MODULE 4│PHARM 4

BIOPHARMACEUTICS
BIOPHARMACEUTICS Biopharmaceutics involves factors that influence:

• Bio – life 1. The design of the drug product.

• Pharmaceutics – General area of study concerned with the 2. Stability of the drug within the drug product.
formulation, manufacture, stability and effectiveness of 3. The manufacture of the drug product.
pharmaceutical dosage forms. 4. The release of the drug from the product.
• Examines the interrelationship of the physical/ chemical 5. The rate of dissolution/ release of the drug at the absorption
properties of the drug, the dosage form (drug product) in site.
which the drug is given, and the route of administration on 6. Delivery of drug to the site of action which may involve
the rate and extent of systemic drug absorption. targeting a localized area for action or systemic absorption of
drug.
INTRODUCTION
PHARMACODYNAMICS
DRUGS
• Refers to the relationship between the drug concentration at
• These are substances intended for use in the diagnosis, the site of action (receptor) and pharmacologic response,
cure, mitigation, treatment or prevention of disease. including biochemical and physiologic effects that influence
• Drugs are given in a variety of dosage forms or drug the interaction of drug with the receptor.
products such as solids (tablets, capsules), semisolid, • What the drug does to the body
liquids, suspensions, emulsion, etc., for systemic or local
activity. Toxicokinetic
• Drug product can be considered to be drug delivery systems • Application of pharmacokinetic principles to the design,
that release and deliver drug to the site of action that they conduct and interpretation of drug safety evaluation studies
produce the desired therapeutic effect and are also designed and in validating dose-related exposure in animals.
specifically to meet the patient’s needs including palatability,
convenience and safety. Clinical Toxicology
• The study of adverse effects of drugs and toxic substances
Drug Product Performance (poisons) in the body.
• The release of drug substance from the drug product either
for local drug action or for drug absorption into the plasma for PHARMACOKINETICS
systemic therapeutic activity.
• The release of the drug substance from the drug product • Is the science of the kinetics of drug absorption, distribution
leading to bioavailability of the drug substance and and elimination (metabolism and excretion)
eventually leading to one or more pharmacologic effect.
PRINCIPLES OF PHARMACODYNAMICS
BIOAVAILABILITY
Pharmacodynamics – “What the drug does to the body”
• Refers to the measurement of the rate and extent of active • Study of the biochemical and physiologic effects of drugs in
drug that reaches the systemic circulation. biological systems,
• means access to the bloodstream • Study of the mechanism by which these effects are produced
→ Mechanism of Drug Action (MOA)
Sequence of events
A. PHARMACODYNAMICS: MECHANISM OF DRUG ACTION
Absorption
1. Receptor-mediated
• Receptor – cellular macromolecule, or an assembly of
Drug release and Drug in systemic
Dissolution circulation
Drug in tissues macromolecules, that is concerned directly and specifically in
chemical signaling between and within cells

2. Non-Receptor-mediated
• Examples:
Elimination
• Direct chemical interaction – acid neutralizers
(antacids), chelating agents (drugs that coat and coat
bind to heavy metals that are present in excessive
Excretion and Pharmacologic
amount in the body)
Metabolism clinical effect
• Colligative mechanism (dependent on the particles of
Critical Manufacturing Variables the drug in solution)/ mass effect – osmotic diuretics
• The most important steps in manufacturing process. • Counterfeit incorporation – purine-pyrimidine analogues

Biopharmaceutical Consideration in Drug Product Design RECEPTOR LOCATIONS

• Cell membrane
Items Considerations
• Cytoplasm
Therapeutic Drug is intended for rapid relief of symptoms,
• Nucleus
Objectives slow extended action given per day (weeks or
longer), or chronic; is the drug for local action
or systemic action
Drug (API) Physical chemical properties of API, including
solubility, polymorphic form, particle size
Route of Oral, topical, Parenteral, transdermal,
Administration inhalation, etc.
Drug Dosage and Large or small drug dose, frequency of doses,
dosage regimen patient acceptance of drug product, patient
compliance
Type of Drug product Orally disintegrating tablets, immediate release
tablets, transdermal, parenteral, implant, etc.
Method of Variables in manufacturing process, including
Manufacture weighing, blending, release testing, sterility

