TOPIC 1

BIOPHARMACEUTICS & PHARMACOKINETICS

BIOPHARMACEUTICS

 The science that examines the interrelationship of the physicochemical properties of the drug, the dosage form
in which the drug is given, and the route of administration on the rate and extent of systemic drug absorption.
 The study of the chemical and physical properties of drugs, their components, and their activities in living
organisms.
 Determine why drugs are made

Bioavailability

 A measurement of the rate and extent of systemic absorption of therapeutically active drug
 Ex. 500 mg tablet, the bioavailability is not eq to 100%

Pharmacokinetics

 The study of the time course of drug movement in the body during absorption, distribution, and elimination.

LIBERATION

ABSORPTION

DISTRIBUTION

METABOLISM

EXCRETION

RESPONSE

Clinical Pharmacokinetics

 Application of pharmacokinetic methods to drug therapy.

 the study of the relationships between drug dosage regimens and concentration–time profiles
 Ex. same drugs same dose but different component

Three fundamental parameters

 Clearance
o volume of fluid completely cleared of drug per unit time
o once a drug enters the body, it should be eliminated
 Volume of distribution
o apparent volume into which the drug has distributed to produce the measured concentration
o there is no such drug in solid form that can penetrate the brain
o receptor site = target site
 Elimination half life
o time taken for 50% of the drug to be eliminated
 o it starts prior to clearance
o process that include sub processes: metabolism and excretion

Population Pharmacokinetics

 Study of pharmacokinetics differences of drugs in various population

 TDM ( Therapeutic Drug Monitoring)
 Employed for very potent drug to optimize efficacy and to prevent any adverse toxicity

 CPKS ( Clinical Pharmacokinetic Service)

 Provides pharmacokinetic and drug analysis services for safe drug monitoring

On set – when the drug enters the systemic circulation

Capsule gives faster relief than tablet

Drug Therapeutic range

mg/L
Digoxin 0.5 - 2.1
Amiodarone 1.0 - 2.5
Salicylate 150 - 300
Theophylline 10 - 20
Phenytoin 10 - 20
Carbamazepine 5.0 - 12

Experimental Pharmacokinetics

 Development of biologic sampling techniques, analytical methods for the measurement of drugs and
metabolites and procedure that facilitates data collection and manipulation

Theoretical Pharmacokinetics

 Development of pharmacokinetics models that predict drug disposition after administration

o In vivo- involves human subjects/ laboratory animals
o In vitro – employs test apparatus and equipment without involving human subjects/ laboratory animals

PHARMACOKINETICS

 Model – a hypothesis using mathematical terms to describe quantitative relationship concisely.

o Empirical
o Physiological
o Compartmentally based

Pharmacokinetic Models

 Catenary
 Mammillary
  Physiologic Pharmacokinetic

Pharmacodynamics

 The study of the relation of the drug concentration or amount at the site of action and its pharmacologic
response.

Clinical Toxicology

 The study of the adverse effects of drugs and toxic substances in the body

BIOPHARMACEUTICS Involves factors that influence:

a. Design of drug product

b. Stability of drug within the drug product
c. Release of the drug from the drug product
d. Rate of dissolution/ release of the drug from at the absorption site
e. Delivery of drug to the site of action

Biopharmaceutic Considerations in Drug Product Design

 Therapeutic objective
 Drug (API)  Route of administration
 Drug dosage and dosage regimen
 Type of drug product
 Excipients
 Method of manufacture

Drug Disposition

 The description of drug distribution and elimination.

 Penetrate to gi tract

Drug Exposure and Drug Response

 Drug exposure refers to the dose and various measure of acute or integrated drug concentrations in plasma and
other biological fluid.
 Drug response refers to the direct measure of the pharmacologic effect of the drug (once the drug went to the
target site)

Design of the appropriate dosage form or delivery system depends on

 Physical and chemical properties of the drug

 Dose of the drug
 Route of administration
 Type of Drug system desired
 Desired therapeutic effect
 Physiologic release of the drug from the delivery system
 Bioavailability of the drug at the absorption site
 Pharmacokinetics and pharmacodynamics of the drug
Physicochemical Properties

