Metabolism - focus: influence on PK/ADME Flashcards
(24 cards)
What is the goal of most metabolism mechanisms?
To increase compound polarity to promote elimination
How are small MW drugs eliminated?
By the kidneys
How are large MW drugs eliminated?
By the bile and feces
What is most characteristic of all phase I metabolic reactions?
They increase polarity of the drug by introducing or revealing a polar N/O/S
What is most characteristic of all phase II metabolic reactions?
They are all conjugation reactions
Where are essentially all metabolic enzymes located?
ER
Name the most common phase I metabolism reactions
Oxidation, reduction, hydrolysis, dealkylation
What is the most important class of metabolic enzymes?
CYP450s
What is bioactivation?
The process of metabolic enzymes converts compounds into something toxic
How does CYP450 induction occur?
Drugs can interact with transcription factors that leads to expression of CYP450s
What is a major complication of CYP450 induction?
Increasing CYP450 concentrations can lead to increased metabolism of other drugs (drug-drug interactions)
What are some side effects of CYP450 induction?
Increased metabolic rate, decreased plasma drug concentration, increased activity/toxicity of pharmacologically active metabolites
What are the two mechanisms in which CYP450s can be inhibited?
Irreversible and reversible inhibition
What are some factors that can influence metabolism?
Liver disease, age, sex, and genetic polymorphisms
How can liver disease influence metabolism?
This can decrease metabolic rates and first-pass metabolism (potentially increase bioavailability)
How can age influence metabolism?
Metabolic enzymes are expressed differentially across differ ages. Physiological changes like blood flow can impact metabolism rate
How can sex influence metabolism?
Some CYPs have sexual dimorphisms. Pregnancy and estrogen are known to influence CYP450 expression
How can genetic polymorphisms influence metabolism?
Certain CYPs have different polymorphisms that influence metabolism rate (extensive, intermediate and poor metabolizers)
What is the most prevalent phase II metabolic reaction?
Glucuronidation by UGT using UDGPA
Since glucuronidation leads to biliary elimination, what other process are these metabolite susceptible to?
Enterohepatic recirculation
What phase II reaction competes with glucuronidation at low drug concentrations?
Sulfation by SULT using PAPS
What are the most common phase II reactions?
Glucuronidation, sulfation, glutathione-conjugation, acetylation and methylation
Of the phase II reactions, which decrease polarity?
Acetylation and methylation
What type of molecules doees gluthatione conjugation target?
Electrophiles
