Elimination of drugs: Drug Metabolism, Renal and Non-renal excretion, Factors affecting excretion with concept of clearance.

1.  Elimination is the major process for removing a drug from the
body and terminating its action.
 It is the irreversible loss of drugs from the body.
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By-
Prathamesh Suhas Patil
M. Pharm (Pharmaceutics)

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Metabolism
Excretion
Elimination

3.  Metabolism or Biotransformation of drugs or xenobiotics is defined as the
chemical conversion of one form to another.
 Biotransformation is necessary for the removal of drugs and to protect the
body from ingested toxins.
 Non-polar, lipid-soluble compounds are made polar lipid insoluble so that they
can be easily excreted.
 Only water-soluble agents undergo renal excretion
 Sites – Primary site: Liver
 Brain, testes, muscles, spleen, etc. also metabolize drugs but to a small extent.
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4. • Biotransformation can –
 Normally results in pharmacological inactivation of drugs; e.g., the conversion
of phenytoin to p-hydroxy phenytoin.
 Occasionally yields metabolites with equal activity; e.g. conversion of
phenylbutazone to oxyphenbutazone.
 Rarely leads to toxicological activation of drugs, i.e. it results in the formation
of metabolites with high tissue reactivity; e.g. the conversion of paracetamol
to reactive metabolites that cause hepatic necrosis.
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5. Absorbed drug
3 types of changes
Metabolic changes by
enzyme
Spontaneous molecular
rearrangement
Excreted Unchanged
E.g.,
Microsomal
Cytoplasmic
Mitochondrial
E.g.,
Hofmann Elimination
E.g.,
Aminoglycosides,
Methotrexate
Neostigmine
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6. Drug Metabolising
Enzymes
Microsomal
enzymes
Non Microsomal
enzymes
 Catalyze a majority of drug
biotransformation reactions like oxidative,
reductive, hydrolytic, and glucuronidation.
 Microsomes are derived from rough ER.
 A number of lipid-soluble substrates can
interact nonspecifically with the
microsomal enzymes.
 E.g. CYP enzymes
 Present in soluble form in the cytoplasm
and attached to the mitochondria
 These are also non-specific enzymes that
catalyze few oxidative reactions, a number
of reductive and hydrolytic reactions, and
conjugation reactions except
glucuronidation.
 Acts on relatively water-soluble xenobiotics
 E.g. oxidases, peroxidases,
dehydrogenases, esterases, etc.
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CHEMICAL PATHWAYS OF DRUG BIOTRANSFORMATION
Phase I Reactions
 Include oxidative, reductive, and hydrolytic reactions which continue to phase II reactions.
 A polar functional group is either introduced or unmasked if already present on the lipid-
soluble substrate, e.g. -OH, -COOH, - NH2, and -SH.
 Thus, phase I reactions are also called as functionalization reactions/ asynthetic reactions.
Phase II Reactions
 Covalent attachment of small polar endogenous molecules such as glucuronic acid, sulphate,
glycine, glutathione, etc. or acetylation, methylation reactions.
 Forms highly water-soluble conjugates which are readily excretable by the kidneys (or bile).
 Thus, these reactions are called as conjugation/ synthetic reactions because it gives product
with different physicochemical properties and increased molecular size

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Excretion of Drugs
The process in which drugs and/or their metabolites are irreversibly transferred
from an internal to an external environment.
Two Types
Renal Excretion Non-Renal Excretion
 Excretion of drugs via kidneys
 Agents excreted in the urine are-
1. Water-soluble
2. Non-volatile
3. Having small molecular size (<500D)
4. Slowly metabolizing
 Excretion of drugs via routes
other than kidneys like
lungs, biliary system,
intestine, saliva, skin, etc.

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RENAL EXCRETION OF DRUGS
 The basic functional unit of the kidney involved in renal excretion is the nephron.
 The principal processes
determining the urinary excretion
of a drug are –
1. Glomerular filtration.
2. Active tubular secretion.
3. Tubular reabsorption.
(Active or Passive)
Rate of Excretion = Rate of Filtration + Rate of Secretion – Rate of Reabsorption

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Glomerular Filtration
 Non-selective, unidirectional process
 Compounds that are not bound to plasma proteins are filtered
 The driving force for filtration is the hydrostatic pressure of the blood flowing in
the capillaries.
 Out of 1.2 liters of blood/min that goes to the kidneys via the renal artery, only
10% or 120 to 130 ml/min is filtered through the glomeruli, the rate is called the
glomerular filtration rate (GFR).
 From the 180 lit of filtrate passing through glomeruli each day, only 1.5 lit is
excreted as urine.
 The agents/markers used to detect GFR are e.g., creatinine, mannitol, inulin, etc.
which are excreted exclusively by filtration and are neither secreted nor
reabsorbed in the tubules.

