The document discusses pharmacokinetics, focusing on the biotransformation and elimination of drugs in the body, emphasizing the role of the liver in drug metabolism. It covers the significance of prodrugs, first-pass metabolism, and distinguishes between phase I and phase II reactions, detailing the involvement of cytochrome P450 enzymes. Additionally, it addresses factors affecting drug metabolism and the importance of renal excretion, highlighting how drug characteristics and biological factors influence pharmacokinetic processes.

1. Pharmacokinetics
biotransformation &
elimination
By:zeel mevada
Dept of pharmacology,
LMCP

2. Biotransformation
Biotransformation means chemical alteration of the
drug in the body. It is needed to render nonpolar
(lipid-soluble) compounds polar (lipid insoluble).
Biotransformation/ metabolism of drug or
xenobiotic requires because lipophilic drug can not
be easily excreted out through the kidney as
lipophilic drugs are reabsorbed into the systemic
circulation during passage through the renal
tubules.
• The primary site for drug metabolism is liver;
• others are—kidney, intestine, lungs and plasma.

3. Significance of metabolism
Inactivation: Most drugs and their active
metabolites are rendered inactive or less active,
e.g.ibuprofen,paracetamol,lidocaine,chlorampheni
c-ol, propranolol
Active metabolite from an active drug Many drugs
have been found to be partially converted
to one or more active metabolite; the effects
observed are the sum total of that due to the parent
drug and its active metabolite.

4. Continue..
Activation of inactive drug Few drugs are
inactive as such and need conversion in the body
to one or more active metabolites. Such a drug is
called a prodrug.
advantages of prodrug
• Better bioavailability
• Less side effects or reduced toxicity
• Some prodrug are activated selectively at a site of
action

5. First pass metabolism
First pass metabolism or
presystemic metabolism or
‘first pass effect’
• After oral administration
many drugs are absorbed
from the small intestine -
transported first via portal
system to the liver, where
they undergo extensive
metabolism before reaching
systemic circulation.

7. Biotransformation reactions can be classified
into:
(a) Nonsynthetic/ Phase I/ Functionalization reactions: a
functional group is generated or exposed—metabolite may be
active or inactive.
(b) Synthetic/Conjugation/ Phase II reactions:
metabolite is mostly inactive; except few drugs,
e.g. glucuronide conjugate of morphine and
sulfate conjugate of minoxidil are active

9. Phase I reactions utilizing the P450
system
The phase I reactions involved in drug metabolism are
catalyzed by the cytochrome P450 system (also called
microsomal mixed-function oxidases).
Cytochrome P450, designated as CYP, is a superfamily of
heme-containing isozymes that are located in most cells,
but primarily in the liver and GI tract.
Nomenclature:
The family name is indicated by the Arabic number that
follows CYP, and the capital letter designates the
subfamily, for example, CYP3A (Figure 1.17). A second
number indicates the specific isozyme, as in CYP3A4

10. • Specificity: Because there are many different genes that
encode multiple enzymes, there are many different P450
isoforms.
• Four isozymes are responsible for the vast majority of
P450-catalyzed reactions. They are CYP3A4/5,
CYP2D6, CYP2C8/9, and CYP1A2
• Considerable amounts of CYP3A4 are found in
intestinal
• mucosa, accounting for first-pass metabolism of drugs
such as chlorpromazine and clonazepam.

11. Genetic variability: P450
enzymes exhibit considerable
genetic variability among
individuals and racial groups.
CYP2D6, in particular, has been
shown to exhibit genetic
polymorphism. CYP2D6
mutations result in very low
capacities to metabolize
substrates. Some individuals, for
example, obtain no benefit from
the opioid analgesic codeine,
because they lack the CYP2D6
enzyme that activates the drug.

