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)
Sulfuration
SULT (Sulfotransferase) transfers sulfonate group from PAPS to a drug or drug metabolite (PAPS, 3’-
phosphoadenosine–5’-phosphosulfate)
glutathione conjugation
GST (glutathione-S-transferase) attach glutathione (Glu-Cys-Gly) to a drug or drug metabolite
outcomes of CYP inhibition
(a) exaggerated drug effects or toxicity due to reduced hepatic metabolism
(b) lack of drug effects due to impaired metabolic activation of prodrug