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Active Tubular Secretion
 It is a carrier-mediated process that requires energy
for the transportation of compounds against the
concentration gradient.
 The system is capacity-limited and saturable.
 Occurs predominantly in the proximal tubule region
of the nephron
 Active secretion is unaffected by protein binding
since the bound drug rapidly dissociates as soon as
the unbound drug gets excreted.
 It is dependent upon renal blood flow.
 The agents used to detect tubular secretion must
be filtered as well as actively secreted. E.g. Para
Amino Hippuric Acid (PAH)

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Competitive secretion of two drugs
 Two structurally similar drugs having the same carrier-mediated process for
excretion can compete for secretion.
 A drug with a greater rate of clearance may retard the excretion of the other
drug.
 The half-life of both drugs increases due to saturation – Accumulation of
drug – toxicity
 E.g., Probenecid inhibits the active tubular secretion of organic acids such as
penicillins increasing their concentration in plasma by at least 2 fold.

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Tubular Reabsorption
 It takes place throughout the renal tubule when the excretion rate values are
less than the GFR of 130 ml/min.
 It results in an increase in the half-life of a drug.
 E.g., glucose is completely reabsorbed after filtration and has a clearance
value of zero.
Tubular reabsorption
can be
Active process Passive process
• Nutrients that the body needs to conserve
such as electrolytes, glucose, vitamins, amino
acids, etc.
• Very few drugs like oxypurinol undergo active
reabsorption.
• Common for a large number of drugs.
• Driving force – concentration gradient
• Diffusion of weakly acidic or basic drugs through
the lipoidal tubular membrane depends upon the
degree of ionization.

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degree of ionization depends on three factors:
1. pH of the urine.
2. pKa of the drug.
3. Urine flow rate.
The pH of Urine –
 The pH of the urine is dependent upon diet, drug intake, and pathophysiology of
the patient.
 Food rich in carbohydrates results in higher urinary pH whereas proteins lower it.
 Drugs such as acetazolamide and antacids such as sodium bicarbonate produce
alkaline urine while ascorbic acid makes it acidic
Drug pKa –
 A polar and ionized drug will be poorly reabsorbed passively and excreted rapidly.
 Reabsorption is also affected by the lipid solubility of the drug; an ionized but
lipophilic drug will be reabsorbed while an unionized but polar one will be
excreted

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Urine Flow Rate –
 Only those drugs whose reabsorption is pH-sensitive, for example, weak acids
and weak bases, show dependence on urine flow rate.
For such agents, reabsorption is inversely proportional to the urinary flow.
 Polar drugs whose excretion is independent of urine pH and are not
reabsorbed, are unaffected by urine flow rate.
 Urine flow rate can be increased by forced diuresis.
 Forced diuresis is the increase in urine flow induced by large fluid intake or
administration of mannitol or other diuretics.
 This can be used to remove excessive drugs in an intoxicated person by
promoting excretion & decreasing the time for reabsorption.

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CONCEPT OF CLEARANCE
Clearance is defined as the hypothetical volume of body fluids containing a drug
from which the drug is removed or cleared completely in a specific period of time.
 Renal Clearance (ClR): can be defined as the volume of blood or plasma which
is completely cleared of the unchanged drug by the kidney per unit of time.
ClR= dX/dt ClR=KeX ClR= Vd. C
C C

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FACTORS AFFECTING RENAL EXCRETION
1. Physicochemical properties of the drug
2. Plasma concentration of the drug
3. Distribution and binding characteristics of the drug
4. Urine pH
5. Blood flow to the kidneys
6. Biological factors
7. Drug interactions
8. Disease states

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1. Physicochemical Properties of the Drug
 molecular size, pKa, and lipid solubility
 pKa and lipid solubility plays the same role as that of the general transport
mechanism through a lipid membrane

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I. A drug that is not bound to plasma proteins and excreted by filtration only, shows a linear
relationship between rate of excretion and plasma drug concentration.
II. In case of drugs that are secreted actively, the rate process increases with an increase in
plasma concentration to a point when saturation of carrier occurs.
III. In case of actively reabsorbed drugs, excretion is negligible at low plasma concentrations.
Such agents are excreted in urine only when their concentration in the glomerular filtrate
exceeds the active reabsorption capacity, e.g. glucose.
2. Plasma Concentration of the Drug
 Glomerular filtration and reabsorption are directly affected by plasma drug concentration
since both are passive processes.