12. Phase I reaction
Oxidation: Addition of oxygen (-ve charged
radical) or removal hydrogen (+ve ).
REACTION:
Microsomal oxidation
• Hydroxylation
(Phenobarbitone to
hydroxyphenobarbitone)
• Oxygenation
• Deamination
• Dealkylation
Non Microsomal oxidation
• Mitochondrial oxidation
(Epinephrine by MAO)
• Cytoplasmic oxidation
(alcohol by alcohol
dehydrogenase)
• Oxidative deamination
(Histamine)

13. Phase I reaction
REDUCTION
Azo reduction (Microsomal)
e.g.: prontosil to
sulfanilamide
• Carbonyl reduction (Non
microsomal)
Alcohol dehydrogenase
(ADH)
• Chloral hydrate is reduced
to trichlorothanol
HYDROLYSIS
Carboxyesterases (Non
microsomal)
• Hydrolysis of esters :
procaine to PABA by
plasma cholinesterase

14. Phase II reaction
MICROSOMAL
Glucuronide
Conjugation
• Parent drug or their phase I metabolite
that contain
phenolic, alcoholic, carboxylic group
undergoes
conjugation with uridine diphospate
glucuronic acid
(UDPGA).
• Catalytic enzyme : UDP –glucuronyl
transferase
• yield drug- glucuronide conjugates that
are polar.
Examples :
• NON-MICROSOMAL
• N acetyl conjugation
• Sulfate conjugation
• Methyl conjugation
• Glutathione conjugation

15. FACTORS AFFECTING BIOTRANSFORMATION OF
DRUGS
1. Physicochemical properties of the drug
2. Chemical factors
a. Induction of drug metabolizing enzymes
b. Inhibition of drug metabolising enzymes
c. Environmental chemicals
3. Biological factors
a. Species differences
b. Strains differences
c. Sex differences
d. Age
e. Diet
f. Altered physiological factors: (pregnancy, hormonal
imbalance, disease states)
g. Temporal factors: ( circadian rhythm, circannual rhythm)

16. Enzyme induction
• Enzyme induction is the process by which
exposure to certain substrates (e.g., drugs,
environmental pollutants) results in accelerated
biotransformation with a corresponding
reduction in unmetabolized drug.

17. Enzyme inhibition
Drug metabolism is an enzymatic process can be
subjected to inhibition.
• Drugs and other substances can inhibit the metabolism
of other drugs.

18. Excretion

20. • Excretion is the passage out of systemically
absorbed drug. Drugs and their metabolites are
excreted in:
• Urine Through the kidney. It is the most important
channel of excretion for majority of drugs
• Faeces:Drugs that attain high concentrations in bile
are erythromycin, ampicillin, rifampin, tetra-
cycline, oral contraceptives, phenolphthalein.
• Certain drugs are excreted directly in colon,
• e.g. anthracene purgatives, heavy metals.

21. • Exhaled air Gases and volatile liquids (general
anaesthetics, paraldehyde, alcohol) are eliminated by
lungs,
• Saliva and sweat These are of minor impor- tance for
drug excretion. Lithium, pot. iodide, rifampin and
heavy metals are present in these secretions in
significant amounts
• Milk The excretion of drug in milk is not important
for the mother, but the suckling infant inadvertently
receives the drug. Most drugs enter breast milk by
passive diffusion.
Continue.

22. RENAL EXCRETION
• The kidney is responsible for
excreting all water soluble
substances. The amount of
drug or its metabolites
ultimately present in urine is
the sum total of glomerular
filtration, tubular reabsorp-
tion and tubular secretion
• Net renal = (Glomerular
filtration + tubular excretion
secretion) – tubular
reabsorption
Schematic depiction of glomerular
filtration, tubular reabsorption and
tubular secretion of drugs
FD—free drug; BD—bound drug;
UD—unionized drug; ID— ionized
drug, Dx—actively secreted organic
acid (or base) drug

23. Glomerular filtration
1) Glomerular filtration:
• Drugs enter the kidney through renal
arteries, which divide to form a glomerular
capillary plexus.
• Lipid solubility and pH do not influence the
passage of drugs into the glomerular filtrate.
• But glomerular filtration rate and plasma
protein binding affects this process.
• As in the renal disease GFR may diminished.