A. Drug Dissolution

B. Drug Solubility

C. Particle Size and Surface Area

D. Partition Coefficient and Extent of Ionization

E. Salt Formation

F. Polymorphism

G. Chirality

H. Hydrates

I. Complex Formation

Physicochemical Properties

a. Drug Dissolution
 the rate at which the solid drug enters into solution is often the rate limiting step in bioavailabilty.
 The Noyes-Whitney equation describes the diffusion controlled rate of drug dissolution
b. Drug Solubility
 in a saturated solution is a static (equilibrium) property. The dissolution rate of a drug is a dynamic property
related to the rate of absorption.
c. Particle Size and Surface Area
 inversely related
 As solid drug particle size decreases, particle surface area increases.


d. Partition Coefficient
 The partition coefficient of a drug is the ratio of the solubility of the drug, at equilibrium, in a non-aqueous
solvent
 Inc in the no of carbon
 Decrease water solubility

 Extent of Ionization
 Drugs that are weak electrolytes (acids or bases) exist in both an ionized form and a nonionized form in
solution.
 The extent of ionization depends on the pKa of the weak electrolyte and the pH of the solution.
 The ionized form is POLAR, and therefore more WATER SOLUBLE, than the nonionized form

 Partition Coefficient and Extent of Ionization

o The Henderson-Hasselbalch equation describes the relation between the ionized and the nonionized forms
of a drug as a function of pH and pKa
o pH = pKa → 50% ionized 50% unionized
e. Salt Formation
 The choice of salt form for a drug depends on the desired physical , chemical , or pharmacologic properties.
o provide slower dissolution
o slower bioavailability
o longer duration of action
o greater stability
o less local irritation at the absorption site
o less systemic toxicity

 Salt Formation
o WEAKLY ACIDIC DRUGS
o potassium and sodium salts
o WEAKLY BASIC DRUGS
o Hydrochloride
o Sulfate
o Citrate
o gluconate salts
o estolate
o napsylate
o stearate salts

f. Polymorphism
 the ability of a drug to exist in more than one crystalline form
 Amorphous, or noncrystalline, forms of a drug have faster dissolution rates than do crystalline forms
 Same CHEMICAL STRUCTURE
 DIFFERENT PHYSICAL PROPERTIES
g. Chirality
 the ability of a drug to exist as optically active stereoisomers or enantiomers
 Individual enantiomers may not have the same pharmacokinetic and pharmacodynamic activity.
 For example, ibuprofen exists as the R- and Senantiomers; only the S-enantiomer is pharmacologically
active.
h. Hydrates
 Drugs may exist in a hydrated, or solvated, form or as an anhydrous molecule
 Dissolution rates differ for hydrated and anhydrous forms.

 Complex Formation

o A complex is a species formed by the reversible or irreversible association of two or more interacting
molecules or ions.
o Chelates are complexes that typically involve a ring-like structure formed by the interaction between a
partial ring of atoms and a metal
Ex. hemoglobin, insulin, cyanocobalamin
o Complex formation usually alters the physical and chemical characteristics of the drug.
o Large drug complexes, such as drug-protein complexes, do not cross cell membranes easily.
o For example: The chelate of tetracycline with calcium is less water soluble and is poorly absorbed.

LADMER SYSTEM

Liberation

 delivery of the active ingredient from a dosage form into solution.

 the first step which determines onset of action, rate of absorption, availability, etc., which is true for all drug
products by all routes of administration (except intravenous and the peroral use of true solutions)
 controlled by the characteristics of the drug product.
Rate Limiting Step

 the process with the slowest rate constant in a system of simultaneous kinetic processes.
 Disintegration and dissolution

Disintegration

 state in which any residue of the tablet, except fragments of insoluble coating, remaining on the screen of the
test apparatus in the soft mass have no palpable firm core.

Dissolution

 the process by which a chemical or drug becomes dissolved in a solvent.

 Small particles to solution

Dosage forms in which liberation is altered

 Parenteral (IV, IM, ID, SC)

 Per oral (sublingual, buccal)

Absorption

 The process of uptake of the compound from the site of administration into the systemic circulation.
 The movement of the drug from the site of application to the bloodstream.
 The amount of perfused blood in the site of application affects the rate of absorption.

