Review of Biopharmaceutics & clinical

pharmacokinetics
Yusuf Jobe Abubakar, Registered pharmacist,
MSc(Pharma)
objectives

• Meaning and use of LADMER

• Relationships of pharmaceutics, pharmacodynamics
and pharmacokinetics
• Applications of basic and clinical pharmacokinetics
• Importance of clinical pharmacokinetics in pharmacy
and drug research & development
Introduction
• A young discipline among the health sciences,
interrelated with bio pharmaceutics, pharmacology
and therapeutics
• The foundation of pharmacokinetics, the study of
change of drug concentration evolved in the 70s.
• It is applied clinically in the routine care of patients as
a form of therapeutic drug monitoring.
• Pharmacokinetic parameters are most useful in
characterizing the drug disposition and/or the
development of individualized dosing regimens.
• Its also useful in clinical research in the area of drug
product development, critical drug evaluation
,evaluation of new biological compounds, as well as
drug product design, individualized cellular therapy
and in the process of approval in regulatory affairs.
• There is a considerable overlap among classical fields
of pharmaceutics, bio pharmaceutics,
pharmacokinetics and pharmacodynamics.
• Pharmacokinetics is derived from Greek words:
• Pharmakon (drug) and Kinetikos (motion, rate of
change).
• This filed of study includes Liberation, Administration,
Distribution, Metabolism ,Excretion and Response
(LADMER).
• LADMER systems provides the basis for the
understanding of what the drug does to the body and
what happens to the drug in the body.
• Drugs moves around the body quickly. During this
course many of the processes which control the
absorption, distribution, metabolism, and excretion of
drugs will be discussed, qualitatively (bio-
pharmaceutics) and quantitatively (pharmacokinetics)
 Meanings of key terms

• Recent understanding about drug-body interaction the inclusion

of two terms Liberation and Response in pharmacokinetics
• 1. Liberation: process of release of drug from the formulation
• 2. Absorption: process of drug entering the body
• 3. Distribution: movement of drug substances throughout the
fluids and tissues of the body
• 4. Metabolism: irreversible transformation of parent drug
molecule into new substances( active or inactive)
• 5. Excretion: elimination of drug substances from the body, some
drug drugs irreversibly accumulate in a tissue in the body.
• 6. Response: qualitative and quantitative effects of drugs on the
body (may be beneficial or non beneficial effects).
• 7. Quantitative effects :onset of action, intensity of effect and
duration of effects. These are controllable.
Tablet after administration
References Cadwallader, D.E. (1983) Biopharmaceutics and Drug Interactions, (3rd ed.), Raven Press, New York, p72

Dedrawn from Cadwallader,

1983


Pharmacokinetics, Appleton-Century-Crofts, New York, p142

Niazi, Niazi, S. (1979) Textbook of Biopharmaceutics and Clinical Pharmacokinetics, Appleton-Century-Crofts, New York, p142
Use of ladmer
• 1. Development of new active compounds , analogues
or derivatives
• 2. Development of dosage forms with desired release
characteristics
• 3. Determination of pharmacokinetic parameters and
pharmacokinetic drug profiles:
• 4. Determination and evaluation of bioavailability;
• 5. Selection of the most appropriate route of
administration;
• 6. Determination of effective dose sizes; and
• 7. Adjustment of dosage regimen to achieve a desired
therapeutic concentration of drug in the body based
on physiologic(body weight, age, sex etc.) and
pathologic factors (renal, hepatic or heart failure,
obesity, malnutrition, etc.)
Who uses pharmacokinetics
• 1. Practicing pharmacists, physicians, Pharmacologists etc. as
guide to problem solving for their professional work.
• 2. Clinical practitioners who need quick information on the
kinetic characteristics of specific drugs
• 3, Researchers in industry of academia engaged in preclinical and
clinical studies, dosage form designs and evaluation, the design of
experimental protocols and the analysis/interpretation .
• Specifically this course is designed to help students understand
how pharmacokinetics in relation to physiological and
environmental factors affect the effects of drugs in the body. The
benefit or otherwise of a drug defends on how much and often is
administered and how long it stays in the body as a biologically
active substance.
• 4. Physicians and clinical pharmacists will want to establish a
correlation between levels of drug(concentration) and
responses.( subclinical, clinical and toxic doses)
General principles
• Three phases of drug activity :
• Pharmaceutical, Pharmacokinetic and Pharmacodynamics
• Pharmaceutical phase- how the pharmaceutical dosage forms
influence ‘kinetic and ‘dynamic activities
• Clinical pharmacokinetics is the discipline that applies
pharmacokinetic concepts and principles in humans in order to
design individualized dosage regimens which optimize
• the therapeutic response of a medication while minimizing
the chance of an adverse drug reaction.
• Pharmacokinetics is simply “the study of the absorption,
distribution, metabolism, and excretion of drugs”. Consider
L(ADME)R.
Routes OF DRUG ADMINISTRATION

