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
