit the synthesis of enzyme
- Inhibitor can be a substrate competing for the enzyme
- Allosteric inhibitor without being a substrate
- Inhibition can result from formation of a metabolite
what disease states influence drug metabolism by requiring dose adjustments or avoidance
- hepatic diseases
- alcohol consumption
- conditions affecting liver blood flow
- non-hepatic disease
what are cofactors of Cytochrome P450?
- NADPH
- flavoprotein NADPH-cytochrome P450 reductase
- molecular O2
*cofactors are abundant in supply and unlikely to display zero-order (saturation) kinetics
Plasma protein binding (reversible) ____ appreciably affect rate of secretion; t1/2 ≈ 1-2 hrs
does NOT
what are examples of phase II biotransformation reactions
-Glucuronidation
-acetylation,
glutathione / glycine / sulfate conjugation
how can conditions that affect liver blood flow influence drug metabolism
- can cause a reduced rate of elimination for “high-extraction” drugs (metabolism limited by liver blood flow)
- ex. cardiac insufficiency, beta-blockade
what are activating polymorphisms and what is their clinical effect
- PMs – CYP2C19 → decreased efficacy of PPIs for peptic ulcer disease
- PMs – CYP2D6 → insufficient analgesia with codeine due to failure to metabolize to active metabolite morphine
- UMs – CYP2D6 → codeine intoxication due to rapid metabolism to morphine
Drug metabolites (usually as conjugates which introduce a strong polar center into the molecule and increase its molecular weight) are also ____ where they can then be ____ back to _____ (more lipid-soluble) and _____ from the gut (enterohepatic recycling).
secreted into the bile
hydrolyzed by bacterial enzymes
the parent drug
undergo reabsorption
where are glucuronyl transferases present?
microsomal enzymes present in liver, kidney, and GI tract
how does alcohol consumption influence drug metabolism
- affects drug metabolism in a complex manner.
- Acute alcohol exposure competitively INHIBITS a variety of biotransformations.
- Chronic exposure without hepatocellular damage results in INDUCTION of some microsomal biotransformations (ethanol induces CYP2E1).
- In alcoholic cirrhosis effect is similar to cirrhosis, i.e., a DECREASE in metabolism.
Passive diffusion occurs with lipid soluble molecules in ___ and ___.
As water is reabsorbed, lumen to blood back-___ is favored as drug is concentrated in luminal fluid.
proximal and distal tubules
diffusion
possible outcomes of drug metabolism
- Metabolism of active drug to inactive or less active compound-comes out more water soluble and less active (most common)
- Metabolism of active drug to more active compound
- Metabolism of inactive compound (Prodrug) to active ingredient (designed)
- Metabolism to toxic metabolite (relatively rare)
*any combination is possible
characteristics of glomerular filtration
- all drugs smaller than albumin (MW: 69,000) will be filtered
- Only free drug is filtered, NOT protein-bound
- Renal excretion is primarily affected by renal blood flow and renal function
- Drugs cleared by this route have t1/2 ≈ 1-4 hrs (but extensive protein binding can prolong t1/2)
what are types of phase I hydrolysis
- Esterases- hydrolyze esters to corresponding alcohol and acid
- Amidases- hydrolyze amides to acids and amines
- Inhibitors of p-glycoproteins will____ plasma levels of drug substrates
- Inducers of p-glycoproteins will____ plasma levels of drug substrates
increase
decrease
what is the most important organ for drug excretion, esp. for water-soluble and non-volatile compounds
kidneys
milk concentration of ethanol and lithium can approximate
maternal plasma levels
what drugs are contraindicated by the AAP
amphetamines cocaine bromocriptine ergotamine lithium nicotine most antineoplastic agents drugs of abuse
how do lipid soluble compounds and high protein binding compounds affect breast milk
lipid soluble compounds–> increased milk concentration
high protein binding–> decreased milk concentration
