Drug metabolism and excretion

1. 1

2. Contents:
• Biotransformation
• Drug Metabolizing Enzymes
• Drug Excretion
• Types of excretion
• Kinetics of elimination
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3. BIOTRANSFORMATION:
Chemical alteration of the drug in a living organism that can lead to
the termination or alteration of biological activity is called drug
metabolism.
Lipid soluble and unionized drug converts into water soluble and
ionized compounds, not reabsorbed in the renal tubules and are more
readily excreted.
If the parent drug is highly polar (ionized), then may not get
metabolized and excreted.
Sites of drug metabolism are liver (main site) termed as hepatic
metabolism, GIT, kidney, lungs, blood, skin and placenta, termed as
extrahepatic metabolism.
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4. Types of metabolic products:
i. Active drug to inactive metabolite:
E.g. Phenobarbitone into Hydroxyphenobarbitone
ii. Active drug to active metabolite:
E.g. Codien into Morphine
iii. Inactive drug to active metabolite:
E.g. Levodopa into Dopamine
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5. PATHWAYS OF METABOLISM:
Phase 1 ( Non-synthetic reactions, Functionalization reactions):
These reactions are carried out mostly by mixed function oxidases, usually
involving CYP450 and occur in the liver. In these reactions, a polar group is
either introduced or unmasked if already present. These reactions are succeeded
by Phase II reactions. Most of the Phase I products are not eliminated directly;
instead they undergo Phase II reactions.
• Phase 2 ( Synthetic reactions, Conjugation reactions):
If the phase 1 metabolite is polar, it is excreted in urine, but many
metabolites are lipophillic and undergo subsequent conjugation with an
endogenous substrate such as glucuronic acid, sulphuric acid, acetic
acid or amino acid.
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6. Phase I Reactions:
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7. Phase II Reactions:
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8. 8

9. Drug Metabolizing Enzymes
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10. Drug Metabolizing Enzymes:
 A number of enzymes in animals are capable of metabolizing
drugs. These enzymes are located mainly in the liver, but may also
be present in other organs like lungs, kidneys, intestine, brain,
plasma, etc.
 Majority of drugs are acted upon by relatively non-specific
enzymes, which are directed to types of molecules rather than to
specific drugs.
 The drug metabolising enzymes can be broadly divided into two
groups: microsomal and non-microsomal enzymes.
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11. Microsomal enzymes:
Microsomal enzymes: The endoplasmic reticulum (especially smooth
endoplasmic reticulum) of liver and other tissues contain a large variety of
enzymes, together called microsomal enzymes
(microsomes are minute spherical vesicles derived from endoplasmic
reticulum after disruption of cells by centrifugation, enzymes present in
microsomes are called microsomal enzymes).
They catalyse glucuronide conjugation, most oxidative reactions, and some
reductive and hydrolytic reactions.
The monooxygenases, glucuronyl transferase, etc are important microsomal
enzymes. 11

12. Non-Microsomal enzymes:
 Non-Microsomal enzymes: Enzymes occurring in organelles/sites other than
endoplasmic reticulum (microsomes) are called non-microsomal enzymes.
 These are usually present in the cytoplasm, mitochondria, etc and occur mainly in
the liver, Gl tract, plasma and other tissues.
 They are usually non-specific enzymes that catalyse few oxidative reactions, a
number of reductive and hydrolytic reactions, and all
• conjugative reactions other than glucuronidation.
 None of the non-microsomal enzymes involved in drug biotransformation is
known to be inducible. 12

13. 13

14. The cytochrome P-450 ENZYMES
Superfamily of haem-thiolate proteins that are widely
distributed across all living creatures.
The name given to this group of proteins because their reduced
form binds with carbon monoxide to form a complex, which
has maximum absorbance at 450 nm.
Depending upon the extent of amino acid sequence homology,
the cytochrome P-450 (CYP) enzymes superfamily contains a
number of isoenzymes, the relative amount of which differs
among species and among individuals of the same species. 14

15. These isoenzymes are grouped into various families designated by
Arabic numbers 1, 2, 3 (sequence that are greater than 40% identical
belong to the same family), each having several subfamilies designated
by Capital letter A, B, C, while individual isoenzymes are again
allotted Arabic numbers 1.2,3 (e.g., CYP1A1, CYP1A2, etc.)
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16. 16

