DRUG ELIMINATION

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Definition :
• Drug elimination refers to the irreversible removal of
drug from the body by all route of elimination.
• Drug elimination is usually divided into two major
components:
Excretion and biotransformation.
• Drug excretion is the removal of the intact drugs or
their metabolites. Nonvolatile drugs are excreted
mainly by kidney (renal excretion). Other pathways for
drug excretion may include the excretion of drug into
bile, sweat, saliva, milk or other body fluids and lungs
for drugs with high volatility (nonrenal excretion).2
• Biotransformation or drug metabolism is the
process by which the drug is chemically converted in
the body to a metabolite. Biotransformation is usually
an enzymatic process. A few drugs may also be
changes chemically by a nonenzymatic process. The
enzymes involved in the biotransformation of drugs
are located mainly in the liver. Other tissues such as
kidney, lung, small intestine and skin also contain
biotransformation enzymes.

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 RENAL EXCRETION OF DRUGS
• Renal excretion is a major route of elimination for
many drugs.
• Drugs that are water soluble, non volatile, small in
molecular size and which are metabolized slowly are
eliminated by renal excretion.
• The process by which a drug is excreted via the kidney
may include any combination of the three principal
processes…
1. Glomerular Filtration
2. Active Tubular Secretion and,
3. Tubular reabsorption.

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1) Glomerular filtration:
• It is non selective, unidirectional process whereby most
comps, ionized or unionized are filtered except those that are
bound to plasma proteins or blood cells.
• The driving force for glomerular filtration is the hydrostatic
pressure of the blood flowing through capillaries .
• The kidneys receive a large blood supply via the renal artery,
with very little decrease in the hydrostatic pressure.
• Out of 25% of cardiac output that goes to the kidneys only
10% filtered through glomerulus (120-130ml/min).
• The rate being called as glomerular filtration rate (GFR)
• The GFR is determined by an agent that is excreted
exclusively by filtration and is neither secreted nor reabsorbed
in the tubules. Creatinine, inulin, mannitol and sodium
thiosulphate are used to estimate GFR.
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2) Active Tubular Secretion:
• It is carrier mediated process which requires energy for
transportation of comp against the conc. gradient.
• The carrier system is capacity limited and saturable.
• Two active tubular secretion mechanisms have been
identified.
A) system for secretion of organic acids/anions:
• Like penicillins, salicylates, glucuronides etc.
• It is the same system by which endogenous acids such as uric
acid are secreted.
B) system for secretion of organic bases/cations :
• like morphine, mecamylamine, hexamethonium and
endogenous amines such as catecholamine, choline, histamine
etc. 7
• Both the systems are relatively nonselective and independent
of each other but both can be bidirectional.
• Active secretion is unaffected by changes in pH and protein
binding.
• It is dependent on renal blood flow.
• Drugs undergoing active secretion have excretion rate values
greater than normal GFR value of 130 ml/min; for e.g.
penicillin has renal clearance value of 500 ml/min.-this high
value is indicative of both glomerular filtration as well as
tubular secretion.
• Agents used to measure active tubular secretion are the ones
that are filtered as well as secreted through the kidneys. Para
amino hippuric acid and iodopyracet are used to determine
active secretion.
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• Two structurally similar drugs having similar ionic charges
and employing same carrier mediated process for excretion
enter into competition.
• A drug with greater rate of clearance will retard the
excretion of the other drug with which it competes.
• The half life of both the drug will increase since the total
sites for active secretion is limited. This may result in the
accumulation of drugs, thus precipitation of toxicity.
• However, the principle of competition can be used for
therapeutic benefits. E.g. of this phenomenon
• Probenecid inhibits the active tubular secretion of organic
acids such as penicillins. Thus increasing their conc. in
plasma by at least two fold. A 50% reduction in penicillin
G dose is suggested. So given in combination with penicillin
to increase its half life. 9
3) Tubular Reabsorption:
• It occurs after glomerular filtration of drugs.
• It takes place all along the renal tubule .
• Reabsorption of drugs is indicated when the excretion
rate values such are less than the GFR of 130 ml/min.
• An agent such as glucose is completely reabsorbed
after filtration has a clearance value of zero.
• Tubular reabsorption results in an increase in the half-
life of a drugs.
• Tubular reabsorption can be either
1) Active process or
2) Passive process. 10
1) Active process:
• Is commonly seen with high threshold endogenous substances
or nutrients that the body needs to conserve such as
electrolytes, glucose, vitamins, amino acids etc.
• Uric acid is also actively reabsorbed .
• Very few drugs undergo reabsorption actively e.g. oxopurinol.
2) Passive process :
• It is common for large no of exogenous substances including
drugs.
• The driving force for such process is the conc. gradient is
established by the back diffusion or reabsorption of water
along with sodium and other inorganic ions.