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3. Distribution and Binding Characteristics of the Drug
 Clearance is inversely related to the apparent volume of distribution of drugs.
 A drug with a large Vd is poorly excreted in the urine.
 Drugs restricted to the blood compartment have higher excretion rates.
 Drugs that are bound to plasma proteins behave as macromolecules and thus
cannot be filtered through the glomerulus.
 E.g., The renal clearance of oxytetracycline which is 66% unbound is 99 ml/min
while that of doxycycline (7% unbound) is just 16 ml/min.
 The drugs excreted by active secretion are unaffected by protein binding.

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4. Blood Flow to the Kidneys
 Drugs excreted by glomerular filtration and those that are actively secreted
are affected by the renal blood flow
 As the perfusion rate increases, drug elimination increases by increasing the
contact of the drug with the secretory site
5. Biological Factors
 Renal excretion is approximately 10% lower in females than in males
 The renal function of newborns is 30 to 40% less in comparison to adults
 In old age, the GFR is reduced and tubular function is altered due to which
excretion of drugs is slowed down and the half-life is prolonged

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6. Drug Interactions
 Drug interaction affecting protein-drug binding characteristics, renal blood flow,
active secretion, urine pH, and forced diuresis may alter the renal clearance of a
drug
• Alteration in P-D binding – The renal clearance of a drug extensively bound to
plasma proteins is increased after displacement with another drug. E.g.,
furosemide can replace gentamycin from its binding site which may cause
nephrotoxicity.
• Alteration of Urine pH – Acidification of urine enhances the excretion of basic
drugs and vice versa.
• Competition for Active Secretion – A drug with a greater rate of clearance may
retard the excretion of the other drug. E.g., Phenylbutazone competes with
hydroxyhexamide for active secretion and thus prolongs its action.
• Forced Diuresis – All diuretics increase the elimination of drugs whose renal
clearance gets affected by urine flow rate.

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7. Disease States—Renal Impairment
 Renal failure caused by diseases like hypertension, diabetes mellitus,
hypovolemia affects greatly the elimination of drugs
 Uremia, characterized by impaired glomerular filtration and accumulation of
fluids and protein metabolites, also impairs renal clearance of drugs
 The half-lives of drugs are increased, which may result in drug accumulation
and toxicity

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Dialysis and Hemoperfusion
Dialysis is a process in which easily diffusible substances are separated from poorly
diffusible ones by the use of a semipermeable membrane.
Procedures for
dialysis
Peritoneal
dialysis
Haemodialysis
• Natural semipermeable membrane of
peritoneal cavity
• Dialysate fluid introduced into the abdomen
by inserting the catheter
• Drained and discarded the same after some
period of time
• Artificial semipermeable membrane
• Also called as extracorporeal dialysis as the system
is outside the body
• Also useful in the treatment of overdose or
poisoning where rapid removal of a toxic substance
is desired

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Factors governing the removal of substances by
hemodialysis:
(A) Water Solubility - Only water-soluble
substances are dialyzed; lipid-soluble drugs such
as glutethimide cannot be removed by dialysis.
(B) Molecular weight - Molecules with a size less
than 500 Daltons are dialyzed easily.
(C) Protein binding - Drugs bound to plasma
proteins or blood cells cannot be dialyzed since
dialysis is a passive diffusion process.
(D) Volume of Distribution - Drugs with a large
volume of distribution are extensively
distributed throughout the body and therefore
less easily removed by dialysis, e.g. digoxin.
schematic representation of hemodialysis

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 The dialysate contains sodium, potassium, calcium, chloride and acetate ions,
and dextrose and other constituents in the same concentration as that in plasma
 The unwanted metabolites in the patient’s blood such as urea, uric acid,
creatinine, etc. diffuse into the dialysate until equilibrium.
 The rate at which a drug is removed by the dialyzer depends upon the flow rate
of blood to the machine and its performance.
Hemoperfusion:
 In this method, blood is passed through a bed of adsorbents such as charcoal or
resin.
 Drugs and other unwanted molecules are adsorbed
 The limitation of hemoperfusion is that it also removes the blood platelets, white
cells, and endogenous steroids

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NON-RENAL ROUTES OF DRUG EXCRETION
Excretion of drugs via routes other than kidneys are known as non-renal routes
of drug excretion
1. Biliary Excretion of Drugs - Enterohepatic Cycling
Bile –
Secreted by- Hepatic cells lining bile canaliculi
Stored in- Gall Bladder
Secreted into- Duodenum
Flow rate- 0.5 to 1 ml/min
Digests- Fats
As biliary secretion is an active process, it is capacity-limited and can saturate.