17. CYP Enzyme Examples of substrates
1A1 Caffeine, Testosterone, R-Warfarin
1A2 Acetaminophen, Caffeine, Phenacetin, R-Warfarin
2A6 17 -Estradiol, Testosterone
2B6 Cyclophosphamide, Erythromycin, Testosterone
2C-family
Acetaminophen, Tolbutamide (2C9); Hexobarbital, S
Warfarin (2C9,19); Phenytoin, Testosterone, R-
Warfarin,
Zidovudine (2C8,9,19);
2E1 Acetaminophen, Caffeine, Chlorzoxazone, Halothane
2D6 Acetaminophen, Codeine, Debrisoquine
3A4
Acetaminophen, Caffeine, Carbamazepine, Codeine,
Cortisol, Erythromycin, Cyclophosphamide, S- and R
Warfarin, Phenytoin, Testosterone, Halothane,
Zidovudine 17

18. Induction of Drug Metabolizing Enzymes:
Several drugs and chemicals have ability to increase the drug
metabolising activity of enzymes called as enzyme induction.
 These drugs known as enzyme inducers mainly interact with DNA and
increase the synthesis of microsomal enzyme proteins, especially
cytochrome P-450 and glucuronyl transferase.
 As a result, there is enhanced metabolism of endogenous substances
(e.g., sex steroids) and drugs metabolised by microsomal enzymes.
Some drugs (e.g., carbamazepine and rifampicin) may stimulate their
own metabolism, the phenomenon being called as auto-induction or self
induction.
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19. Since different cytochrome P450 isoenzymes are involved in the
metabolism of different drugs, enzyme induction by one drug
affects
metabolism of only those drugs, which are substrate for the
induced
isoenzyme.
• However, some drugs like Phenobarbitone may affect
metabolism of a large number of drugs because they induce
isoenzymes like CYP3A4 and CYP2D6 which act on many drugs.
Enzyme inducers are generally lipid-soluble compounds with
relatively long plasma half-lives.
Repeated administration of inducers for a few days (3 to 10 days)
is often required for enzyme induction, and on stoppage of drug
administration, the enzymes return to their original value over 1
to 3 weeks.
Non-microsomal enzymes are not known to be induced by any
drug orchemical.
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20. Inhibition of Drug Metabolizing
Enzymes:
 Contrary to metabolising enzyme induction, several drugs
or
chemicals have the ability to decrease the drug
metabolising activity of certain enzymes called as enzyme
inhibition.
Enzyme inhibition can be either non-specific of microsomal
enzymes or specific of some non-microsomal enzymes
(e.g., monoamine oxidase, cholinesterase and aldehyde
dehydrogenase).
The inhibition of hepatic microsomal enzymes mainly
occurs due to administration of hepatotoxic agents,
which cause either rise in the rate of enzyme degradation
(e.g., carbon tetrachloride and carbon disulphide) or fall in
the rate of enzyme synthesis
(e.g., Puromycin and Dactinomycin). 20

21. • Nutritional deficiency, hormonal imbalance or hepatic
dysfunction, etc.also inhibit microsomal enzymes
indirectly.
• Inhibition of non-microsomal enzymes with specific
function
usually results when Structurally similar compounds
compete for the active site on the enzymes.
• Such an inhibition is usually rapid (a single dose of
inhibitor
may be sufficient) and clinically more important than the
nonspecific microsomal enzyme inhibition.
• Enzyme inhibition generally results in depressed
metabolism
of drugs.
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22. Drug Excretion
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23. Excretion:
• Excretion is a process whereby drugs/metabolites are transferred
from the internal to the external environment.
• Types of excretion:
• 1. RENAL excretion
• 2. Biliary excretion
• 3. Pulmonary excretion
• 4. Salivary excretion
• 5. Mammary excretion
• 6. Dermal excretion
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24. 24

