Drug Metabolism Flashcards
Major Routes for Drug Elimination
1) excreted through KIDNEY UNCHANGED
2) biotransformation of drugs or xenobiotics
Major Route I
Excreted through KIDNEY UNCHANGED
- pivotal role with drugs that have small molecular volumes or possess polar characteristics
Major Route II
Biotransformation of drugs or xenobiotics
- biotransformation into more HYDROPHILIC metabolites is critical for termination of biological activity and elimination for the body
Drug Metabolism
- biotransformation of drugs to polar and hence more readily excretable products
Drug Metabolizing Enzyme Groupings I vs II
- enzymes catalyze PHASE I or Functionalization Reactions
2. enzymes catalyze PHASE II or Conjugation (biosynthetic) Reactions
Phase I
Functionalization Reactions
- introduce or expose a polar functional group on the parent compound
(add handle)
Phase II
Conjugation (Biosynthetic) Reaction
- typically involve the conjugation of endogenous compounds to phase I products to yield highly polar conjugates
(add something to handle)
Examples of Phase I Reactions
- Aliphatic hydroxylation to alcohol (add OH)
- Aromatic hydroxylation to phenol
- Oxidation at S (on N)
Sites of Drug Metabolism/Biotransformation (Tissue Level)
- Liver: principal organ of drug metabolism
- other tissues include GI tract, lungs, skin, and kidneys
Sites of Drug Metabolism/Biotransformation (Subcellular Level)
- most drug metabolizing activity occurs in the ER and the cytosol
- Phase I Enzymes: ER of liver (microsomal enzymes)
- Phase II Enzymes: cytosol of liver cell
Cytochrome P450 Mixed Function Oxidase System
- major enzymatic system for Phase I drug metabolism reactions
- metabolizes large number of environmental chemicals, food toxins, and drugs
P450 Oxidative Reaction Requirements
- enzymes
- cytochrome p450
- NADPH-cytochrome P450 reductase
- cofactor NADPH
- ACTIVATED molecular O2
Cytochrome P450 Specificity
- low substrate specificity and inducibility
- not high specificity; just needs high level of lipophilicity
Activated Oxygen
- very potent oxidizing reagent
Most Important Phase I Enzyme
Cytochrome P450
CYP450 General Properties (LIST)
- have tremendous capacity to metabolize a large number of structurally diverse chemicals
- —- a single compound can be metabolized at different positions on the molecule
- —- a single molecule can be metabolized by different CYPs (overlapping substrate specificities)
- inducible by a variety of chemicals
- —- induced by presence of substrate
Phase II (Conjugation) Reactions (description)
- involves specific transferases, which typically are located in the CYTOSOL of ER
- catalyze the coupling of an “energy-rich” (activated) endogenous substance with an exogenous or other endogenous compound
highly polar nature promotes elimination in the urine or bile
Types of Phase II (Conjugation) Reactions
- glucuronidation
- acetylation
- glutathione conjugation
- sulfate conjugation
- methylation and water conjugation
etc
Glucuronidation
Enzymes, Endogenous Reactant
MOST ABUNDANT\IMPORTANT Phase II
- Versatile: O-, N-, S- glucuronidations
The Enzymes: UDP-glucuronosyltransferases
Endogenous Reactant: UDP-Glucuronic Acid
Glutathione Conjugation (Enzymes, Endogenous Reactant, Two Genes)
Phase II
- conjugation of reactive electrophilic compounds with the tripeptide glutathione is a major detoxification pathway for drugs and carcinogens
The Enzymes: Glutathione-S-transferase Endogenous Reactant: Glutathione (Glu-Cys-Gly) The Genes: two supergene family --- Cytosolic GSTs: 16 genes --- Membrane GSTs: 6 genes
v. important for detox; not enough glutathione = liver damage
Sulphation
Enzymes, Endogenous Reactant