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Several factors influence the secretion of drugs in bile –
1. Physicochemical Properties of the Drug
 Greater the polarity, better the excretion. Thus, metabolites are more excreted in
bile than the parent drugs because of their increased polarity.
 The molecular weight threshold for the biliary excretion of drugs is also
dependent upon its polarity. The polar drugs above 300 Daltons are excreted
effectively.
2. Nature of Biotransformation process
 A metabolic reaction that greatly increases the polarity as well as the molecular
weight of the drug favors the biliary excretion of the metabolite.
 Thus, phase II reactions, mainly glucuronidation, and conjugation with glutathione
result in metabolites with an increased tendency for biliary excretion.
 E.g., Morphine, stilbesterol, chloramphenicol, etc.

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3. Other Factors
 Sex and species differences, protein-drug binding, disease states, drug
interactions, food etc.
 Protein-bound drugs can also be excreted in the bile since the secretion is an
active process.
 In cholestasis, the bile flow rate is reduced decreasing the biliary excretion of
drugs.
 Agents such as phenobarbital stimulate biliary excretion of drugs, firstly, by
enhancing the rate of glucuronidation, and secondly, by promoting bile flow.
 Protein and fat-rich food increase bile flow.
• The ability of the liver to excrete the drug in the bile is expressed by
biliary clearance.

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Enterohepatic Cycling
 As 90% of the bile secreted in the intestine is reabsorbed, several drugs which
are excreted unchanged in bile are also absorbed back into the circulation.
 Some drugs which are excreted as glucuronides or as 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
enterohepatic cycling.

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 Enterohepatic circulation is important in the conservation of important
endogenous substances such as vitamin B12, vitamin D3, folic acid, several
steroid hormones, and bile salts.
 The half-life of drugs undergoing enterohepatic circulation is increased.
 E.g., contraceptives, cardiac glycosides, rifampicin, etc.
 Drug interactions can affect enterohepatic cycling when agents such as
antibiotics kill the intestinal microflora and thus retard the hydrolysis of drug
conjugates and their subsequent reabsorption.

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2. Pulmonary Excretion
 Gaseous and volatile substances like general anesthetics (e.g. halothane)
are excreted through the lungs by simple diffusion.
 Factors like pulmonary blood flow, rate of respiration, the solubility of
the volatile substance, etc. influence the pulmonary excretion of drugs.
 Generally intact gaseous drugs are excreted not their metabolites.
3. Salivary Excretion
 The excretion of drugs in saliva is also a passive diffusion process.
 Unionized, lipid-soluble drugs at salivary pH are excreted passively into
saliva.
 The bitter after taste in the mouth of a patient on medication is an
indication of drug excretion in saliva.
 Drugs excreted in saliva can undergo cycling in a fashion similar to
enterohepatic cycling, e.g. sulphonamides, antibiotics, clonidine, etc.

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4. Mammary Excretion
 Milk consists of lactic secretions originating from the extracellular fluid and is rich
in fats and proteins.
 The excretion of a drug in milk is important since it can gain entry into the breast-
feeding infant.
 The excretion of drugs in milk is a passive process and is dependent upon pH-
partition behavior, molecular weight, lipid solubility, and degree of ionization.
 Free, unionized, lipid-soluble drugs diffuse into the mammary alveolar cells
passively.
 The amount 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.
 E.g., Chloramphenicol: Possible bone marrow suppression, Diazepam:
Accumulation and sedation, Tetracycline: Permanent staining of infant’s teeth.

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5. Skin Excretion
 Drugs excreted through the skin via sweat also follow the pH-partition
hypothesis.
 Excretion of drugs through the skin can cause hypersensitivity reactions
like urticaria and dermatitis.
 E.g., benzoic acid, salicylic acid, alcohol, etc.
6. Gastrointestinal Excretion
 Excretion of drugs into the GIT usually occurs after parenteral administration
when the concentration gradient for passive diffusion is favorable.
 Water soluble and ionized form of weakly acidic and basic drugs is excreted in
the GIT, e.g. nicotine and quinine.

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