Drug Metabolism Flashcards
Xenobiotics
foreign substances that are not naturally found in the body
first-pass effect
Substances absorbed via the GI tract go to the liver before they enter general circulation, then may either be redelivered to the liver or go to some other tissue
Often the same chemical property that enhances bioavailability of drugs may also make ____ difficult
Often the same chemical property that enhances bioavailability of drugs may also make renal excretion difficult
phase I reactions
Redox
phase II reactions
Conjugation/hydrolysis
Oxidation reactions typically transform the drug into more ____ metabolites by _____
Oxidation reactions typically transform the drug into more hydrophilic metabolites by adding or exposing polar functional groups such as hydroxyl (-OH) or amine (-NH2) groups
Most liver enzymes which catalyze phase I reactions are _____.
Most liver enzymes which catalyze phase I reactions are heme protein mono-oxygenases of the cytochrome P450 class.
Importance of iron to the p450 enzymes
The iron within the heme group of the p450 enzyme is what activates oxygen for the p450 oxidation reactions.
This is so synonymous with p450 function that the p450 enzmyes are sometimes also called “oxygen guns”
alcohol dehydrogenase
non-p450 oxidative liver enzyme
oxidizes alcohols to their aldehyde derivatives as part of the overall process of excretion. These enzymes are the basis for the toxicity of methanol. Methanol is oxidized by alcohol dehydrogenase to formaldehyde
monoamine oxidase
non-p450 oxidative liver enzyme (also found outside of the liver)
responsible for the oxidation of amine-containing endogenous compounds such as catecholamines and tyramine.
Hydrolysis of ester- and amide-containing drugs is sometimes included among the. . .
. . . phase I reactions, despite its mechanism (hydrolysis) more closely resembling that of a phase II reaction.
____ is the most common group that is conjugated to drugs to facilitate their excretion
Gluconuric acid is the most common group that is conjugated to drugs to facilitate their excretion
Common phase II adducts
Glucuronic acid, acetate, glycine, sulfate, glutathione, and methyl groups
____, an important exception to the phase II reactions, does not increase drug hydrophilicity
Methylation, an important exception to the phase II reactions, does not increase drug hydrophilicity
Enzymes involved in redox and conjugation/hydrolysis reactions often ____.
Enzymes involved in redox and conjugation/hydrolysis reactions often compete for substrates
Following phase I and II reactions, drug metabolites may be too polar to ______.
Following phase I and II reactions, drug metabolites may be too polar to leave the cell
For this reason, liver cells have pumps which may actively secrete processed, highly hydrophilic molecules
P-glycoprotein
An example of a hepatocyte ATP-dependent hydrophilic small molecule pump
Also expressed in various other tissues to serve similar functions
P-Glycoprotein in the placenta
Actively pumps drugs back into the mother’s blood
Pathologic overexpression of ______ can play a role in development of resistance of cancer cells to drugs.
Pathologic overexpression of P-glycoprotein can play a role in development of resistance of cancer cells to drugs.
The metabolism of drugs from the portal circulation (i.e., the first-pass effect) often requires the transport of compounds into hepatocytes via ____ and ____.
The metabolism of drugs from the portal circulation (i.e., the first-pass effect) often requires the transport of compounds into hepatocytes via the organic anion transporting polypeptide (OATP) and the organic cation transporter (OCT) family of proteins.
____ are particularly relevant for the metabolism of several statins.
OTAP and OCT are particularly relevant for the metabolism of several statins.
organic anion transporter (OAT) family
responsible for renal excretion of many clinically important anionic drugs, such as β-lactam antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), and antiviral nucleoside analogs.
Induction
Occurs when one drug drug induces upregulation of a P450 enzyme that metabolizes the another drug, resulting in faster activation/inactivation of the second drug.
The primary mechanism is through increased transcription
Carbamazepine’s interaction with p450 enzymes
An antiepileptic drug, not only induces P450 3A4 but also is metabolized by P450 3A4. Hence, carbamazepine increases its own metabolism by inducing P450 3A4.
Inhibition
When addition of a second drug intereferes with the metabolism of the first drug. May be the result of competitive antagonism or irreversible inhibition.
Mitomycin C
A naturally occurring compound that is activated to a powerful DNA alkylating agent after it is reduced by several enzymes including a cytochrome P450 reductase.