Drug may be given IV(100% in systemic circulation) or by other

routes: IM, SC & other routes (< 100% in blood)
Oral route-
most common(<100%)..sequence :
--admin of formulated (dose) drug-->disintegration (if tablets
or capsule->dissolution solution->absorption.

• Enteral comprise:
oral, sublingual and buccal
Oral-
advantages-easy, self admin, overdose can be overcome by use of antidotes
Disadvantages- Presence of food, harsh environment like acid ,first pass effect
(FPE)

Sublingual- capillary network, rapid absorption convenience, avoid harsh GIT

environment and First Pass Effect.
Routes cont.

Parenteral routes

• Drug is direct in the systemic circulation.

• Good for unconscious patients, poorly absorbed
oral medications (atracurium, heparin) and those
that are unstable with no GIT irritation (insulin,
penicillin).Those likely to produce GIT irritation
• Highest bioavailability
• Dose control but irreversible
• IV,IM, SC etc
Other routes
Inhalation
• -provide rapid effect similar to IV
• Large surface area, local and systemic effects
• Gaseous drugs are suited-anesthetics
• Good for respiratory medications
Intranasal-
direct into nose
Mometasone (anti-inflammatory), desmopressin
(diabetes insipidus) calcitonin(osteoporosis)
Topical
- local effect for drugs like miconazole, tropicamide
Rectal
- 50% drainage bypasses portal circulation…minimizes
FPE, prevent GIT destruction of drugs
 ABSORPTION
• -Process of drug entering systemic circulation across a barrier.
• Transport proteins are available for transportation of drugs
• -Rate and efficiency depend on the route
• -No absorption for intravascular, no loss of drug (100% in the body)
• -Extravascular are associated with absorption and possible loss- bioavailability
consideration
• -Determinants of absorption are drug solubility are blood flow to the site of
absorption, concentration, total surface area available and contact time at
absorption site:
• -Solubility-extremes of either water or lipid solubility is associated with poor
absorption, best for drug to have both water and lipid solubility.
• -Blood flow-absorption in intestine better than stomach, massaging of IM site
for some drugs may enhance absorption. Shock severely reduces blood flow
thus minimizing absorption.
• -Concentration- drugs diffuse down a concentration gradient, only free
unionized drug contributes to the conc. gradient. Drugs that move against
concentration gradient require energy(ATP)
Determinants cont.
• -Total surface area- intestine rich in microvilli, more area
than stomach, absorption is efficient across intestine
• -Contact time- severe diarrhea hampers absorption from GIT
• Delay of drug transport from stomach to intestine delays
rate of absorption
• ANS insolvent:
• i. Sympathetic stimulation reduces as in exercise or stress
and ant cholinergic drugs (atropine) prolong gastric
emptying time (GET).
• ii. Parasympathetic stimulation increase rate of GET
• Food(heavy meal) dilutes drug and slow GE.
 Transport from GIT
• Drugs can be non electrolytes, weak acids, weak bases.
• Only unionized fraction pass across the membrane.
• Drugs depending on their chemical properties may be absorbed from GI
by passive diffusion, facilitated diffusion and active transport. Also
endocytosis and exocytosis.
• Passive-no energy, and carrier needed, not saturable, down the gradient,
shows structural specificity. Majority of drugs, lipid soluble pass readily
across and water soluble pass across through aqueous channels or pores,
alcohol, digoxin.
• Facilitated –no energy, needs carrier (proteins), down gradient and is
saturable and may be inhibited drug like vit. B12.
• Active transport- needs energy, carrier, against gradient (electrical or
concentration) and is saturable.-testosterone, estradiol, digoxin.
• Ion-pair transport for ionized compounds like ampicillin, doxorubicin.
• Endo/pinocytosis- Vit A, D, E. process of engulfing.
• Convective transport mechanism- drug dissolved in aqueous medium at
transport site move along with solvent through pore example:
sulfonamides.
 Transport proteins
• Drug transporters are expressed in various tissues,
intestine kidney etc. play key role in absorption,
distribution and excretion.
• E.g. multi drug resistant gene/p-glycoproteins,
oligopeptide transporter 1, Multidrug resistance
associated proteins 1, 2 & 3.
• Others are: Bile salt export pump/glycoprotein.

