Drug Metabolism Flashcards
Metabolism
chemical modification of compounds by enzymes
What is the predominate site of metabolism? Explain
Liver
- Smooth ER of liver
- High concentration of drug metabolizing enzymes
- First organ perfused by compounds absorbed in the gut
Oral bioavailability
What is it influenced by?
Fraction of total dose that reaches systemic circulation
- solubility
- membrane permeability
- P-gp efflux (these transporters actively pump drug out of cell)
- Presystemic first pass metabolism
Phase I of drug metabolism
chemical modification (biotransformation) including oxidation, hydroxylation, etc. to introduce new functional group of expose group for Phase II reactions
mediated largely by P450
Phase II of drug metabolism
conjugation of polar group (e.g. acetyl, sulfate, etc.) with drug
drug conjugate displays increased water solubility and decreased lipid solubility
Roles of drug metabolism
- Termination of xenobiotic action
- bioinactivation
- detoxification
- elimination - Bioactivation
- prodrugs
- toxification
Bioinactivation
The drug metabolite(s) may be less active or completely inactive. The active site affinity for metabolites are frequently much lower than the parent compound
How is metabolism helpful in elimination?
Metabolism increases the polarity of drug metabolism, thereby:
- decreasing lipid solubility
- increasing water solubility
- –> increases ability to excrete drug
Prodrugs
The drug metabolite(s) may be more active than the parent compound, or the parent compound may require activation for biological activity
What molecules do CYP450s use in oxidation?
NADPH and oxygen
Important structural features of CYP450s?
- Heme group - iron group catalyzes oxidation
- Membrane bound
- Entry and exit pathways - determine specificity b/c determine what can fit
P450 reductase
protein associated with P450 in the CYP450 system; contains two prosthetic groups (FAD, FMN); serves as an electron transport protein
CYP nomeclature
Example: CYP2D6 * 1A
2 - familiy - 40% identity
D - subfamily - 50% identity
6 - individual gene
1A - allele
1/3 of all drugs are metabolized by
CYP3A4
1/5 of all drugs are metabolized by
CYP2D6
Catalytic center
Active site of CYP contains an iron-heme cofactor
Iron is coordinated to four N atoms of the heme, to one thiolate ligand derived from cysteine, and in the native state to a water molecule
Every CYP is in principle able to catalyze the same metabolic reactions, BUT …?
topography of protein binding site and steric hindrance of the access to the catalytic heme group are important factors for drug metabolism
Which intrinsic factors determine if and to which extent a chemical group of compound is metabolized?
- can compound enter binding site?
- Orientation, position, and conformation of ligand binding
- Strength of binding
- intrinsic reactivity
- accessibility of chemical group
What types of molecules have a strong affinity to the heme iron?
Molecules with nitrogen
Induction
Drugs bind to transcription factor proteins that induce transcription of CYP genes –> increased metabolism
Drug-drug interaction definition
DDI occur when the efficiency or toxicity of a drug is altered by the co-administration of another drug, food or chemical
What are the most common phase II enzymes?
UGT - [UDP]-glucouronosyl transferases