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 • Cell membrane • Voltage-gated Na+ channel – blocked by Class I
• GPCRs antiarrhythmics, local anesthetic, tetrodotoxin, saxitoxin
• Ion Channels • Voltage-gated K+ channel – blocked by Class III
• Kinases antiarrhythmics such as Amiodarone and Sotalol
• Catalytic receptors • Voltage-gated Ca2+ channels – blocked by CCBs such as
• Enzymes Verapamil, Diltiazem, Amlodipine.
• Transporters
• Structural protein and other molecules b. Ligand-gated
• Cytoplasm and Nucleus
• Structural protein and other molecules
• Thyroid hormone receptor
• Steroid receptors
*Gating mechanism is controlled by a certain binding site, particularly a ligand
RECEPTORS may be able to interact. So, if a ligand interacts at the binding site, it will cause
a change in configuration of the gate causing the gate to open and that will
1. GPCR (G protein-coupled receptor) now allow the movement of certain molecules or ions

• 7-transmembrane spanning receptor • Nicotinic receptor (Na+) Channel) – blocked by

• Metabotropic – effects due to metabolites (or 2nd neuromuscular blockers derived from tubocurarine
messengers) • GABAA receptors (Cl- channel) – stimulated by BZDs,
• Involved in signal transduction Barbs
• Most common receptor
3. Kinases and Catalytic Receptors

* The cell membrane and the GPCR consist of molecule that reverses the
entire span of the cell membrane 7 times so that’s the reason we call it 7-
transmembrane spanning receptor. Now intracellularly, this receptor is
associated with the G-Protein it is called G-Protein because this protein is
intimately link to GDP. When a Drug or a Ligand bind to receptor the GDP is
replaced by GTP and once this happens it will lead to production of 2nd
messengers. If on the other hand the G-protein is not activated meaning the
GDP is not replaced by GTP then what we expect would be a decrease in the
2nd messengers. This process where a drug binding to receptor that is found at *Are characterized by receptors that exist as monomers. What happens with
the cell membrane which leads to stimulation of intracellular protein like the G- the monomers is that when the ligand interacts with the monomers, they
protein is what we refer to as a Signal transduction process. dimerize and this dimerization of receptors will lead to the activation of the
receptors. There are several types of Kinases and Catalytic Receptors, and
this type will depend on whether the kinase is an integral component or part of
Types of GPCR: the entire receptor molecule or is a separate molecule from the receptor
molecule.
Gs
• Activation of AC (Adenylyl cyclase)
✓ Increase in cAMP
✓ Ex: Beta-receptors
*It will activate the enzyme called Adenylyl cyclase this
enzyme coverts ATP to the active cAMP intracellularly.
cAMP inside the cell is metabolized by the enzyme
Phosphodiesterase III which converts it to the inactive AMP.
Gi
• Inhibition of AC (Adenylyl cyclase)
✓ Decrease in cAMP → inhibitory
4. Enzymes
✓ Ex: alpha 2 presynaptic receptors
• ACE (Angiotensin Converting Enzyme) or Kininase II –
Gq
responsible for converting Angiotensin I to the more active
• Activates PLC (Phospholipase C) – acts in triglycerides Angiotensin II (responsible for vasoconstricting effect and drug such
✓ Splits PIP2 → IP3 + DAG (2nd messengers; primarily as: Captopril, Enalapril, Lisinopril can inhibit the activity of
involved in smooth muscles activities, so they increase Angiotensin Converting Enzyme this class of drugs are called ACEi)
intracellular calcium level in smooth muscles and are involved in • COX (Cyclooxygenase): inhibit by NSAIDS
the phosphorylation and activation of the myosin light chain
• MAO: inhibited by MAO-Is
kinase)
• Non-specific: Tranylcypromine, Isocarboxazid,
✓ Ex: alpha postsynaptic receptors
Phenelzine
✓ Location: smooth muscles → contraction
• MAOA: Moclobemide (RIMA)
• MAOB: Selegiline, Rasagiline, Safinamide
2. Ion channels
5. Transporters
a. Voltage-gated

*Cell membrane and examples of Ion channel at the end, you see a gating
mechanism that prevents ions from moving in or out through the channel. A
voltage-gated ion channel is primarily governed by a change in the membrane The characteristics of a transporter or carrier molecule, is that it brings ions
potential. So, at resting state we know that the inside of the membrane is more into or out of the cell by changing its confirmation or configuration. In the case
negative than the outside if there is a change however in the membrane of Na+-K+ ATPase it brings out 3 Sodium ions as it brings in 2 Potassium ions,
potential such as the inside becomes less negative or even positive there will the movement of this carrier requires energy or ATP.
now be a change in configuration of the gate which prevents the movement of
ions through the channel and may lead to opening of the gate.

