Advanced Drug Metabolism Flashcards
What is the primary site of metabolism?
Liver
What is activation in metabolism?
Activation refers to the process when a drug is metabolized to a metabolite that has greater pharmacological activity than the administered drug
Pro-drug –> drug
What is bioactivation in metabolism?
Metabolic activation of a drug to a toxic metabolite
Drug –> toxic metabolite
What is the primary Phase I enzyme class?
P450
Out of the P450 superfamily, CYP 3A4 is the most important in drug metabolism (50% of drugs can be metabolized by CYP 3A4)
What are some characteristics of P450 enzymes?
Responsible for the hydroxylation, oxidation, or reduction of structurally diverse drugs
High affinity, but low capacity. Can be easily saturated (higher risk for drug interaction)
Associated with smooth ER and active site lies within ER membrane (drug needs to cross membrane into ER to be metabolized by P450)
List the Phase II enzymes
- UDP-Glucuonosyl transferases (UGT)
- Sulfotransferases (ST)
- Glutathione transferases (GST)
- N-Acetyltransferases (NAT)
- Methyltransferases
- Amino Acid conjugases
What are the characteristics of UGT enzymes?
Mediate the conjugation of UDPGA to drug substrates
Found in the lumen of the ER
ex. UGT1A and UGT2B
What are the characteristics of ST enzymes?
Catalyze the conjugation of inorganic sulfate to drugs containing hydroxyl functional groups
Found in the cell cytosol
Overlap substrate specificities with UGT enzymes
What are the characteristics of GST enzymes?
Catalyze the conjugation of glutathione to reactive intermediates
What are the characteristics of NAT enzymes?
Mediate conjugation of acetyl moiety of Acetyl-CoA to NAT substrates
Show genetic polymorphisms (slow vs. rapid metabolizers)
What are some factors that can impact the efficiency of metabolizing enzymes on PK?
- Drug-drug interactions (competitive enzyme binding)
- Interpatient variablility in enzyme efficiency
- Effect of Disease
What are some type of enzyme-related drug interactions?
Two types of enzyme-related drug interactions
- Direct competitive inhibition
- Induction of enzyme and/or transporter
What is direct competitive inhibition?
Victim vs. perpetrator drug
-Acute decrease in metabolism/transport of drug (victim drug) by simultaneously present drug (prepetrator drug)
- This caused by competitive binding by the perpetrator drug
- Consequence: Reduction in victim drug elimination, and its accumulation in the body to potentially toxic concentrations
What is enzyme induction?
- Net increase in enzyme/transporter upon exposure to drug
- Consequence: Increased metabolism of Drug A, such that plasma concentrations may fall below therapeutic window
What causes differences in enzyme efficiency?
Differences in enzyme efficiency can be caused by genetic, physiological, and environmental factors
Individuals in the population have a varied ability to metabolize certain compounds due to allelic diversity
ex. genetic polymorphisms
What is a genetic polymorphism?
It is a change in the nucleotide sequences of a gene encoding a drug metabolizing enzyme/transporters
This results in alleles with high or low efficiency and form biomodal distribution of phenotypes
What are the consequences of interpatient variability in enzyme/transporter efficiency?
- Reduction in Cls leads to increased half-life
- Altered metabolite profiles and production of active or toxic metabolites
- Altered drug-drug interactions
- Potential reduction in first-pass metabolism (increased bioavailability)
- Alteration to therapeutic effects of a drug (reduced efficacy)
How does disease affect how enzymes/transporters impact PK?
Disease is a major source of variability
Due to reduced function of elimination organs (Liver, kidneys, etc.)
What are the four phases of hepatic drug metabolism?
Phase 0 (transport in and out of cell thru basolateral membrane)
Phase I (ex. P450, MAO)
Phase II (conjugation)
Phase III (efflux into bile or other cells)
What are the two superfamilies of transporters?
- Solute Carrier (SLC) transporters
- ATP Binding Cassette (ABC) transporters
What are some characteristics of solute carrier (SLC) transporters?
- Facilitated diffusion (active in some cases)
- Bidirectional movement of drugs (commonly uptake transporters)
- Charged or uncharged weakly acidic or basic drugs, inorganic ions, ammonia, other endogenous compounds
ex. OCTs, OATs, PEPTs
What are some characteristics of ATP Binding Cassette (ABC) transporters?
- Primarily active transport (use ATP)
- Efflux (play a protective role, push drug out of cell even against concentration gradient)
- Lipophillic drugs, endogenous compunds, other polar or charged compunds
ex. P-glycoprotein (MDR1), MRPs, BCRPs (breast cancer resistance protein)
What is the importance of transporters?
- Influence drug absorption, distribution, and elimination
- Exert a protective function at blood-organ barriers
- Are sites for potential drug-drug interactions
How are transporters from the two transporter superfamilies distributed in the liver?
- Uptake (SLC) transporters expressed on the basolateral membrane (good for pulling drug from blood in hepatic vein into the liver)
- Efflux (ABC) transporters expressed at the apical (bile canicule) membrane (good for pushing drug into liver)
- Some Efflux (ABC) transporters at basolateral membrane (important for drug efflux and drug conjugates back into systemic circulation)
How are transporters from the two transporter superfamilies distributed in the intestine?
- Uptake (SLC) transporters expressed on the apical membrane (good for absorbing drug from the intestinal lumen)
- Efflux (ABC) expressed at the apical membrane (good for pushing drug into the systemic circulation)
- MIxed SLC (uptake) and ABC (efflux) transporters at the basolateral membrance
How are transporters from the two transporter superfamilies distributed in the kidneys?
Location of SLC (influx) and ABC (efflux) transporters if dependent on the location of the nephron
Some sites will see more influx, while others will see efflux
What is enterohepatic recycling (recirculation)?
Conjugated compound is deconjugated to parent drug and reabsorbed back into sytemic circulation
May lead to double peak due to original peak in concentration, and a second shorter peak caused by enterohepatic recycling
Review slide 30
Is enterohepatic recycling a component of elimination?
No, enterohepatic recycling functions to prolong the residence of drug in the body