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• The primary determinant in the passive reabsorption
is their lipophilicity.
• Lipophilic subs. are extensively reabsorbed while polar
molecules are not.
• Since majority of drugs are weak electrolytes diffusion
of such agents through lipoidal tubular membrane will
depend on degree of ionization which in turn depends
on following factors.
A.) pH of the urine
B.) pKa of the drug.

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A) Urine pH:
• It is an imp factor in the sense that it is not constant like the
plasma pH but varies between 4.5 to 7.5. Thus, the large pH
gradient may exist between urine and plasma.
• The pH of the urine is dependent upon diet, drug intake and
pathophysiology of the patient.
• Food rich in the carbohydrates results in higher urinary pH
whereas proteins lower it.
• Drugs such as acetazolamide and antacids such as NaHCO3
produce alkaline urine while ascorbic acid makes it acidic.
• Metabolic acidosis and alkalosis results in acidification and
alkalization of urine.

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B) Drug pKa:
• The pH dependent excretion for any particular comp
is greatly dependent on its pKa and lipid solubility.
• pKa values governs ionization at a particular pH.
• A polar and ionized drug will be poorly reabsorbed
passively and excreted rapidly.
• Reabsorption is also govern by the lipid solubility of
drug: an ionized but lipophilic drug will be
reabsorbed while an unionized but polar one will be
excreted.

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C) Urine flow rate:
• In addition to urine pH and pKa of drugs the rate of
urine flow also influence the extent of reabsorption .
• Polar drugs whose excretion is independent of urine
pH are not reabsorbed and unaffected by urine flow
rate. An increase in flow rate of urine in case of such
drugs will produce only dilute urine.
• Drugs whose reabsorption is pH sensitive for e.g.
weak acid or weak bases show dependence of urine
flow rate. For such agents reabsorption is inversely
proportional to urinary flow.

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• These compounds can be divided into 2 types based
on their extent of reabsorption in relation to that of
water :
1) Drugs which are reabsorbed to an extent equal to or
greater than the absorption of water .
• E.g. phenobarbitone.
2) Drugs which are reabsorbed to an extent lower than
the reabsorption of water
• E.g. theophylline.

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• In addition to modification of urinary pH, urinary
elimination can also be enhanced by forced diuresis.
• It is the increase in urine flow by large fluid intake or
adm. of mannitol or other diuretics.
• Both urine pH and forced diuresis can be used to treat
toxicity with drug overdose when…
1) Urinary excretion is the major route of elimination of
drug.
2) The drug is extensively reabsorbed passively from the
renal tubules .
3) The reabsorption is sensitive to urine pH.

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 CONCEPT OF CLEARANCE
• It was first used to describe renal excretion of
endogenous comp. to measure the kidney function.
• It is now also apply to all organs involved in drug
elimination such as liver, lungs, biliary system etc.
• The sum of individual clearances by all eliminating
organs is called as total body clearance.
• It is defined as “the hypothetical volume of body fluid
containing drug from which the drug is removed or
cleared completely in a specific period of time.”
• It is expressed in ml/min.