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Examples: • Types: GPCRs, Ion channels, Transporters, Enzymes,
• Na+-K+ ATPase: inhibited by Digitalis (Digoxin) Structural proteins, nuclear receptors
• Proton Pump (H+-K+ ATPase): inhibited by PPIs
(Omeprazole) B. PHARMACODYNAMICS: CHARACTERISTIC OF DRUG-
RECEPTOR INTERACTION
6. Structural Proteins and other molecules
Definitions:

Affinity
• Ability to bind to a receptor or target protein
• Ligand-activity

Intrinsic activity
• Ability to generate a series of biochemical events leading to
an effect after receptor-binding

Constitutional activity
• Ability to generate a series of biochemical events leading to
receptor effects even in the absence of a ligand

Receptor Binding Sites:

Orthosteric site
• Primary binding site
• Allosteric site.

Allosteric site
• Binding site of other molecules
Microtubule consists of Dimers (α-tubulin and β tubulin), these dimers can • Can alter binding of endogenous ligand to the orthosteric site
be added to the chain or they can be removed from the chain. So, when
additional dimers are added in to the chain, we called it polymerization and Agonists, Inverse Agonists, Antagonists
there is lengthening of the microtubule, in contrast when dimers are removed
from the chain, we called it depolymerization and there is shortening of the
microtubule.

Microtubules:
• Cytoskeleton
• Organelle movement
• From mitotic spindles
Agonists
• Stabilizes active
receptor state

Inverse Agonist
• Stabilizes inactive
receptor site
Inhibitors:
• Griseofulvin Antagonist
• Colchicine • Maintains equilibrium
• Anti-mitotics – Taxanes, Vincas, Estramustine, Epothilones between the inactive
(Ixabepilone) and active receptor
states
7. Nuclear Receptor – are found initially at the Cytoplasm and when • Prevents binding of
the ligand is bound to them, they form a complex and they are then agonist
translocated into the nucleus
Allosteric modulators:
Thyroid hormone receptors Allosteric agonists
Steroid receptors • Improve/ enhance binding of endogenous ligand to the
orthosteric site
MOA:
Allosteric antagonists
• Reduce or prevent binding of endogenous ligand to the
orthosteric site
Agonists:
Full agonists
• Produce the maximal clinical effects expected with receptor
interaction

Partial agonists
• Produce less than the maximal clinical effects expected with
receptor interaction.
Summary: • Produce some of the anticipated effects with receptor
interaction and inhibit other effects attributed to receptor
Two General MOAs: Receptor-mediated and non-receptor- interaction (Mixed agonist-antagonist activity)
mediated
Antagonists:
• Non-receptor-mediated: direct chemical interaction, Clinical antagonist
colligative mechanism, counterfeit incorporation • Drugs that produce clinical effects that are opposite of
• Receptor-mediated: another drug or of the endogenous agonist
• Cell membrane, cytoplasmic, nuclear • Includes Antagonists and Inverse agonists

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Classification of Antagonists:

a. Based on Mechanism of antagonist action

Pharmacologic
• opposite effects produced by binding to the same receptor or
receptor system

Example: Stress or Anxiety

• Due to Epinephrine/ Adrenaline
• Increase HR by binding to β1
• Tremors due to binding to β2 Hill-Langmuir Equation
• Treatment: Propranolol 𝐾
• Decreases HR by binding to β1 𝐴 + 𝑅 ⇄ [𝐴 − 𝑅]
• Reduces tremors by binding to β2 Where:
A: agonist or ligand
Physiologic R: receptor
• Produce opposite effects by binding to a different receptor [A-R]: agonist-receptor complex
K: equilibrium dissociation constant
Example: Anaphylactic shock pAR: proportion of binding sites occupied by ligand at equilibrium
• Due to massive Histamine release
• Vasodilation/ Hypotension by binding to H1 receptors Affinity
• Bronchospasm by binding to H1 receptors [𝐴 − 𝑅] [𝐴]
𝑝𝐴𝑅 = =
• Treatment: Epinephrine 𝑅 + [𝐴 − 𝑅] [𝐴] + 𝐾
• Vasoconstriction by binning to α1 receptors
• Bronchodilation by binding to β2 receptors

b. Based on ability to surmount antagonist/ opposite effect

Guide question: Dose-Response Graphs

Can the effect of the “antagonist” be completely overcome by
increasing the dose or concentration of the “agonists”? 1. Graded Dose-Response Graph
• YES (completely) – Competitive antagonist
• NO (or incompletely) – Non-competitive antagonist Plot of Response against Dose or Log Dose

