Drug Metabolism Flashcards
Drug metabolism
is the chemical transformation of a drug into one or more products within the body
Drug metabolism does
- not occur for all drugs (like lithium)
- protect the body against xenobiotics (e.g., drugs, toxins) - liver (primary) and other organs/tissues
- first-pass (pre-systemic) metabolism (gut wall & liver)- ↓ bioavailability of orally administered drugs
Drug metabolism is mediated by what and involves what reactions
enzymes
oxidation, reduction,
hydrolysis and/or conjugation
drug metabolising enzymes (DMEs)
- Rich in liver
- On membrane of ER of hepatocytes (liver cell like CYP450)
- In cytosol (AD) or mitochondria (AldD) and other tissues/organs like the brain, lungs, plasma and intestines
First pass
the substance degradation of an orally administered drug caused by enzyme metabolism in the liver before the drug reaches the systemic circulation. It decrease the bioavailability administered of drugs
Phase 1 Metabolism
Oxidation, reduction, hydrolysis
Parent drug (P1) metabolites (P2) conjugated metabolites
conjugated metabolites
virtually always inactive, very polar and/or ionized, and easily excreted.
(products of Phase II reactions)
Phase 1 metabolism ethanol example
Ethanol (CH3CH2OH)
ADH (Alcohol Dehydrogenase) - removes H from parent drug
Forms: Acetaldehyde (CH3CH2O)
Phase 1 metabolism tenofovir disoproxil example hydrolysis
- hydrolysis ester and (less readily) amide bonds
- prodrug - a useful strategy to ↑ oral drug delivery
- molecules with little or no pharmacological activity
that are converted in vivo to active drugs
- molecules with little or no pharmacological activity
[Tenofovir Disoproxil
esterase
Tenofovir - not active and needs phosphorylation]
Phase 2 metabolic reactions
- Glucuronidation (UGT)
- Sulfation (SULT)
- Glutathione conjugation (GST)
Phase 2 metabolism
Conjugation reactions in which a polar molecule is linked to a suitable functional group on a drug or one of its Phase 1 metabolites
attach a polar endogenous molecule to a functional group in a drug - ↑ hydrophilicity to facilitate excretion
Glucuronidation
UGT (UDP glucuronosyltransferase) transfers glucuronic acid from UDP-glucuronic acid to a drug or drug metabolite (UDP = uridine diphosphate)
sulfation
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
Morphine P2
M -UGT2B7-> morphine-3-glucuronide (Major/pharm-inactive)
or
M -UGT2B7-> morphine-6-glucuronide (Minor/Pharm-active)
NAPQI
(the toxic metabolite of paracetamol) - detoxification by glutathione conjugation
Outcomes of drug metabolism
(I) increases molecular size and hydrophilicity
(II) decreases drug elimination half-life (t1/2)
(III) alters pharmacological activity or induces toxicity
D.Meta outcomes
Increases molecular size and hydrophilicity
- reduce tendency to accumulate
- facilitate renal excretion
- If drug is hydrophilic it doesn’t undergo metabolism in liver and is removed by renal excretion.
Phase 1–> functional groups
Lipophilic
Goes through hepatic Metabolism to make hydrophilic metabolites that go through hepatobiliary excretion to either bile or renal excretion.
D.Meta outcomes
Decreases drug elimination half-life (t1/2) definition
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
Plasma conc without drug metabolism
Has a longer half life
Plasma conc with drug metabolism
Shorter half life
D.Meta outcomes
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
parent drug
e.g., morphine →
pharmacologically in/active
morphine-3-glucuronide(in)
morphine-6-glucuronide
paracetamol →
toxic and reactive
NAPQI
codeine →
pharmacologically active
morphine
DMEs - cytochrome P450 (CYP)
- metabolism of drugs and xenobiotics - CYP1, CYP2 and CYP3
- 57 CYP genes in human genome
- classified into 18 families and 43 subfamilies
key drug metabolising CYPs
CYP3A4
CYP2D6
CYPs are ___-containing proteins
heme
CYPs use _____ (cofactor) and __ to metabolise xenobiotics/drugs (SH)
NADPH
O2
- 1 for oxidation
- 1 added to H+ to make H2O
CYP-POR (P450 oxidoreductase) complex- electron transfer
NADPH
FAD
FMN
P450
CYP450 found on ____ ____
of hepatocytes
Liver homogenates undergo sequential______ at ultra-high speed
CYP450 concentrated in_____ (formed
from ER fragments)
Used in __ ____studies to investigate drug
metabolism
endoplasmic reticulum (ER)
centrifugation
microsomes
in vitro
microsomes
Microsomes are small sealed vesicles that originate from fragmented cell membranes (often the endoplasmic reticulum [ER]).
Drug interaction definition
Process by which a substance alters the action and/or kinetics of a drug
-e.g., different CYPs have distinct but often overlapping substrate specificity
Drug metabolism can be modified by endogenous and exogenous factors such as
genetics, disease
states and xenobiotics.
CYP-mediated drug-drug interactions
(i) CYP induction
(ii) CYP inhibition
CYP induction
drugs cause ↑ CYP expression
-rifampicin (treat tuberculosis)
- some antiepileptic drugs, e.g.,
o phenytoin
o phenobarbital*
o carbamazepine
CYP inhibition
drugs compete for the active site of an enzyme when co-administered
- a CYP inhibitor itself may or may not be a substrate for the enzyme
Competitive Inhibition
substance that resembles the normal substrate competes with the substrate for the active site
mechanism-based inhibition
irreversible inhibition of an enzyme due to formation of a complex between the enzyme and a reactive
metabolite via covalent bonding, e.g., ritonavir* and cobicistat*
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
Hepatic Metabolism
most drugs, once absorbed, are distributed to sites of action and then undergo metabolic changes when returned in blood through the liver.
rifampicin is a CYP3A4_____
inducer
itraconazole is a CYP3A4___
inhibitor
Cobicistat
- CYP3A4 inhibitor
- no antiretroviral activity
hepatic metabolism of alcohol
- alcohol dehydrogenase (primary and saturable)
- CYP2E1
Alcohol and Paracetamol
Ethanol induces enzyme activity resulting in an increase in the metabolism of paracetamol to NAPQI