24. 2) Proximal Tubular secretion:
• Drugs that were not transferred into the
glomerular filtrate leave the glomeruli
through efferent arterioles, which divide to
form a capillary plexus surrounding the
nephric lumen in the proximal tubule.
Secretion primarily occurs in the proximal
tubules by two energy-requiring active
transport systems: for Anions & for cations.
Premature infants and neonates have an
incompletely developed tubular secretory
mechanism and, thus, may retain certain
drugs in the glomerular filtrate.

25. 3) Distal tubular reabsorption:
• The drug, if uncharged, may diffuse out of the nephric
lumen, back into the systemic circulation.
Ion trapping:
• Ionized drug gets trapped on one side of a membrane
that divides compartments with different pH.
• So, weak acids can be eliminated by alkalinization
of the urine, whereas elimination of weak bases may
be increased by acidification of the urine.
• For example, a patient presenting with phenobarbital
(weak acid) overdose can be given bicarbonate,
which alkalinizes the urine and keeps the drug
ionized, thereby decreasing its reabsorption.

26. A. Total body clearance
• The total body (systemic) clearance, CLTotal, is the sum
of all clearances from the drug-metabolizing and drug-
eliminating organs.
• Total clearance is calculated using the following
equation:
• CLTotal = CLhepatic + CLRenal + CLPulmonary + CLOther
• where CLhepatic + CLrenal are typically the most
important.
B. clinical situation resulting in changes in drug half-
life:
• When a patient has an abnormality that alters the half-
life of a drug, adjustment in dosage is required

27. • Patients who may have an increase in drug half-life include
those with
• 1) diminished renal or hepatic blood flow, for example,
in cardiogenic shock, heart failure, or hemorrhage;
• 2) decreased ability to extract drug from plasma, for
example, in renal disease; and
• 3) decreased metabolism, for example, when a
concomitant drug inhibits metabolism or in hepatic
insufficiency, as with cirrhosis.
• These patients may require a decrease in dosage or less
frequent dosing intervals.
• In contrast, the half-life of a drug may be decreased by
increased hepatic blood flow, decreased protein
binding, or increased metabolism.

28. SIGNIFICANCE OF PROTEIN BINDING OF
DRUG
A. Absorption:
• As we know the conventional dosage form follow first
order kinetics. So when there is more protein binding
then it disturbs the absorption equilibrium.
B. Distribution:
• A protein bound drug in particular does not cross the
BBB, the Placental barrier, the glomerulus.
• So, protein binding decreases the distribution of
drugs.
C. Metabolism:
• Protein binding decreases the metabolism of drugs &
enhances the biological half life.
• Only unbound fraction get metabolized.
• Eg. Phenylbutazone, Sulfonamide.

29. D. Elimination:
• Only the unbound drug is capable of being eliminated.
• Protein binding prevent the entry of drug to the
metabolizing organ (liver) & to glomerulus filtration.
• Eg. Tetracycline is eliminated mainly by glomerular
filtration.
E. Systemic solubility of drug:
• Lipoprotein act as vehicle for hydrophobic drugs like
steroids, heparin, oil soluble vitamin.
F. Drug action:
• Protein binding inactivates the drugs because sufficient
concentration of drug can not be build up in the receptor
site for action.
• Eg. Nephloquinone

30. G. Sustain release:
• The complex of drug protein in the blood act as a
reservoir & continuously supply the free drug.
• Eg. Suramin sodium-protein binding for
antitrypanosomal action.
H. Diagnosis:
• The chlorine atom of chloroquine replaced with
radiolabeled I-131 can be used to visualize-
melanomas of eye & disorders of thyroid gland.

31. Reference
o Lippincott illustrated reviews pharmacology,
Sixth Edition.
o Goodman and Gillman's the pharmacological
basis of Therapeutics