Example:
Drug A decreases SBP from 160mmHg to 120mmHg at 10mg/day.
Dug B is taken by the patient at 500mg dose causing the SBP to
increase to 160mmHg. You advise to increase the dose of Drug A to
15mg/day which caused the SBP to drop again to 120mmHg. Did
the increase in the dose of Drug A completely overcome the effect of
Drug B?
YES. So, Drug B is a competitive antagonist of Drug A Parameters:
c. Based on reversibility of drug-receptor interaction a. Efficacy: maximum achievable response
• Ceiling effect
D + R → [D-R] or D + R ⇄ [D-R] b. Ceiling Dose (DC): smallest dose that produces the
maximum response
Reversibility is dependent on the Type of bond/ Interaction formed c. Potency (P): dose producing 50% of the maximum
between the Drug and Receptor response
Reversible: interaction involves IMFAs (intermolecular forces of d. Mid-slope: degree of change in response with change in
attraction) dose
• H-bond, vDW forces of attraction, dipole interaction, London
forces, etc.

Irreversible: interaction involves a permanent bond

• Covalent bond

Clinical clue: duration of action

• Duration of action < 24 hours – likely reversible
• Propranolol lowering of HR <8 hours
• Duration of action > 24 hours – likely irreversible
• Antiplatelet effect of aspirin lasting for about 7 – 10
days after stopping therapy

C. PHARMACODYNAMICS: DOSE RESPONSE RELATIONSHIP

Relationship between concentration/ dose and effect

Hill Equation:
𝐸 [𝐴]𝑛𝐻
=
𝐸𝑚𝑎𝑥 [𝐴]𝑛𝐻 + [𝐴]50 𝑙𝑛𝐻
Where:
E: Effect
Emax: Maximum Effect
[A]: concentration of the agonist
[A]50: concentration of agonist producing half maximal effect
nH: Hill coefficient (slope of a logarithmically transformed binding
curve

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 Mid-slope
• Steep slope: small increase in dose leads to a large
change in response
• “Toxicity”
• Necessities to “start LOW, go SLOW”

Applications

Differentiate Potency and Efficacy

Efficacy: A = C >> B
Potency: A > B > C

Non-competitive antagonism: Shift pf the graph down and to the

right

2. Quantal Dose-Response Graph

Plot of cumulative number of Responders against the Dose

A more effective drug is NOT necessarily more potent

A more potent drug is NOT necessarily more effective

Differentiate Partial agonist from Full agonists

Parameters:

a. ED50: median effective dose

b. TD50: median toxic dose
c. Therapeutic index (I) = TD50/ED50

Therapeutic index: measure of the relative safety of drug

PRINCIPLES OF PHARMACOKINETICS

Pharmacokinetics – What the body does to the drug

• study of the different process a drug undergoes as it reaches
Differentiate Competitive from Non-competitive antagonist and leaves the biologic state

A. PROCESSES

Transport processes

Liberation

Absorption

Distribution
Competitive antagonism: Shift of the graph to right

Metabolism

Elimination
Excretion

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 1. TRANSPORT PROCESSES ii. Facilitated diffusion
• ATP – independent
Mechanism of drug movement across the cell membrane • Movement along concentration gradient

Passive Transport c. Convective Transport

Carrier-mediated Transport Key Properties:

