Drug Metabolism Flashcards
Reasons for Drug Metabolism
- lipophilic xenobiotics are not rapidly eliminated which become toxic
- Evolution of enzymes that metabolize lipophilic and toxic xenobiotics to prevent accumulation and toxicity
- Enzymes xenobiotics –> polar compounds by adding reactive groups = increased hydrophilic nature
- Convert xenobiotics to more polar compounds
What are examples of functional groups added to drug by enzymes?
OH, COOH, NH2, sulfate, glucuronic acid, glutathione
Biotransformation Phases
Phase 1: Oxidation - catalyzes drug to yield a functional group
Phase 2: Conjugation - adds a functional group
How does metabolism “eliminate” parent drug?
transformation
Function group has what main effect?
barely affects solubility, main effect is inactivation of drug
Consequences of Phase I metabolic reaction
Inactivation of parent drug
Conversion of active drug to active metabolite
Conversion of inactive drug (pro-drug) to an active drug metabolite
Generation of “reactive” metabolite
Phase II Reactions (Conjugation reactions) definition
covalently conjugates endogenous compounds to function groups catalyzed by phase I reactions on drug
Examples of conjugates added to drug during phase Ii reaction
glucuronic acid, sulfate, glutathione, amino acids, acetate
What is the goal of adding functional groups to create drug conjugate?
lead to inactive metabolites, higher MW, highly ionized, more polar and hydrophilic, therefore easier to eliminate
What does acetylation do?
yields less polarized metabolites, but inactivates drug
Permutations of Drug Metabolism & Elimination
Drug –> active metabolite –> conjugation –> elimination
Drug –> inactive metabolite –> conjugation –> elimination
Drug –> BYPASS phase I –> conjugation –> elimination
Drug –> BYPASS phase I AND phase II –> elimination
Hydrophobic drug –> hydrophilic –> elimination
Types of Metabolic Reactions
Phase I (Functionalization Reactions) Phase II (Conjugate Reactions) Phase III (Transporter Enzymes)
Effects of Phase III Reactions
- regulate bioavailability, distribution, and excretion of drugs
- source of resistance to anti-neoplastic drugs/antibiotics
- responsible for NT reuptake at nerve endings
How do transporter enzymes impact bioavailability, distribution, and excretion of drugs?
act with phase I and II to reduce xenobiotic
affect endothelial barrier function so drugs can be pumped out after crossing membrane
How do transporter enzymes impact resistance to anti-neoplastic drugs/antibiotics?
In cancer cells:
- mutations will lead to decreased enzyme uptake
- upregulation will increase efflux of chemotherapeutic agents
In bacteria:
- mutations decrease expression/function of bacteria
- transporter decreases uptake of antibiotics by bacteria
How do transporter enzymes impact NT reuptake at nerve endings?
DAT and SERT transporters
SSRIs target these transporters
Metabolism of Biological Protein Drug (Biotherapeutics)
used to treat chronic conditions
range of 3 kDa to 150 kDa to 1000 kDa
metabolized by degradation due to serum and tissue proteases
change size and/or charge to increase absorption and distribution
mAbs or Fc containing proteins bind to neonatal Fc receptor to increase residence times to weeks
Recycling vs. Transcytosis
Uptake of antibody, antibody binds to FcRn receptor and becomes bound to protect it from lysosomes, which is then released on the same side of where it entered (recycling) or opposite side of where it entered (transcytosis)
Sites of Metabolism
mucosal sites and microflora express many of the same metabolizing enzymes as found in liver Liver Lung Kidney Intestines Adrenals Skin Placenta
What is “pre-absorption”?
other sites that add to 1st pass metabolism even before the liver
Liver & intestine enzymes
CYP1A1, 1B1, 2C, 2D6, 2E1, 3A4, 3A5
Liver only enzymes
CYP1A2, 2A6. 2A7, 2B6, 2F1, 3A7, 4B1
Site of Biotransformation
drug enters via portal venule, converges with hepatic arteriole, enters space of Disse, moves to sinusoid, close contact with hepatocyte, moves to central vein
Subcellular sites in hepatocytes for metabolizing enzymes/transporters
SER - phase I enzymes
cytosol - phase II enzymes (except UGTs are in SER)
Phase I Enzymes - Cytochrome P450 Complex (CYP)
cytochrome P450 (CYP) and NADPH-P450 reductase
Role of Cytochrome P450 (CYP)
heme-containing mono-oxygenase that requires NADPH. O2, and phospholipid
Role of NADPH=P450 Reductase
transfer electrons to CYP to activate O2 to an oxidizing state
