Drug elimination

RONNY
Drug elimination

• Irreversible loss of drug from the body

Occurs by 2 processes

1.Metabolism

2.Excretion
1. Metabolism

• Involves enzymic conversion of one chemical entity

to another within the body

Excretion

• Elimination from body of chemically unchanged

drug or its metabolites

Main routes by which drugs & their metabolites are
excreted from the body

1.Kidneys (most important)

2.Hepatobilairy system

3.Lungs ;important for volatile gaseous drugs

4.Fecal route

5.Breast milk

6.Sweat
 Renal excretion of drugs & drug metabolites
• Most important route for drug excretion

• Drugs differ greatly in rate at which they are

excreted by kidney
• E.g. penicillins are cleared frm blood almost
completely on a single transit thru the kidney
• Diazepam is cleared extremely slowly frm kidney
• Drug metabolites are nearly always cleared more
quickly frm than parent drug

Fundamental processes that account for renal drug

excretion
• Glomerular filtration

• Active tubular secretion

• Passive diffusion across tubular epithelium

Glomerular filtration

• Glomerular capillaries allow small drug molecules of

MW < 20000 to diffuse thru the filtrate
• Thus plasma albumin has a large MW approx
68,000 is completely impermeable
• Must drug molecules pass thru this barrier freely
except heparin
• Thus drugs like heparin that bind to plasma albumin
are not filtered thru the filtrate
Tubular secretion

• Up to 20% of renal plasma blood flow is filtered

thru the glomerulus
• Thus 80% of delivered drug passes on to
peritubular capillaries of PCT
• At PCT drug molecules are transferred to tubular
lumen by two independent & relatively non
selective carrier systems
 • One of the systems transports acidic drugs &
endogenic acids like uric acid
• Other transport system transports organic bases

• Carriers can tpt drug molecules against an

electrochemical gradient & thus can reduce
[plasma] to nearly zero

• Coz 80% of drug delivered to kidney is presented to

the carrier system
 • Thus tubular secretion is potentially the most
effective mechanism of renal drug elimination
• Tubular secretion even clears drugs that are highly
protein bound in plasma e.g. penicillins
• Most drugs compete this transport system leading
to drug interaction
 • E.g. probenecid was developed was developed
originally to prolong action of penicillins by
retarding its tubular secretion

Diffusion across the renal tubule

• Water is reabsorbed as fluid transverses the tubules
thus vol of urine emerging being only about 1% of
the of glomerular filtrate
• If tubules are freely permeable to drugs some 99%
of the filtered drug wld be passively reabsorbed
• Lipid soluble drugs thus are poorly excreted & polar
drugs with poor lipid permeability remain in the
lumen & become progressively [ ]ed as water is
reabsorbed

• E.g. digoxin & aminoglycosides are handled in this

way
• Thus rate of renal elimination is the main factor
that determines their action
• Such drugs are used with special care among;

1.Elderly

2.Renal pts

3.Any acute severe illness

• Many drugs are weak acids /bases thus they change
their ionization wth PH & this can affect their renal
excretion
• Ion trapping means that acid drugs are excreted
more in alkaline urine coz an alkaline PH favors
more ionization of the drug & vice versa

• Thus urine alkalization increases excretion of

salicylic acid (aspirin) during over dose
Biliary excretion
• Some drugs are secreted into bile via liver, but most
are then reabsorbed frm intestines
• Several drugs are excreted mainly in the bile

• Later drugs leaves the body via feaces

• E.g. Vecuronium a non depolarizing muscle relaxant

is excreted unchanged in bile.
Enterohepatic circulation

• Liver cells transfer various substances including

drugs frm plasma to bile by means of tp
mechanisms similar to those of renal tubules

• Metabolized hydrophilic drug conjugates esp

glucuronides are concentrated in bile & later
delivered to intestines
• In the bowel the glucuronide is hydrolyzed / broken
down to release active drug once more.
• Free drug that is released can then be reabsorbed
once again thus Enterohepatic circulation
• This effect creates a reservoir of recirculating drug
& can amount to about 20% of total drug in body &
prolongs drug action

• E.g. morphine undergoes enterohepatic circulation

 Lung elimination
• Is important in volatile /gaseous agents e.g ether
used for G/A