• Pore size: 7-10 Angstroms, allow passage of drugs with MW
< 400-600
Convective Transport • Allows passage of ions with charge opposite of pore lining
• Movement along electrochemical gradient
Ion Pair Transport
d. Pinocytosis
Pinocytosis Key Properties
• ATP-driven
• Transport of large lipids in micelle form
a. Passive Transport
• involves movement across a bilipid barrier 2. LIBERATION
• Dominant
• No need for ATP • Release of drug from the drug product
• Movement along concentration gradient • Drug must be in aqueous solution – required for most
• Slow transport processes (except pinocytosis)
• Solid dosage forms → Disintegration → Dissolution
Fick’s Law of Diffusion • Liquid non-solutions → Dissolution
𝑑𝑄 𝐷. 𝐴. (𝐶1 − 𝐶2)
(𝑟𝑎𝑡𝑒 𝑜𝑓 𝑡𝑟𝑎𝑛𝑠𝑝𝑜𝑟𝑡) =
𝑑𝑡 ℎ Noyes-Whitney:
Where: D = Diffusion Coefficient 𝑑𝑀 𝐷𝐴(𝐶𝑠 − 𝐶𝑏)
A = Surface Area of Membrane =
h = Thickness 𝑑𝑡 ℎ
(C1 – C2) = Concentration gradient
Where: dM/dt = rate of dissolution
D = diffusion coefficient
Diffusion Coefficient – property of drug dependent on particle size
A = surface area of the particle
and lipophilicity
C = concentration in the stagnant layer
Cb = concentration in the bulk layer
Surface Area of Membrane – the greater the surface area the
h = thickness of the stagnant layer
faster the rate (Ling > Small Intestine > Stomach)

Thickness – inversely related

Intermediate vs Modified-Release Dosage Forms
Concentration gradient – concentration from where the drug is
coming from and the concentration where the drug is going to

Increased Diffusion Coefficient:

Smaller particle size

• Increases surface area contact with cell membrane
• Application: micronization to improve bioavailability of
Rifampicin

Greater lipophilicity
• Less degree of ionization or dissociation into charged
molecules/ions 3. ABSORPTION
• Weakly acidic drug in an acidic environment (lower pH)
• Weakly basic drug in a less acidic (basic or higher pH) • Pharmacokinetic: rate and extent of a drug entry into the
environment systemic circulation
• High lipid-water partition coefficient • Physiologic: rate and extent of disappearance of the drug
• Experimental procedure: solubility in an octanol-water from the site of administration or absorption
system
• Lipid-water partition coefficient: ratio of solubility in lipid Factors affecting absorption:
(octanol) to solubility in water
a. Dose size
b. Carrier-mediated Transports • ↑ Dose = ↑ Rate and Extent
b. pH of the absorbing environment
Common Properties of Carriers: • Acidic environment for weak acids, basic environment for
weak bases = ↑ Rate and Extent
1. Specificity/ Selectivity: carrier recognizes only certain molecular c. Degree of perfusion of the absorbing environment = blood
configuration/ conformation supply
• L-DOPA vs Dopamine • ↑ Blood supply = ↑ Rate and Extent
d. Surface area of the absorbing organ
2. Subject to competition/ inhibition/ antagonism: molecules with • ↑ Surface Area = ↑ Rate and Extent
similar configuration/ confirmation will compete for the same carrier e. Gastric emptying time
• L-DOPA vs 3-O-methyl-DOPA • ↑ GET = ↓ Rate

3. Saturability: limited number of carriers Gastric Emptying Time

i. Active transport • GET = 1/GER (reciprocal relationship of Time with rate)

• ATP – dependent • Increase GET = Decrease Rate of Absorption
• Movement against concentration gradient (at least one) • Stress, Vigorous exercise, Gastric ulcer, Lying on the
• Fast left side, anti-motility drugs (anticholinergics, opioids)

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 • Decrease GET = Increase Rate of Absorption How it is done
• Mild exercise, Extremes of food temperature, 90% Confidence Interval
Gastrectomy, Duodenal ulcer, Lying on the right side, AUC = 80 – 125%
DM, promotility drugs (D2-antagonists) Cmax = 30 – 125%
Tmax = 80 – 125%
Measuring Absorption
• Bioavailability: measure of rate and extent of drug entry into
the systemic circulation
• Blood measurement
• Urine measurement

Measurement of Blood Levels of Drugs at Timed Intervals

4. DISTRIBUTION
Time Plasma Concentration
0 hr 0.0 mg/L • Process of drug movement from the systemic circulation to
0.5 hr 0.8 mg/L the different body compartments (organs/ tissues)
1.0 hr 1.2 mg/L • Objective:
2.0 hr 2.5 mg/L • Most biological sites of action are outside the systemic
circulation
• Distribution allows drug to reach the biological site of
Measurement of Cumulative Amount of Drugs or Metabolites action
Excreted at Timed Intervals
Two Distribution Parameters
Time Cumulative Amount
0 hr 0.0 mg a. Protein Binding
0.5 hr 18 mg • Free Drug ↔ Bound Drug
1.0 hr 40 mg • Blood proteins:
2.0 hr 80 mg • Albumin: for weak acids
• α1 acid glycoprotein: for weak bases
• Globulin: for hormones
Amount time = Urine Concentration x Volume • Highly protein drugs: Diazepam, Digitoxin, Indomethacin,
Cumulative Amount time = Amount time + Amount previous times Tolbutamide, Warfarin, Midazolam
• Relevance
Bioavailability – blood measurement • Limit access to compartments
• Longer duration
tmax • Drug Displacement (?)