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• Clearance = elimination rate / plasma drug conc.
Renal clearance :
• It can be defined as the volume of blood or plasma
which is completely cleared of the drug by the kidney
per unit time.
• Renal Clearance = Rate of urinary excretion / plasma
drug conc.
KIDNEYS
BLOOD CLEAN
+ BLOOD
DRUG 30 ml/min

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• Physiologically renal clearance is the sum of rate of
glomerular filtration and active secretion minus the
rate of reabsorption divided by the plasma drug conc.
C.
• Clearance value for the drug can be determined by
comparing the clearance value obtained for a drug
with that of standard reference such as creatinine or
inulin which is cleared by glomerular filtration only.
• The ratio of drug clearance to creatinine clearance is
called as renal clearance ratio or excretion ratio.
• Renal clearance ratio = Clr of drug/ Clr of creatinine

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 Factors affecting renal excretion
1)Physicochemical properties of the drug:
Molecular size, pKa and lipid solubility:
• Molecular weight is very critical in urinary excretion.
• An agent of small molecular size can be easily filtered
through glomerulus.
• Comp. of weight below 300 daltons if water soluble
are readily excreted by the kidneys .
• Drugs in mol. weight range 300 to 500 daltons can be
excreted in both urine and bile.
• Molecules of size greater than 500 daltons are excreted
in urine to a lesser extent. 21
2) Plasma conc. of the drug:
• Glomerular filtration and reabsorption are directly affected by
plasma drug conc. since both are passive processes.
• A drug that is unbound and excreted by filtration only, shows
linear relationship between rate of excretion and plasma drug
conc.
• Drugs which are secreted or reabsorbed actively, the rate
process increases with an increase in plasma conc. to a point
when saturation of carrier occurs.
• In case of actively reabsorbed drugs, excretion is negligible at
low plasma conc.

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3)Distribution and binding capacity of the drugs:
• In general drugs that are highly bound to plasma protein
have reduced overall drug clearance.
• For a drug that is metabolized mainly by the liver, binding
to plasma proteins prevents the drug from entering the
hepatocytes, resulting in reduced drug metabolism by the
liver.
• In addition, molecularly bound drugs may not be available
as substrates for liver enzymes, thereby further reducing the
rate of metabolism.
• Protein bound drugs act as larger molecules that cannot
diffuse easily through the capillary membranes in the
glomeruli. The elimination half lives of some drugs are
generally increased when the percent of drug bound to
plasma proteins increases.
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• The serum protein binding affects the renal clearance and
elimination half life of several tetracycline analogs.
• On the other hand, actively secreted drugs like penicillin is
much less affected by protein binding and has a short
elimination half life because active secretion takes
preference in removing the drug from the proteins as the
blood flows through the kidney.
4)Blood flow to the kidneys:
• The renal blood flow is imp. in case of drugs excreted by
the glomerular filtration only and those that are actively
secreted .
• In the later case increased perfusion increases the contact
of drugs with the secretory sites and their elimination.
• Renal clearance in such cases is said to be perfusion rate
limited. 24
5) Biological factors:
• Age, sex, species, strain diff, diff in genetic make up etc alter
drug excretion.
• Renal excretion is app 10% lower in female than male.
• The renal function of new born is 30-40% less in comparison
to adults.
• In old age GFR is reduced and tubular function is altered, the
excretion of drugs is thus slowed down and half life is
prolonged.

6)Drug Interactions:
• It results in alteration in binding characteristics, renal blood
flow, active secretion, urine pH and forced diuresis would
alter the renal clearance of a drug.
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7)Disease states – Renal impairments:
• Renal dysfunctions greatly impairs elimination of such
drugs which are primarily excreted by kidneys.
• Some of the causes of renal failure are hypertension,
Diabetes mellitus, Hypovolemia, Pyelonephritis and
nephrotoxic agents such as amino glycosides and
heavy metals.
• Uremia characterized by impaired glomerular filtration
and accumulation of fluids and protein metabolites. In
both these conditions, half lives of drug are increased
leading to drug accumulation and toxicity. In such
conditions, determination of renal function is
important to monitor dosage regimen. 26
• Renal function can be determined by measuring the
GFR .
• The marker like inulin and creatinine which is use for
this purpose should entirely excreted in unchanged
form by glomerular filtration only and should be
physiologically and pharmacologically inert.
• Inulin clearance provides accurate measure of GFR
but has the disadvantage of being a tedious method.
• Creatinine is most widely used to assess renal
function.
• The method involves determination of the amount of
creatinine excreted in urine in 24 hrs and the mean of
serum creatinine from blood samples taken just before
and immediately after the urine collection period .
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• Clcr = rate of creatinine excretion/Serum creatinine
• The normal creatinine clearance value is 120 to 130
ml/min.
• A value of 20-50 ml/min denotes moderate renal
failure and below 10 ml/min indicates severe renal
impairment.
• Renal function is calculated by..
RF= Clcr of patient / Clcr of normal person.

