Drug Metabolism Flashcards
Structural modification of the drug via oxidation, reduction, or hydrolysis:
Phase 1 Reactions
Consequences of phase 1 modifications:
- inactivation of the parent drug
- conversation of active drug to an active drug metabolite
- conversion to a toxic metabolite
- generation of a “reactive” metabolite
- conversion of an inactive drug to an active drug metabolite
Also called conjugation reactions because produce of phase 1 reaction is conjugated to a large, endogenous molecule:
Phase 2 Reactions
Conjugation almost always results in conversion of drug to inactive metabolite that are highly:
ionized, polar, hydrophilic
Action of drug efflux transporters regulates bioavailability, distribution, and excretion of drugs; act in concert with. phase I and II enzymes to reduce systemic exposure to xenobiotics:
Phase 3 Reactions
Contribute to endothelial barrier function:
Phase 3 Reactions
Most important site of enzymes that metabolize and transport drugs:
Liver - greatest concentration of metabolizing enzymes
T/F. Hepatic metabolism is not high enough to remove most of the drug from the portal blood passing through the liver.
False; hepatic metabolism IS high enough.
First-pass or presystemic metabolism is referring to:
metabolism in the liver; oral drugs transported via portal vein
Subcellular locations of drug metabolizing enzymes/transporters for Phase 1 enzymes, Phase 2 enzymes, and Phase 3 transporters:
Phase 1 enzymes: smooth endoplasmic reticulum of the liver;
Phase 2 enzymes: cytosol, enzymes are soluble (except UGTs in SER);
Phase 3 transporters: apical (luminal side) and basolateral (blood side) membranes of GI and renal tubular epithelial cells, plasma and canalicular membranes of hepatocytes
Cytochrome P450 Complex (CYP) is what kind of enzyme?
Phase 1 enzyme
The net result of CYP-catalyzed oxidation (hydroxylation) reaction is:
Drug + O2 +NADPH + H+ –> Drug-OH + H2O + NADP+
Nomenclature: How to name CYP gene superfamily:
CYP + family number + subfamily letter + individual gene number, ex: CYP1A2, CYP2D6
Three CYP isozymes that account for the metabolism of most drugs:
CYP 3A4/5, 2C8/9, 2D6
Amine oxidases, dehydrogenase, flavin-containing monooxygenase (FMO), reductases are what kind of enzymes:
Phase 1 enzymes
Monoamine oxidase (MAO); oxidize endogenous catecholamine neurotransmitters and synthetic analogs:
amine oxidases
Alcohol (ADH) and aldehyde (ALDH) dehydrogenases, oxidize alcohols to aldehydes and aldehydes to acids:
Dehydrogenases
Oxidizes substrates with N-, S-, P- moieties, not C, similar to CYPs but are only minor contributors to drug metabolism, can metabolize nicotine, some H2 receptor antagonists, and antipsychotics
Flavin-containing monooxygenase (FMO)
Carry out reduction of ago-, nitro-, and carbonyl groups on drug molecules, located in the liver and in anaerobic bacteria of the GI tract
reductases
Hydrolysis inactivates some parent ester drugs, but activates other ester prodrugs (bioactivation) (esterification improves oral bioavailability) with these enzymes:
Hydrolytic enzymes
Carboxylesterases, amidases, epoxide hydrolase (EH) are examples of what kind of enzymes?
Hydrolytic
Acetylcholinesterase (neurons) and butyrylcholinesterase (plasma) hydrolyze ester-containing drugs, acetylcholine and its synthetic analogs; bioactivation of lovastatin (pro-drug) inhibits formation of mevalonate (precursor for cholesterol), what enzyme is this?
carboxylesterases
This enzyme hydrolyzes amide linkages in drugs:
amidases
This enzyme hydrolyses epoxide metabolites produced by CYP-mediated metabolism of aromatic rings (epoxides are reactive metabolites):
epoxide hydrolase (EH)
Conjugation or synthetic reactions refers to these types of enzymes:
Phase 2 enzymes
Where are phase 2 enzymes mostly found and what is the exception?
cytosol (except UGTs in SER)
These enzymes use reactive of functional groups on drugs or drug metabolites to covalently combine an endogenous molecule:
Phase 2 enzymes
Acceptor site functional groups of Phase 2 enzymes:
hydroxyl, epoxide, nitrite, amine, sulfide
Endogenous donor molecules of phase 2 enzymes:
glucoronic acid, sulfate, glutathione, amino acids, or acetate
Phase 2 enzymes have what effects on drugs?
- inactivates
- usually makes drug more polar
- greater molecular weight
- more easily excreted in bile and urine
UDP-glucuronyltransferase (UGT) is what type of enzyme?