Fecal loss
• Fecal loss can account for a large elimination of
unchanged drugs frm body e.g. digoxin ,Rifampicin.
• Digoxin becomes more eliminates frm feaces in
advancing renal failure
 Elimination thru sweat & breast milk
• Eliminates a small amounts of drugs

• Excretion into milk can affect the baby

• Elimination by such routes is negligible compared to

renal excretion
 Drug metabolism

• Occurs mainly in liver esp by cytochrome P450

enzymes system

• Some p450 enzymes are extra hepatic & play an

important role in biosynthesis of steroid hormones

eicosanoids
 • Drug metabolism in liver Involves 2 kinds of

reactions known as;

– Phase1

– Phase2

• These often occur sequentially

• Thus drugs are converted to other metabolites &

later excreted
• Some metabolites are active like parent drug while

others could be inactive

Phase1 reactions

• Are catabolic e.g. oxidation, hydrolysis & reduction,

• Pdts are often more chemically reactive thus

paradoxically at times more toxic or carcinogenic

than parent drug

Phase 2 reactions

• Are anabolic (synthetic)

• Involve conjugation

• Usually result into inactive products

• Exceptions occur e.g. active sulphate metabolite of

Minoxidil a potassium channel activator is used to

RX severe hypertension
• Phase 1 reaction often introduce are active group
such as hydroxyl into a molecule a process known
as functionalisation
• This group serves as the point of attack for
conjugating system to attach a substituent like
glucuronide

• This explains why phase 1 reactions often precede

phase 2 reactions
• Both phases decrease lipid solubility thus increasing
rate elimination

Other sites of drug metabolism

1.Plasma e.g. suxamethonium by plasma

cholinesterase.

2.lungs
• Hepatic drug metabolizing enzymes are embedded

in smooth endoplasmic reticulum & are often called

microsomal enzymes

• To reach metabolizing enzyme drug must cross the

plasma membrane

• Thus polar molecules do this less easily than non

polar molecules except in presence of specific

transport mechanisms
 • Thus polar drugs are easily excreted by kidneys

• Intracellular metabolism is important for non polar

drugs (lipid soluble drugs)

Phase 1 reactions
• The p450 mono-oxygenase system

• Cytochrome p450 enzymes are haem enzymes

• Each is referred to as CYP followed by set of

numbers defining & a letter
 Enzymes differ frm one another by;
• Amino acid sequence

• Sensitivity to inhibiting & inducing agents

• In specificity of reactions they catalyze

• 74 CYP gene families have been identified

• But 3 main ones ( CYP 1,CYP2 ,CYP3) are involved in
drug metabolism in human liver
 Mechanism
• Drug oxidation by P450 system requires;

– Drug Substrate (DH)

– P450 enzymes

– Molecular oxygen,

– NADPH & a flavo-protein (NADPH-P450

reductase)
• Mechanism involves a complex cycle but the overall
net effect of the reaction is quite simple,
• Namely the addition of one atom of oxygen ( frm
molecular oxygen) to thru drug to form a hydroxyl
group (pdt DOH)
• Other oxygen atom is converted to water
 P450 & biological variation
• Within human popn there are major sources of
inter-individual variation in p450 enzymes that are
of great importance in therapeutics
• They include genetic polymorphisms e.g. gene
CYP2D6 leads to poor or extensive hydroxylation of
debrisoquine

• Environmental factors are also important

• Enzyme inducers & inhibitors are present in diet &
environment

E.g.
• A component of grapefruit juice inhibits drug
metabolism leading to disastrous consequences,
including cardiac arrhythmias

• Brussels sprouts & cigarette smoke induce P450

enzymes.
 Inhibition of P450

• Inhibitors of p450 differ in their selectivity towards

different isoforms of the enzyme
• Some drugs compete for active site but are not
themselves substrates e.g quinidine a potent
competitive inhibitor of CYP2D6 but is not a
substrate for it

• Non competitive inhibitors include Ketoconazole

 Other phase 1 reactions
• Not all drug oxidation reactions involve p450
system
• Ethanol is metabolized by a soluble cytoplasmic
enzyme alcohol dehydrogenase in addition to
CYP2E1
• Other P450 independent enzymes involved in drug
oxidation include Xanthine oxidase, that inactivates
6 mercaptopurine
• Monoamine oxidase inactivates biologically active
amines e.g. noradrenaline,adrealine,tyramine,5-
hydroxytrptamine
• Oxidative reaction; less common than oxidation
reactions. E.g. warfarin inactivated by conversion of
a ketone to hydroxyl group
• Hydrolytic reactions