25. Glomerular Filtration:
 The ultrastructure of the glomerular capillary wall is such that
it permits a high degree of fluid filtration while restricting the
passage of compounds having relatively large molecular
weights.
 This selective filtration is important in that it prevents the
filtration of plasma proteins (e.g., albumin) that are important
for maintaining the plasma volume.
 Several factors, including molecular size, charge, and shape,
influence the glomerular filtration of large molecules.
 Ionized or unionized drugs are filtered, except those that are
bound to plasma proteins.
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26.  Driving force for GF is hydrostatic pressure of blood flowing in
capillaries.
 Out of 25% of cardiac out put or 1.2 liters of blood/min that goes
to the kidney via renal artery only 10% or 120 to 130ml/min is
filtered through glomeruli. The rate being called as glomerular
filtration rate (GFR).
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27.  All unbound drugs will be filtered as long as their
molecular size and shape are not excessively large.
 GFR normally is 120ml/min.
 GFR declines progressively after the age of 50 and also
low in renal failure.
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28. Active Tubular Secretion:
o Many drugs which do not enter into GF but do so by
tubule secretion which maily occurs in proximal tubules.
o It is carrier mediated process which require energy for
transportation of compounds against the conc. gradient.
o System for secretion of organic acids/anions e.g.
Penicillin, salicylates etc
o System for organic base / cations e.g. morphine Atropine.
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29. o It is the active transfer of organic acids and bases by two
separate classes of relatively nonspecific transporters
(OAT and OCT) which operate in the proximal tubules.
o In addition, efflux transporters P-gp and MRP2 are
located in the luminal membrane of proximal tubular
cells.
o However, for drugs and their metabolites (exogenous
substances) excrete into the tubular lumen whereas an
endogenous substrate like uric acid is predominantly
reabsorbed
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30. Tubular reabsorption:
 Some substances filtered at the glomerulus are
reabsorbed by passive diffusion and depends on the
lipid solubility and ionization of drug at the existing
urinary pH.
 A reason for this is that much of the water, in the
filtrate, has been reabsorbed and therefore the
concentration gradient is now in the direction of re-
absorption hence drug may be readily reabsorbed.
 It occurs after the glomerular filtration of drugs. It takes
place all along the renal tubules.
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31. lipid soluble drugs filtered from GF but 99% of the drug
is reabsorbed but non-lipid soluble and highly ionized
drugs are unable to do so.
 Active reabsorption is particularly important for
endogenous substances, such as ions, glucose, and
amino acids, although a small number of drugs also may
be actively reabsorbed.
 Takes place all along renal tubule.
 Lipophilic substances are extensively reabsorbed and
polar are not.
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32.  Majority of drugs are weak electrolytes, so their Re-
absorption depends upon
 pH of urine
 urine flow rate
 Many drugs are either weak bases or acids and
therefore the pH of the filtrate can greatly influence the
extent of tubular re-absorption for many drugs
 In the case of a drug overdose it is possible to increase
the excretion of some drugs by suitable adjustment of
urine pH. In the case of pentobarbital (a weak acid)
overdose it may be possible to increase drug excretion
by making the urine more alkaline with sodium
bicarbonate 32

33. FACTORSAFFECTING RENAL
EXCRETION:
Molecular size
• Size < 300 Daltons: easily excreted in urine
Lipid solubility
• urinary excretion is inversely related to lipophilicity.
• Plasma concentration of drug:
• Glomerular filtration and Reabsorption are directly affected by
plasma concentration
• Biological factors
• Renal excretion is 10% lower in females
 Newborns: 30-40% less
 Old age: GFR decreased, excretion decreased 33