• Drug may be absorbed by more than one mechanisms

e.g. in mouth cavity (passive & and convective)
stomach (passive, convective and active) small
intestine(passive, convective, facilitated ion pair
pinocytosis and active)
 Effect of pH
Definition: pH is a measure of acidity or basicity of the environment.
-pH - 14 point scale indicating concentration
of free H+ ions.
• pH of 7 is “neutral”.
• pH of < 7 is acidic.
• pH of > 7 is basic (alkaline
Ionization Rule:
• Basic drugs tend to be ionized in acidic
environments.
• Acid drugs tend to be ionized in basic
environments.
• The stomach environment is very acidic, so
________ drugs aren’t absorbed very well
Henderson-Hasselbach EQUATION

• Determination of how much drug will be found on either

side of a membrane is by use of Henderson-Hasselbalch
equation, that is:
• pH-pKa = log ionized/unionized or
• pH =pKa+ log unionized/ ionized
• (protonated = ionized or charged)
• (non-protonated = unionized or uncharged)
 Absorption cont.
• Weak bases or acid drugs:
• Weak acid (HA-neutral is uncharged) release H ion and weak base (BH+) also
release H ion to produce neutral or uncharged BH
• Only uncharged will cross the membrane
• Effective concentration of permeable form of each drug at its
absorption site is determined by relative concentration of
charged and uncharged which in turn determined by pH at site
and strength of acid or base represented by pKa. See fig.1.5
&1.6
• The pKa is a measure of the strength of the interaction of a compound with a
proton (How strong an acid or base is a compound)
• The lower the pKa, the more acidic and the higher the pKa, the more basic is
the drug.
• Distribution equilibrium is reached when permeable form of drug achieves
an equal concentration in all body water.
Bioavailability

• -Fraction (f) of drug admin that appears or reaches

systemic circulation in a chemically unchanged form,
expressed as % /decimal i.e. 90/0.9
• E.g. intravascular doses have f=1 or 100%
• Affected by First Pass hepatic metabolism, solubility,
chemical stability and nature of drug formulation.
• Any other route of administration, the “f” is less
than 1 or 100%
• Determination of bioavailability (f)will be discussed
at another time.
 Biequivalence.
• For bioequivalence to exist between 2 drugs, they must have same
bioavailability and same rate of absorption , that is: comparable
bioavailability and similar times to achieve peak (maximum)
blood/plasma concentration.

• If two (2) related (A & B)drugs have no significant difference in

bioavailability they are bio-in equivalent.
• If they have significant difference, then they are not bioequivalent.
• Also if they have same bioavailability but differ in rates of
absorption, they are bio-in equivalent.
• Time (tmax) to reach maximum conc. and Cmax( max
concentration) are rate dependent.
• The faster the rate of absorption the smaller will be maximum time
(Tmax )and the larger will be maximum concentration (Cmax)
conversely, the slower the rate of absorption the larger will be the
Tmax and the lower will be Cmax
 Equivalences

• Therapeutic equivalence:
• Bioequivalent products are defined as pharmaceutical equivalent drugs whose
rates and extent of absorption do not show significant difference.
• Two drugs with comparable efficacy and safety are therapeutically equivalent.
Drugs that are bioequivalent may not be therapeutically equivalent.
• Food and Drug Administration imposed a requirement that drug products must
satisfy in-vitro and/ or in-vivo testing as a condition for marketing.

• Pharmaceutical equivalence:
Defined as drug meeting compendia standards in terms of identity, potency,
strength, purity, quality and disintegration & dissolution times. For this to be valid
the drugs m ust contain identical amounts of identical ingredient ( same salt, or
ester of the same therapeutic potion in identical dosage form but not necessarily
same inactive ingredients). Drugs that conform to this definition are called
Pharmaceutical Equivalents.
The equivalents
Pharmaceutical equivalents:
• Codeine phosphate 15mg oral liquids containing different
flavors or other additives.
Pharmaceutical Alternatives:
• These are drug products that contain the identical
therapeutic portion or its precursor, but not necessarily in
the same amount or dosage form or as same salt or ester.
Examples:
• Ibuprofen 400mg and Ibuprofen 800mg
• Ampicillin capsules and ampicillin suspension
• Acetaminophen elixir and Acetaminophen tablets
• Codeine phosphate and codeine sulphate
 Distribution
• Drug reversibly leaves the blood stream and enters
the extra cellular fluids and/or cells of tissues. Fig 2-1
p11
• Correlates doses given with resultant blood levels.
• Delivery from plasma to interstitium depends
primarily on blood flow, capillary permeability,
degree of protein binding and relative
hydrophobicity/lipophilicity
• Only unionized drugs get across membrane
Factors affecting drug distribution