b. Volume of Distribution
Log Plasma Drug Conc

Log Cmax
• Hypothetical volume of body fluid necessary to dissolve a
given dose or amount of drug to a concentration equal to that
of the plasma
• Vd = D / CO (D = dose size, CO = concentration at time 0)
• Vd = A / CP (A = amount of drug, CP = drug plasma conc)
• Relevance
AUC • Estimating loading doses
Loading Dose (DL) = Vd x C desired
• Predicting fluid compartment of distribution
time Fluid Compartment % Body Weight Volume in a 70kg patient
Parameters: Total Body Water 60% 42 liters
a. Intracellular Water 40% 28 liters
Cmax – rate and extent
b. Extracellular Water 20% 14 liters
Tmax – rate i. Interstitial Water 15% 10-11 liters
AUC – extent ii. Intravascular Water 5% 3-4 liters

Absolute Bioavailability (Fabs) Drug A: Vd (70kg patient) = 5,000 liters Total body water
Drug B: Vd (70kg patient) = 40 liters Total body water High Vd
𝐴𝑈𝐶(𝑡𝑒𝑠𝑡 𝑑𝑟𝑢𝑔 𝑝𝑟𝑜𝑑𝑢𝑐𝑡)
𝐹𝑎𝑏𝑠 = Drug C: Vd (70kg patient) = 30 liters Intracellular
𝐴𝑈𝐶(𝑠𝑎𝑚𝑒 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑔𝑖𝑣𝑒𝑛 𝐼𝑉) Drug D: Vd (70kg patient) = 2 liters Intravascular Low Vd

Relative Bioavailability (Frel) Drugs with high Vd Drugs with low Vd

• Atropine • Chlorpramide
𝐴𝑈𝐶(𝑡𝑒𝑠𝑡 𝑑𝑟𝑢𝑔 𝑝𝑟𝑜𝑑𝑢𝑐𝑡) • Chloroquine • Furosemide
𝐹𝑟𝑒𝑙 = • Digoxin • Tolbutamide
𝐴𝑈𝐶(𝑠𝑎𝑚𝑒 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑛𝑜𝑛−𝐼𝑉 𝑐𝑜𝑚𝑝𝑎𝑟𝑎𝑡𝑜𝑟 𝑜𝑟 𝑟𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 𝑑𝑟𝑢𝑔)
• Fluoxetine • Valproic acid
• Imipramine • Warfarin
Bioequivalence • TCAs
• Measure of similarity in bioavailability of generic drug product • BBs
to that of the innovator or reference drug product
• Measures: 90% confidence interval about the ratios of AUC, 5. METABOLISM
Cmax and Tmax:
• AUC ratio = AUC generic / AUC innovator • Biotransformation: chemical change
• Cmax ratio = Cmax generic / Cmax innovator
• Tmax ration = Tmax generic / Tmax innovator First Pass Effect/ First Pass Metabolism (FPE/FPM)
• Acceptable 90% confidence interval: 80 – 125% (extended to • Initial metabolism a drug undergoes before reaching the
75 – 133% for Cmax) systemic circulation
• Minimum Number: 12 (immediate release), 20 (controlled Outcomes:
release) • Goals: metabolites that are
• Less active/ inactive
• Less toxic/
• Polar and easily excreted

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 • Exceptions • CYP3A4: indinavir, nelfinavir, ritonavir, saquinavir,
• Prodrug → Active telithromycin, aprepitant, erythromycin, fluconazole,
• Active → Active grapefruit juice, verapamil
• Non-toxic → Toxic
Genetic Polymorphism: Genetic differences in the expression of
Phase of Drug Metabolism enzymes

Phase I: Functionalization Phase Categories based on enzyme expression:

• Addition or unmasking of a functional group a. EM (extensive metabolizers)
• Reactions: Oxidation, Reduction, Hydrolysis • produce normal/ adequate amount of enzymes

Phase II: Conjugation or Synthetic Phase b. UM (ultra-rapid metabolizers)