• E.g. aspirin do not involve hepatic microsomal

enzymes

• Occurs in plasma & many tissues

• Ester & amide bonds are susceptible to hydrolysis

 Phase 2 reactions
• Drug molecule having a suitable handle e.g.
hydroyxl, thio ,amino group, either in parent
molecule or in a phase 1 pdts
• They are susceptible to conjugation i.e. attachment
of substituent group
• Resulting pdts is almost always pharmacologically
inactive ,less lipid soluble than its precursor & is
excreted in urine/ bile
• Groups commonly involved are glucuronyl

• Methyl

• Acetyl

• Glycyl
• Glucuronide formation involves formation of high
energy compound uridine diphosphate (UDP)
glucuronic acid (UDPGA),frm which glucuronic acid
is transferred to electron rich atom(N,O or S) on the
substrate, forming an amide ester or thio
• UDP glucuronyl transferase ,which catalyses these
reactions
 • This has got very broad substrate specificity
embracing many drugs & foring molecules
• Several important endogenous substrates including
bilirubin, adrenal corticosteroids are conjugated by
the same system
 • Acetylation & metylation reactions occur with
acetyl CoA & s-adenosyl methionine respectively
acting as donor compounds
• Many conjugation reactions occur in liver but other
tissues are involved like
– Lungs

– kidneys
 Pharmacologically active drug metabolites

• In some cases a drug becomes pharmacologically

active only after it has been metabolized
• E.g. Enalapril an ACEI is hydrolyzed /converted to
enalaprilat an active from of the drug
• Thus such drugs in which the parent compound
lacks activity are referred to as prodrugs
• Prodrugs are some times designed deliberately to
overcome problems of drug delivery
• Some metabolites have pharmacologic actions
similar to that of parent compound e.g.
benzodiazepines
• In some cases drug metabolites are responsible for
toxicity e.g. paracetamol metabolites coz
hepatotoxicity
First pass /pre-systemic metabolism
• Is were some drugs are extracted /inactivated so
efficiently by liver or gut wall
• Thus amount reaching systemic circulation is
considerably less than amount absorbed
• This is known as first pass metabolism

• It reduces drug bioavailability even whn drug is well

absorbed frm gut
• First pass /pre-systemic metabolism is a problem
bcoz;

1.Large doses of a drug is needed whn its given orally

than when given by other routes

2.Unpredictability of out come of Rx whn such drugs

are taken orally as marked individual variations
occur in extent of first pass metabolism
• Examples of drugs that under substantial first pass
metabolism

1.Aspirin

2.Propranolol

3.Salbutamol

4.Glyceryl trinitrate
 Bioavailability

• Fraction of unchanged drug reaching the systemic

circulation following administration by any route
• IV dose of the drug, bioavailability is assumed to be
equal to unity (100%).
• PO drug bioavailability may be >100% coz of ;

1. Incomplete extent of absorption of a drug

2. First-pass elimination/metabolism
Drug routes , x-tics & their Bioavailabilities (%)

1. IV ;100 %

X-tics
• Has most rapid onset

2. IM ;75 to 100%

X-tics
• Large volumes often feasible

• May be painful
3. Subcutaneous (SC) ; 75 to 100%

X-tics

• Requires smaller volumes than IM

• May be painful

4. Oral (PO); 5 to <100

X-tics

• Most convenient route

• First-pass effect may be significant

5. Rectal (PR); 30 to <100

X-tics

• Less first-pass effect than oral

6. Inhalation; 5 to <100

X-tics
• Often very rapid onset
7. Transdermal; 80 to 100

X-tics

• Usually very slow absorption

• Used for lack of first-pass effect

• prolonged duration of action

Half-Life
• Time required to change the amount of drug in the
body to ½ its original [ ] during elimination .

Factors that may affect half life of drugs

• Disease states e.g. renal failure ,liver failure

• Drug interaction. other drugs can cause increased

hepatic drug metabolism or renal excretion

end