A. Blood flow:
• Unequal blood flows to different tissues.
• Blood flow to :
• Brain
• Liver
• Kidney
->greater than blood flow to skeletal muscles
• Adipose tissues- low rate of blood flow.
• Drugs like thiopental moves rapidly into CNS thus results in short duration of
anesthesia because of high blood flow and superior lipid solubility.
• There is lower flow to skeletal muscles and adipose tissues as well as sole of
the foot.
• More blood flows under the tongue ( sublingual)and between the chick and
gum (buccal), back of the ear.
Distribution cont.
•Redistribution also accounts for extreme short
duration of action in some compounds.
•Drugs redistribute from their site of activity.
This will result in the duration of action of first
dose depending upon the rate of redistribution
into fat depots and not the half life of the drug
and after several doses, when the fat depots
are saturated, duration of action will depend
upon half life of the drug. This usually means
that duration of action of second dose will be
longer that the first.
Factors cont.
B .Capillary permeability:
• 1. Capillary structure and chemical nature are the determinants.
- Structure: membrane have slit junctions
- Brain has no slit junctions, have continuous structure
- Liver and Spleen have slit junctions allowing drugs to exchange freely
between blood and interstitium in these organs
- Blood-Brain –Barrier (BBR)- have tightly juxtaposed cells forming tight
junctions
-Certain drugs need carrier to pass into brain from blood by active transport
- lipid soluble readily pass
- ionized/polar drugs fail to pass.

• 2. Drug structure
• Hydrophobic drugs readily move across most membrane as they dissolve in
lipid membrane
• Permeate entire cell surface thus move across most biological membranes
whereas non lipid soluble pass across slit junctions
Factors cont.
C. Binding to proteins and tissues
- drugs bind to plasma proteins and tissues. The complex
formed are bulky to pass through the base membrane
readily.
-drugs are thus sequestered in non diffusible forms serving
as reservoir
-binding is non selective in most cases
- binding is reversible, The drug can be moved from the
plasma to the tissue until the equilibrium is established
- the free drug that dissociates from the D-P complex, if it
enters site of action interacts with receptors
- only free drug is due for elimination by metabolism and
excretion.

D. Other factor is cardiac output,

• See figure 1.8 p.8 for cross section of liver and brain
capillaries
Protein and Tissues binding to drugs
• Drugs can bind to same tissues or proteins
• Drug A with higher affinity displaces the drug B with lower
affinity from binding sites increasing the intensity of action,
side effects and toxicity of drug B.
• Hydrophobic drugs bind to considerably to plasma proteins
and erythrocytes.
• Drugs bind by van der Waals forces, hydrophobic bonds,
hydrogen bonds and ionic bonds
• Types of proteins-Albumin (large portion)
• serum albumin in human, basic group of the amino acids like
histidine, arginine and lysine are responsible for binding to
acidic drugs
• Acidic group of the aspartic acid, glutamic acid and tyrosine
bind to basic drugs.
Protein &tissue binding cont.
• Serum albumin in human, basic group of the amino
acids like histidine, arginine and lysine are
responsible for binding to acidic drugs
• Acidic group of the aspartic acid, glutamic acid and
tyrosine bind to basic drugs.

• Alpha acid glycoproteins (orosomucoid) is an alpha

globulin binds to only basic drugs, highly lipophilic
• drugs- Bupivacaine, diazepam, disopyramide,
fentanyl, fluphenazine, trihexyphenidyl, meperidine
etc.
 protein binding- competition
• Hypoalbuminemia may alter the level of free drug.
• Binding may be low capacity or high capacity( a number of drug
molecules bind to a single albumin)
• Competition exist for binding to albumin.
• Two classes of drug exist :
• Class 1- Clinically useful drugs in which the dose of drug is less
than the binding capacity for albumin, sites are in excess of
available drugs and thus bound-drug fraction is high. Drug like
warfarin. Prone to toxicity.
Protein binding cont.
• Class 2- drugs whose dose given greatly exceed the
number of albumin binding sites and are relatively
high doses, unbound exist in free states. Drugs like
sulfonamides (Co.trim:septra/bactrim).