There are many routes of absorption:

 Buccal
 Oral
 Sublingual
 Parenteral
 Nasal
 Ocular
 Inhalation
 Etc.
Distribution

 transfer of the drug from the blood to extravascular fluids and tissues
 The amount of blood perfusion in an area of the body also affects the rate at which the drug could be
distributed there.
 Perfused = blood dominant site

Volume of distribution (VD )

 Estimate the extent of drug distribution in the body

 Relates the plasma conc to the amount of drug present in the body
 theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the
desired blood concentration of a drug.
 Location of DRUG based on VD

CIRCULATORY SYSTEM 5L
EXTRACELLULAR FLUID 10-20L
INTRACELLULAR FLUID 25-30L
WHOLE BODY FLUID 40L

Apparent partition coefficient and extent of protein binding-way of estimating VD

Metabolism

 Detoxification/Biotransformation (transforms active drug to less active)

 enzymatic or biochemical transformation of the drug substance to (usually less toxic) metabolic products, which
may be eliminated more readily from the body
 changes the drug composition from active to inactive
 Xenobiotics – foreign chemicals
 Goal of metabolism  make drug more polar
o Polar – the drug is easily excretable
o Ionized – polar substance that can dissolve in water

Excretion

 final loss of the drug substance or its metabolites from the body
 polar metabolites through the kidney
 non-polar drugs through the liver

Topic 2

Drug Administration

 Often the goal is to attain a therapeutic drug concentration in plasma from which drug enters the tissue
 Affect the ONSET, INTENSITY and DURATION of the drug in the body

 Onset – the systemic circulation, the time in which the patient reaches the pharmacologic effect

 Intensity – maximum concentration in which the drug delivers into the body

 Duration – time span for the drug to produce effect.

  Bacterial infection : high body temperature

Minimum effective concentration is considered as the concentration that would lead to pharmacologic response

Common Routes of Drug Administration

 Parenteral
 Enteral
 Transdermal
 Inhalation and Intranasal

Route BA ADV DIS

PARENTERAL
Intravenous bolus (IV 100% Immediate effect Inc. chance of adverse
bolus) – direct, small reaction
volume
Intravenous infusion 100% • Plasma drug levels Requires skill of insertion
(IV infusion) – large precisely controlled Tissue damage at the site of
volume parenteral • May inject large injection
where there is a time fluid volumes
for drug to enter to • Drugs with poor lipid
the body sol and irritating drugs
Intramuscular (IM) Rapid(aqueous soln) Easier to inject than IV Irritating drugs may be
Slow (non aqueous Larger volume may be painful
soln) used compared to SC
soln
Subcutaneous (SC) Prompt from aqueous For insulin injection Depends on blood flow and
soln injection volume
Slow absorption from
repository formulation
ROUTE BA ADV DIS
ENTERAL
Buccal or Sublingual Rapid abs from lipid No “First Pass Effect” Not for most drugs with
soluble drugs -prevents the drug from higher doses
entering the liver, it will
not quickly circulate on
the liver
Oral (PO) Abs may vary Safest and easiest route • Some may have erratic
Slower absorption abs
compared to IV • First pass effect
Rectal Abs may vary For patient who cannot • Supp may migrate to
swallow different position
• discomfort

ROUTE BA ADV DIS

OTHER
Transdermal • Slow abs • Easy to use Irritation Permeability
Ex. Creams, paste, • Inc abs with occlusive • Used for lipidsoluble vary Type of cream or
ointment dressing (ex. ointment) drugs with low dose and ointment base affects
low MW drug release
Inhalation and intranasal Rapid absorption For local or systemic • Particle size determines
Below 100% effects anatomic placement in
respiratory tract
• Stimulate cough reflex

OTHER SITES FOR MEASURING DRUG CONCENTRATION

o Drug concentration in tissues (all tissues have their concentration of drugs)

o Urine and feces
o Saliva
o Forensic drug measurement

 When a high concentration of a drug is seen in the feces, it means it is not absorbed.
 When a drug is seen in the urine, it means it is successfully absorbed.

 Drugs that don’t liberate are true solutions because they are already in a solution or liquid form
 When a drug enters our body, majority of the drug is absorbed in the small intestine

 Not all drugs are absorbed

 Those drugs that are nonpolar (non ionized, lipid soluble) can only penetrate the membrane
 Ionized form allows the drug to be in liquid form, then the particles of the drug that are non ionized are the only
drug that will penetrate into the system
 Non ionized drug that penerates into the system are usually the one that circulates
 When a drug penetrate the systemic circulation, the drug will circulate into the liver
 Every drug that enters the liver again and again, portion of it metabolized
 From nonpolar to polar
 Water soluble substance in our blood will be filtered out when drug enters our kidney
 When drug is not eliminated, it will cause toxic effect

 There are different routes of drug because they are well absorbed in that particular site