Drug Metabolism Flashcards
describe drug metabolism
Drug metabolism is the chemical transformation of a drug into one or MORE products within the body
Describe first pass metabolism
reduces the the bio availability of drugs that are administered orally (presystemic metabolism)
- occurs in liver and stomach (gut wall)
Describe the main sites involved metabolism
metabolism is mediated by enzymes (DMEs)
Found mainly in Liver
- membranes of endoplasmic reticulum of hepatocytes
- cytosol
- mitochondria
Can occur in other tissues e.g. brain, lungs, stomach, plasma
describe the main reactions to phase 1
- oxidation
- add an oxygen atom to the parent drug
- remove an hydrogen from a parent drug - hydrolysis
- ester and amide bond - Dealkylation
- e.g. demethylation - removal of a methyl group
the main reactions in phase 2 metabolism
goal is to attach a polar endogenous molecule to a functional group in a drug - increasing hydrophilicity
- glucuronidation
- UGT transfers glucuronic acid from UDP-glucuronic acid to a drug
or drug metabolite - Sulfuration
- SULT transfers sulfonate group from PAPS to a drug or drug metabolite - glutathione conjugation
- GST attach glutathione to a drug or drug metabolite
describe outcomes of drug metabolism with drug examples
- increases molecular size and hydrophilicity
- reduce tendency to accumulate
- facilitate renal excretion - decreases drug elimination half-life (t1/2)
- drug elimination half-life (t1/2) is the time taken for the drug plasma concentration to decrease by 50% and is calculated during the elimination phase - alters pharmacological activity or induces toxicity
- drug metabolism can terminate the action of a drug
- drug metabolism generates metabolites that have their own chemical properties and may be
biologically active or inert
CYP450 enzymes
Family of drug metabolising enzymes
57 CYP genes in human genome
- classified into 18 families and 43 subfamilies
- metabolism of drugs and xenobiotics - CYP1, CYP2 and CYP3
CYP-rich microsomes
1.found in ER of hepatocytes
2. Liver homogenates undergo sequential
centrifugation at ultra-high speed
3. CYP450 concentrated in microsomes (formed
from ER fragments)
4. Used in in vitro studies to investigate drug
metabolism
name important CYP450 members
CYP3A4
- most important
- broad substrate specificity
CYP2D6
CYP2E1
explain CYP450-mediated drug-drug interactions
Drug interaction is the process by which a substance alters the action and/or kinetics of a drug
1. CYP Induction
- drugs cause ↑ CYP expression
- ↑ Metabolism
2. CYP inhibition
- drugs compete for the active site of an enzyme when co-administered
- a common mechanism of drug-drug interactions
- a CYP inhibitor itself may or may not be a substrate for the enzyme
- mechanism-based inhibition: irreversible inhibition of an enzyme due to formation of a complex between the enzyme and a reactive
metabolite via covalent bonding
examples of CYP450-mediated drug-drug interactions
Clinical use of pharmacokinetic enhancers
Used as an inhibitor to treat HIV protease - reducing the metabolism of CYP3A4 and enhancing therapeutic effects by increasing plasma conc.
Ritonavir
- potent CYP3A4 inhibitor
Cobicistat
-a CYP3A4 inhibitor
UGT
UDP glucuronosyltransferase
UDP
uridine diphosphate
glucuronidation
- most common reaction
- UGT (UDP glucuronosyltransferase) transfers glucuronic acid from UDP-glucuronic acid to a drug
or drug metabolite (UDP = uridine diphosphate)
