Enzymes and Transporters Flashcards
What is the equation for Cls?
Cls=Clh+Clr
What are the hepatic clearance mechanisms?
phase 1 (P450)
phase 2 (conjugating enzymes)
phase 3 (biliary excretion)
What are the renal clearance mechanisms?
glomerular filtration
tubular secretion and reabsorption
What is metabolism?
refers to chemical modification of a drug
results in formation of a metabolite
-typically results in inactivation of drug
What is the primary site of metabolism?
the liver
metabolism in other organs/tissues may be important for site specific toxicity or drug activity
How does formation of a metabolite help in excretion?
the metabolite is more polar so facilitates excretion by the kidney
Differentiate between activation and bioactivation.
activation:
-process when a drug is metabolized to a metabolite that has greater pharmacological activity than the administered drug
bioactivation:
-usually reserved to the metabolic activation of a drug to a toxic metabolite
What is phase 1 metabolism?
phase 1 pathways primarily involve CYP P450 enzymes
-uncover or introduce a functional group on the drug molecule
Aside from CYP P450, what are some other phase 1 enzymes?
xanthine oxidase
alcohol and aldehyde dehydrogenase
epoxidases
esterases
What is the action of CYP P450 enzymes?
superfamily of heme containing enzymes responsible for the hydroxylation, oxidation, or reduction of structurally diverse drugs
often referred to as mixed-function oxidases
What is the reason why CYP enzymes metabolize lipophilic drugs?
they are typically associated with the smooth ER and active site of the enzyme lies within the ER membrane
Why can CYP P450 enzymes saturate? What is the significance of this?
they demonstrate high affinity but low capacity
means many potential drug interactions occur at P450 enzymes
What is the most important CYP enzyme in drug metabolism?
CYP 3A4
What is phase 2 metabolism?
mediates the conjugation of an endogenous molecule to a functional group on a drug molecule or metabolite
-many of these endogenous molecules are derived from compounds involved in CHO, fat, and protein metabolism
What are the important phase 2 enzymes?
UGT
ST
GST
NAT
methyltransferases
amino acid conjugates
What is the action of UGT enzyme?
mediate the conjugation of UDPA to drug substrates
-family of enzymes found in smooth ER
-two families: UGT1A and UGT2B
-broad and overlapping drug substrate specificities (many drugs are metabolised by UGT enzymes); includes endogenous cpds
Are UGT enzymes easily saturated?
UGT enzymes demonstrate high capacity and therefore are difficult to saturate
-this means few drug interactions occur at UGT enzymes
What is the action of sulfotransferase (ST) enzymes?
catalyze the conjugation of inorganic sulfate to drugs containing hydroxyl functional groups
-found in the cell cytosol
-the different ST enzymes exhibit overlapping substrate specificities that overlap as well with the UGT enzymes
Are ST enzymes easily saturated?
ST enzymes show lower capacity and may saturate at higher drug concentrations
What is the action of GST enzymes?
catalyze the conjugation of glutathione to electrophilic or reactive substrates
-protective function in the cell by mediating the conjugation of glutathione to reactive intermediates and alkylating agents that arise during normal cell metabolism
What is the action of NAT enzymes?
mediates the conjugation of the acetyl moiety of acetyl-CoA to NAT substrates
-two families: NAT1 and NAT2
-NAT2 demonstrates a genetic polymorphism, which contributes to wide interindividual variability associated with NAT substrates
What percentage of drugs on the market are metabolized by CYP3A4? What about CYP2Cs, CYP2D6, and CYP1A2?
CYP3A4: ~50% of drugs on the market
CYP2Cs: ~30% of drugs on the market
CYP2D6 and CYP1A2: significant fraction
What are the three important reasons to have knowledge of the drug metabolizing enzymes that mediate the elimination of a drug?
drug-drug interactions
interpatient variability in drug PK (genetic polymorphism)
effect of disease (major source of variability in response)
When do drug-drug interactions occur?
when either the PK or PD of one drug is altered by a second drug