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Dose adjustment in renal failure:
• The required dose in patients with renal impairment
can be calculated by..
Required dose = Normal dose X RF
• The dosing interval in hours can be computed from…
New dosing interval (hr) = Normal interval (in hours)/RF
• When the drug is eliminated both by renal and non
renal mechanisms the dose to be adm in patient can
be calculated from…
Required dose = Normal dose X [RF X Fraction
excreted in urine + Fraction eliminated nonrenally]
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 Non renal routes of drug excretion:
• Drugs and their metabolites may also be excreted by
routes other than the renal routes called as extra renal
or nonrenal routes of excretion.
1. Biliary excretion
2. Pulmonary excretion
3. Salivary excretion
4. Mammary excretion
5. Skin/dermal excretion
6. Gastrointestinal excretion
7. Genital excretion.
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Biliary excretion of drugs- Enterohepatic Cycling:
• Just as the major portion of bile salts excreted in
intestine is reabsorbed, several drugs which are
excreted unchanged in bile are also absorbed back into
the circulation.
• Some drugs which are excreted as glucuronide or
glutathione conjugates are hydrolyzed by the intestinal
or bacterial enzymes to the parent drugs which are
then reabsorbed.
• The reabsorbed drugs are again carried to the liver for
resecretion via bile into the intestine. This
phenomenon of drug cycling between the intestine
and the liver is called as enterohepatic cycling or
enterohepatic circulation of drugs.
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Pulmonary excretion:
• Gaseous and volatile subs such as general anesthetics
and alcohol are excreted by this route.
Salivary excretion:
• Excretion of drugs into saliva is also passive diffusion
process and predictable on the basis of pH-partition
hypothesis.
• The pH of saliva vary from 5.8-8.4.
• Drugs that are passively secreted in saliva are caffeine,
theophylline, phenytoin, carbamazepine etc. some
drugs are actively secreted in saliva such as lithium,
phenytoin and penicillin.
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• The bitter taste in mouth of a patient on medication is
an indication of drug excretion in saliva and in some
cases responsible for side effects like black hairy
tongue in patients receiving antibiotics, hyperplasia
due to phenytoin etc.
Mammary excretion:
• Excretion of a drug in milk is important since it can
gain entry into the breast feeding infant.
• The amt of drug excreted in milk is generally less than
1% and the fraction consumed by the infant is too less
to reach therapeutic or toxic levels. But some potent
drugs such as barbiturates, morphine and ergotamine
may induce toxicity in infants. 33
Skin excretion:
• Drugs are excreted through skin via sweat.
• Passive excretion of drugs and their metabolites
through skin is responsible to some extent for the
urticaria and dermatitis.
• Comp such as benzoic acid, salicylic acid and heavy
metal like lead, mercury and arsenic are excreted in
sweat.

Gastrointestinal excretion:
• Few drugs are excreted in GIT after parental adm by
passive diffusion.

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• Nicotine and quinine are excreted in stomach.
• Orally administered drugs can also be absorbed and
excreted in GIT. Drugs excreted in GIT are
reabsorbed into circulation and undergo cycling.

Genital excretion:
• Reproductive drugs and genital secretion may contain
some amt of excreted drugs.
• Some drugs have been detected in semen.

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