• Addition of a polar conjugate • produce more than the normal amount of enzymes
• Glucuronidation, Acetylation. Glycine conjugation, etc.
c. PM (poor metabolizers)
Phase I → Phase II or Phase II → Phase I • produce less than the normal amount of enzymes
Phase I:
a. Oxidation (CYP-mediated) Common enzyme system subject to polymorphism
CYP Substrate CYP2D6
1A2 Theophylline, Caffeine, Duloxetine, Melatonin, Clozapine, • PM: increase risk of cardiotoxicity with thioridazine and anti-
Ramosetron depressants (poor Debrisoquin metabolism)
2B6 Cyclophosphamide, Ifosfamide, Bupropion, Efavirenz NAT2 (N-acetyltransferase-2)
2C8 Repaglinide, Montelukast, Pioglitazone • PM: slow acetylators, have higher risk of side effects with
2C9 Celecoxib, Phenytoin, 2nd Gen Sulfonylureas, Tolbutamide, S- substrates of acetylation (procainamide, hydralazine,
Warfarin Isoniazid)
2C19 Omeprazole, Lansoprazole, Rabeprazole, Diazepam, • EM: rapid acetylators
Voriconazole, S-Mephenytoin
2D6 Desipramine, Dextromethorphan, Eliglustat, Nebivolol,
Nortriptyline, Perphenazine, Tolterodine, Venlafaxine, 6. EXCRETION
Amitriptyline, Encainide, Imipramine, Metoprolol, Propafenone,
Propranolol, Tramadol, Trimipramine Elimination
3A4 Macrolides, Amiodarone, Cortisol, Diazepam, Grapefruit juice • Metabolism and Excretion
• Excretion: loss of the drug from the body
b. Reduction • Site: Kidneys (major), Biliary, Lungs,
• Nitro-reduction: Chloramphenicol Sweat/Secretions, Mammary
• Carbonyl reduction: Naloxone, Methadone • Prerequisite: Drugs must be polar or water soluble
• Azo reduction: Prontosil
PK Parameters
c. Hydrolysis
• Esters: Procaine, Aspirin, Enalapril (prodrug), Cocaine Biological half-life
(metab = benzoic acid) • t ½ = 0.693/k
• Amides: Lidocaine, Indomethacin, Procainamide • Time it takes for the amount of drug in the body to be
reduced to half its current amount
Phase II:
a. Glucuronidation No. of t ½ elapsed % Remaining in the body
• Acetaminophen, Diazepam, Chloramphenicol, Digoxin, 0 100
Morphine 1xt½ 50
• Enzyme: UDP-Glucuronosyl Transferase 2xt½ 25
3xt½ 12.5
b. Acetylation 4xt½ 6.25
• Isoniazid, Hydralazine, Procainamide 5xt½ 3.125
• Enzyme: NAT1 and NAT2
• Predicts when a steady state level is achieved when drug
c. Glycine conjugation doses are given at regular intervals
• Nicotinic acid
No. of t ½ elapsed % to reach steady state level
d. Glutathione conjugation 0 0
• Ethacrynic acid 1xt½ 50
2xt½ 75
3xt½ 87.5
e. Methylation
4xt½ 93.75
• Dopamine
5xt½ 96.875

Enzyme inhibition-induction
Clearance (CL)
Enzyme inducers: Benzo[a]pyrene, Phenobarbital, Phenytoin,
• Volume of blood that is cleared of the drug per given time
Rifampicin
• CL = k*Vd k = elimination rate constant
• CYP1A2: broccoli, brussel sprouts, char-grilled meat
• CL = (0.693/t ½) * Vd
(benzo[a]pyrene), omeprazole, tobacco
• CYP2C9: rifampin
Total Clearance (CLtotal) = CLrenal + CLliver + CLother sites
• CYP2C19: rifampin
• CYP2D6: rifampin, dexamethasone
• CYP3A4: rifampin, Phenobarbital, St. John’s wort,
Carbamazepine, glucocorticoids

Enzyme inhibitors:
• CYP1A2: fluvoxamine, ciprofloxacin
• CYP2C9: fluconazole, amiodarone
• CYP2C19: PPI except pantoprazole (for Clopidogrel
activation)
• CYP2D6: fluoxetine, paroxetine, quinidine, duloxetine,
terbinafine

Module 4 – Biopharmaceutics Page 8 of 8 RJAV 2022