Phase II
The Enzymes: Sulphotransferase
Endogenous Reactant: PAPS (3’-Phosphoadenosine-5’-phosphosulfate)
Isoniazid (INH)
Phase II reactions precede phase I reactions
Importance of Drug Metabolism: Alter Pharmacodynamic Properties of Drugs
- metabolic products are OFTEN INACTIVE or LESS ACTIVE than parent drugs
- some metabolic products may have ENHANCED activity
- – e.g. inactive prodrugs may convert metabolically to active drugs
Importance of Drug Metabolism: Alter Pharmacokinetic Properties of Drugs
- OFTEN DRAMATICALLY INCREASE CLEARANCE AND SHORTEN HALF LIVES
Importance of Drug Metabolism: Affect Toxicity Properties of Drugs
- USUALLY DETOXIFY
- – some metabolic products have enhanced toxic properties (acetaminophen)
Importance of Drug Metabolism
- alter pharmacodynamic properties of drugs
- alter pharmacokinetic properties of drugs
- affect toxicity properties of drugs
FDA Mandate: before NDA can be applied
route of metabolism and enzymes involved must be known
Factors Affecting Drug Metabolism
- Genetic Factors: defects; polymorphisms
- Non-Genetic Factors: age; sex; diseases
- Environmental Determinants: dietary factors; environmental factors; drug-drug interactions; drugs and endogenous compound interactions
Environmental Determinants
- Dietary factors: smoking, alcohol consumption, etc
- Environmental factors: pollutants, pesticides, etc
- Drug-Drug interactions: inhibition or induction of drug metabolism
- Drugs and Endogenous Compound interactions
Genetic Factors in Drug Metabolism
- contribute to large interindividual differences in metabolic rate
N-Acetylation of Isoniazid
NAT2 mutation
- genetic factors change metabolism
- polymorphism of NAT2 gene (if 2 of “slow” NAT2) slow acetylation
- – reducing dosage or increasing dosing interval is recommended
Induction
3 examples
- increasing the amount of enzymes -> increasing metabolism -> decreased effect
- induce cytochrome P450 gene (making more of enzyme) and increase metabolism rates of drugs
- charcoal-broiled food
- cruciferous vegetables
- induces CYP1A3 (warfarin)
Inhibition
2 examples
- inhibiting activity of enzymes
- ** DANGEOUS: because if keep increasing level of drug to induce response you could reach toxicity***
- increasing enzyme inhibition -> decreased metabolism -> increased effect
- grapefruit juice (CYP3A4): cyclosporine
- Alcohol
Drug-Drug Interactions: Inhibition of Metabolizing Enzymes
- inactivation of CYP enzymes by certain drugs
- consequence: may impair elimination of the more slowly metabolized drug, prolong or potentiate pharmacological effects, and incidence of drug-induced toxicity
- induce/inhibit metabolizer of other drugs
Diseases & Effect of Drug Metabolism
- acute and chronic diseases that affect LIVER function or architecture markedly diminish the metabolism of some drugs
cyclosporine inhibition
grapefruit juice (CYP3A4)
Warfarin Inhibition
- charcoal-broiled food
- cruciferous vegetables
- induces CYP1A2
Chlordiazepoxide and Diazepam t1/2 increase
hepatitis & cirrhosis
diseases that affect liver function
Aminopyrine Impaired Oxidative Metabolism
cancer
CYP3A4 and John’s Wort interaction
John induces CYP3A4; reduce concentration of oral contraceptives and other drugs co-administered
How are drugs eliminated from the body?
- make polar and soluble so can eliminate
Pathways of drug elimination
Phase II (conjugate) -> elimination Phase I (drug metabolite with modified activity / inactive drug metabolite) -> Phase II (conjugate) -> elimination
Lipophilic -> Hydrophilic
What increases half life of chlordiazepoxide and diazepam
Hepatitis and Cirrhosis
What impairs oxidative metabolism of aminopyrine
cancers