Phase 2 enzyme
UGT is only phase 2 enzyme found where?
SER (not cytosolic), it is in Cole proximity with CYPs
T/F. UGT attaches glucuronic acid to acceptor sites (OH, NH2, COOH, sulfonamide) on drug substrates. And the enzyme produces what metabolite?
TRUE, produce “glucuronide conjugate” metabolite
UGT1 and UGT2 are involved in conjugation of?
Drugs and bilirubin
Attaches sulfo- groups to acceptors sites (-OH groups) on drug substrates
sulfotransferase (SULT); “sultan conjugate” metabolite which is very polar
Attaches glutathione (GSH) to acceptor sites on substrates (which are often reactive metabolites of certain drugs)
Glutathione-S-transferase (GST); produce a “GSH conjugate” metabolite
Attaches acetate to aromatic amine and hydrazine drug substrates:
N-acetyltransferase (NAT); produces an “acetylated” metabolite; two human acetylkator genes: NAT1, NAT2
Methylates various substrates:
Methyltransferase (MT)
These enzymes metabolize over 80% of all drugs:
NATs, GSTs, UGTs, and SULTs
Types of Phase III Enzymes:
ATP Binding Cassette (ABC) Transporters, SoLute Carrier (SLC) Transporters
Rate of metabolism can control ______ and _____.
Drug Efficacy and Toxicity
What is the major source of adverse drug interactions?
Drug Metabolism
8 factors influencing drug metabolism:
enzyme induction, enzyme inhibition, pharmacogenetics, age, nutrition and diet, disease, hormonal effects, intestinal microflora
The increase in concentration of metabolizing enzymes or transporters following exposure to xenobiotics; up-regulation:
Induction
Enzyme inducing xenobiotic examples:
Tobacco smoke and charbroiled foods - CYP1a (carcinogens), Ethanol - CYP2E1 (acetaminophen), St. John’s wort (herbal) - CYP3A4, MDR1
Xenobiotic sensing receptors:
Inducers (enzyme induction)
Examples of xenobiotic sensingg receptors:
MDR1, OATP2, UGT1A2, GSTA1
Consequences of enzyme induction:
- diminish plasma drug levels to below therapeutic levels
- may increase toxic metabolites
- Long term chronic exposure may induce enzyme levels that never return to baseline after cessation (smoking induced expression of CYP1A)
Diminishes rate of enzyme activity:
Enzyme inhibition
Terms to describe inhibition ceasing when inhibitor eliminated vs. when inhibitors are irreversible:
competitive vs. non-competitive
Consequences of inhibition:
drug-drug interactions when taking multiple drugs, one drug inhibits the metabolism of another
Examples of inhibiting enzymes:
grapefruit juice (CYP3A4, 1A2, 2B6 in intestine), Antifungals and histamine antagonists in liver, HIV-1 protease inhibitors inhibit CYP 3A4
Why is it important to have accurate history of all reactions and drug combinations of your patient?
to avoid drug-drug interactions
Addresses the influence of genetic variations on drug responses:
Pharmacogenetics
Polymorphisms- Populations with tri-modal activities of:
poor (gene deleted), rapid (wild type), and ultra-rapid (gene duplicated)
Examples of Phase 1 Enzyme Polymorphisms:
CYP2D6 = antiarrhythmics, beta-blockers, CYP2C9 = warfarin, phenytoin, CYP2C19 = warfarin, antidepressants, CYP3A4 = few polymorphisms affect enzyme activity
Effects of inactive or multiple CYP2D6 genes:
1 functional group = SLOW, exhibit toxic drug effects, 13 functional groups = RAPID, exhibit no beneficial effects of drug
Examples of Phase II Enzyme Polymorphisms:
NAT2 (n-acetyl transferase-2) and UGT1A1 (glucuronidation of bilirubin)
Difference between NAT24 vs. NAT25:
NAT24 = rapid acetylator (US asians) vs. NAT25 = slow acetylators (US whites and blacks)
Gilbert’s Syndrome is related to what polymorphism:
UGT1A1*28, TATA Box
A 70-80% reduction in UGT activity results in:
HYPERbilirubinemia leading to coronary artery disease
The study to devise drug regimens to maximize efficacy and minimize adverse effects
Pharmacogenetics
How does age influence drug metabolism?
The older you are, the more drugs you probably take. Therefore, start with a low dose and give very slowly to help with adverse drug effects. Use Phase II (UGT) more in elderly or those with liver disease.
Intestinal microflora can diminish Beta-glucuronidases. T/F.
True, bacteria plays role.