Mitomycin C selectively kills hypoxic cancer cells in the core of solid tumors because: (1) these cells have increased levels of the cytochrome P450 reductase that activates mitomycin C; and (2) reoxidation of the drug is inhibited under hypoxic conditions.
Neonatal jaundice
results from a deficiency of the bilirubin-conjugating enzyme UDPGT
Gray baby syndrome
Excretion of chloramphenicol requires an oxidative transformation followed by a conjugation. The oxidation metabolite of chloramphenicol is toxic; if this metabolite fails to undergo conjugation, it can build up in the plasma and may reach toxic concentrations. Toxic levels of the metabolite can cause neonates to experience shock and circulatory collapse, leading to the pallor and cyanosis that give the syndrome its name.
In the elderly, a general ____ in metabolic capacity is observed
In the elderly, a general decrease in metabolic capacity is observed
Grapefruit juice effect and hepatic metabolism
The psoralen derivatives and flavonoids in grapefruit juice inhibit both P450 3A4 and MDR1 in the small intestine. Inhibition of P450 3A4 significantly decreases the first-pass metabolism of co-administered drugs that are also metabolized by this enzyme, and inhibition of MDR1 significantly increases the absorption of co-administered drugs that are substrates for export (efflux) by this enzyme.
Rifampin
Antibiotic which induces p450 enzmyes that cause estrogen-based hormonal contraception to be ineffective at standard doses due to metabolism of the common estrogenic component 17α-ethynylestradiol
Tolerance
when a drug induces its own metabolism and thus reduces its efficacy over time
Because drugs are often prescribed in combination with other pharmaceuticals, careful attention should be paid to drugs that are ____
Because drugs are often prescribed in combination with other pharmaceuticals, careful attention should be paid to drugs that are metabolized by the same hepatic enzymes
One treatment for methanol poisoning is the administration of ____, which competes with methanol for oxidation by alcohol dehydrogenase
One treatment for methanol poisoning is the administration of ethanol, which competes with methanol for oxidation by alcohol dehydrogenase
In addition to hepatic and renal regulation, ___ is a major regulator of drug metabolism
In addition to hepatic and renal regulation, the thyroid is a major regulator of drug metabolism
At steady state, ____ equals ____.
At steady state, drug infusion equals drug elimination.
Relationship between drug infusion and elimination kinetics
A drug will reach steady state in about ____ half-lives
A drug will reach steady state in about four half-lives
The sole determinant of the rate that a drug approaches steady state is . . .
The sole determinant of the rate that a drug approaches steady state is the t1/2
The rate of approach to steady state is not affected by the rate of drug infusion. Rather, increasing the infusion rate will increase the steady state concentration.
Oral dosing and IV infusion pharmacokinetics
Loading dose calculation
A loading dose is most useful for drugs that are eliminated from the body ___
A loading dose is most useful for drugs that are eliminated from the body relatively slowly
Dosing
Role of P glycoprotein in various tissues
Most important of the p450 enzymes
CYP2D6 and CYP3A4
Both also highly polymorphic
Variants of ___ may classify individuals as “ultrametabolizers” or “undermetabolizers”
Variants of CYP2D6 may classify individuals as “ultrametabolizers” or “undermetabolizers”
Some ____ inhibit the activity of CYP2D6
SSRIs
Codeine is a ____.
Codeine is a prodrug. It is metabolized to morphine in the liver by CYP2D6. On this basis, it is though to be substantially more dangerous to use than just plain old morphine. This is because:
- Ultrametabolizers may metabolize codeine too quickly, resulting in morphine toxicity
- Undermetabolizers may not obtain pain relief because they metabolize codeine too slowly
There is seriously no reason to give codeine instead of morphine
Only step of ADME that P glycoprotein has no effect on
Metabolism
the 4 x t1/2 rule only applies to ___.
the 4 x t1/2 rule only applies to 1st order elimination kinetics.
RD calculation
RD = [Drug]steady state x RC x F-1
Where RC = 0.693 x Vd / t1/2
Vd is often given as
L/kg
Definition of RD’
RD’ may be defined as
RD’ = RD x F
such that
RD’ / RC = [Drug]steady state