34. DISTRIBUTIONANDBINDING
CHARACTERISTICSOFTHE DRUG:
Drugs that are bound to plasma proteins behave as
macromolecules and cannot be filtered through glomerulus.
Only unbound or free drug appear in glomerular filtrate.
 Kidney failure
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35. Excretion
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36. Biliary Excretion: (secretion through bile)
Apart from the unabsorbed fraction, most of the drug
present in feces is derived from bile.
 Bile juice is secreted by the hepatic cells of the liver.
It is important for the digestion and absorption of fats.
Greater the polarity better the excretion.
Generally larger molecules (MW>300) are eliminated by
bile
Some drugs which are excreted as glucuronides are
hydrolysed by intestinal/bacterial enzymes.
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37. Biliary Excretion:
 90% of bile acid is reabsorbed from intestine and transported
back to the liver for re secretion.
 Compounds excreted by this route are
 Sodium
 Potassium
 Glucose
 Bilirubin
Sucrose
 Inulin etc.
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38. Enterohepatic Cycling:
The phenomenon of drug cycling between the intestine
and the liver.
e.g. cardiac glycosides, chlorpromazine, indomethacin.
Some drugs which are excreted as glucuronides
hydrolyzed by intestinal/ bacterial enzymes to the parent
drugs which are reabsorbed.
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39. Enterohepatic Cycling:
The reabsorbed drugs are again carried to the liver for re
secretion via bile into the intestine.
 This phenomenon of drug cycling between the intestine
& the liver is called Enterohepatic circulation.
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40. PULMONARY EXCRETION:
Lungs also serve to trap and extrude any particulate
matter that enters circulation.
Gases and other volatile substances are eliminated by
lungs, irrespective to their lipid solubility.
Alveolar transfer of the gas/vapour depends on its
partial pressure in the blood.
 Eg: Alcohol, general anesthetics
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41. Saliva and sweat:
Less important
Lithium, potassium iodide and heavy metals are present
in
these secretions in significant amounts.
Substances excreted into saliva are usually swallowed.
Thus, the bitter after taste in the mouth of a patient is an
indication of drug excretion.
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42. Saliva and sweat:
• E.g: caffeine, metronidazole, alcohol etc.
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43. Mammary excretion:
Milk consists of lactic secretions which is rich in fats and
proteins with pH 7.0
Low-molecular weight un-ionized water-soluble drugs will
diffuse passively across the mammary epithelium and transfer
into milk
The excretion of drug in milk is not important for the mother.
but the suckling infant inadvertently receives the drug.
However, the total amount of the drug reaching to the infant
through breast feeding is generally small.
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44.  majority of the drugs can be given to lactating mother
without ill effects on infant
 but some are contraindicated that should be avoided.
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45. Kinetics of elimination
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46. Kinetics of elimination:
 First order kinetics
 Zero order kinetics
 Clearance
 Plasma half life of drug
 Loading dose
 Maintenance dose
 Steady state plasma concentration
 Prolongation of drug action
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47. WHAT IS KINETICS OFELIMINATION?
• It includes:
• First order kinetics
• Zero order kinetics
 First order kinetics:
• When rate of elimination of drug depends on concentration of
drug present in plasma, then it will be called as first order
kinetics.
• Rate of elimination ∝ drug concentration in plasma
 Zero order kinetics:
• Elimination occurs at constant rate or a constant amount of
drug is eliminated in unit time, independent of concentration.
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48. WHATIS CLEARANCE?
• Volume of plasma from which
the drug is completely removed
in a unit time.
• CL = Rate of elimination/C
• C = Plasma concentration
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49. PLASMAHALF-LIFEOFDRUG
• The Plasma half-life (t½) of a drug is the time taken for its
plasma concentration to be reduced to half of its original value.
• Examples:
• Aspirin 4 hour
• Penicillin-G 30 minutes
• Digoxin 40 hour
• Metronidazole 8 hour
Steady state plasma concentration:
• If a drug is repeated at short intervals it accumulate in body
until elimination balance input and gain steady state plasma
concentration.
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50. Dosing can be administeredby:
1. Loading dose
2. Maintenance dose
Loading dose:
• This is a single or few quickly repeated doses given in the
beginning to attain target concentration rapidly. It may be
calculated as;
loading dose=(target Cp V)/F
Maintenance dose:
• This dose is one that is to be repeated at specified intervals
after the attainment of target Cpss so as to maintain the same
by balancing elimination.
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51. PROLONGATION OFDRUGACTION:
• Modification of drug in such a way that it acts for a longer
period of time.
Advantages:
• Frequency of drug administration is reduced
• Improved patient compliance
• Reduce fluctuation in Cp
• Drug plasma concentration can be maintained overnight
without disturbing sleep of patient
Methods:
• Oral: coating of drug materials by plastics and resins (almost 4
– 6 hrs)
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52. PROLONGATIONOF DRUGACTION:
Parenteral: subcutaneous and intramuscular injections of a
drug in insoluble form (e.g. Benzathine, Penicillin, and Lente
Insulin)
By increasing plasma protein binding
Drugs which bound to plasma protein are slowly released in
the free active form (e.g. Sulfadoxin)
By retarding route of metabolism
Addition of ethinyl group to estradiol
By retarding renal excretion
The tubular secretion of a drug being an active process, can be
suppressed by a competing substance (e.g. Probenecid
prolongs the duration of action of penicillin and ampicillin) 52

53. Reference:
• From book: Essentials of medical pharmacology, seventh
edition, (KD Tripathi).
• From book: KATZUNG & TREVOR’S Pharmacology, Examination
and board review, eleventh edition.
• From YouTube: Pharmacokinetics part 04 Drug Excretion, Easy
Dentistry by Pranali Satpute.
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54. References:
• K. D. Tripathi, “Essentials of Medical Pharmacology,” 5th
Edition, Jaypee Brothers Medical Publishers (P) LTD, New
Delhi, 2003.
• Katzung, Bertram G. 2004. Basic & clinical pharmacology. New
York: Lange Medical Books/McGraw Hill.
• Achike, F. I., & Ogle, C. W. (2000). Information overload in the
teaching of pharmacology. Journal of Clinical Pharmacology,
40, 177-183.
• Katzung, Bertram G. Basic & Clinical Pharmacology. New York:
Lange Medical Books/McGraw Hill, 2004. 6th Edition
• Nagai, J. and Takano, M. (2004) Drug Metabolism and
Pharmacokinetics, 19, 159-170.
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55. Thank you
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