• If class 1 and 2 are given simultaneously, displacement

of class one drug results in toxicity.
• Warfarin and other highly bound coumarin-like drugs
are displaced by mefenamic acid, clorfibrate,
ethacrynic acid.

• Tolbutamide is displaced by salicylates, sulfisoxazole

 Disease and protein binding

•Hypolbuminemia as in
-burns, cancer, cardiac failure, cystic fibrosis, enteropathy,
inflammations, liver impairment, malabsorption, nephrotic
syndrome, renal failure, sepsis, and trauma also in geriatric
patients after prolong immobilization, during pregnancy, after
prolong stress and in smokers.

•Low Alpha acid glycoproteins is seen in cancer, inflammation, trauma

and myocardial infarction
- drugs affected (Liver)
morphine, prednisolone, triamterene, barbiturates, phenytoin.
(Renal) Furosemide, salicylates, sulfonamides, triamterene, barbiturates
 Uptake of drugs by RBC

•Drugs are taken by RBC controlled by the drugs lipid

solubility which is dependent on drugs ionization.
•Drugs: alfentanil, artemisinin, bupivacaine,
flurazepam, pentazocin,bepridil, etc.
•Binding results in lower tissue reuptake and lesser
retention in critical organs like kidney in the case
auranofin
•Highly bound drugs to RBC like meperidine in high
altitude makes the drug ineffective due to lack of free,
unbound drug as a consequence of increase in the
number of erythrocytes
Volume of distribution (Vd)

•This is a hypothetical •It is defined as the volume in which

volume(not real or true vol) the amount of drug would need to be
uniformly distributed to produce the
of fluid into which a drug is observed blood concentration.
dispersed it is useful to
Volumes in the body are:
compare the distribution of
drug with volumes of water •Total body water: 40-42L
compartments in the body •Extracellular fluid:12-14 L
•It is term used to quantify •Blood: 5 L
the distribution of a drug •Plasma: 3 -4L
throughout the body after •Total blood and plasma volume is
oral or parenteral dosing. approximately 9L
Vd cont.
•1.Plasma volume – •2.Extracellular volume
drug like heparin with (about 20% of body weight)
high MW binds to
plasma proteins •drug with low MW and
hydrophilic can move into
becomes too large to interstitial fluid through the slit
cross the slit junctions junctions of the capillaries.
of capillaries and thus Hydrophilic cannot cross through
trapped in vascular the lipid membrane to enter water
area (plasma) phase inside the cell. Drugs like
streptomycin, amikacin etc.
•Drug on entering
body, distributes in
into any of the three
functionally distinct
compartments or
become sequestered
in in a cellular site.
Vd cont.
• Total body water (about 60% of body weight,40- 42
L)- a low molecular weight drug which is hydrophobic
(hydrophilic) moves across into interstitial and into
cell membrane. Drugs like alcohol, benzodiazepines,
barbiturates.
• Other sites; pregnancy and fetus take up many drugs

• The volume of distribution is given by the following

equation:
• Vd = total amount of drug in the body/Blood
concentration
.Therefore the dose required to give a certain plasma
concentration can be determined if the Vd for that
drug is known.
 Vd cont.

The Vd is not a real The units for Volume of

volume; it is mere distribution are typically
reflection of how a reported in (ml or liter)/kg body
drug will distribute weight.
throughout the body The fact that Vd is a ratio of a
depending on several theoretical volume to a fixed
physicochemical unit of body weight explains why
properties, e.g. the Vd for children is typically
solubility, charge, size, higher than that for adults, even
etc. though children are smaller and
weigh less.
It is important to
note that the volume As body composition changes
of distribution cannot with age, Vd decreases.
be smaller than the
physiological volume of The Vd may also be used to
intravascular plasma, determine how readily a drug
which is approximately will displace into the body tissue
3L in humans compartments relative to the
blood:
 Vd cont.
•Vd =D/C •Rate of drug
•E.g. if a drug is elimination is
administered in a dose of proportional to the
25mg and plasma conc. was concentration of drug
assayed as 2mg/L then its (C)
Vd will be 12.5L •Most drugs distribute
•Drugs are eliminated from unevenly in several
body and a plot of plasma compartments and thus
concentration vs. time the Vd is not the real
shows two phases. volume rather a ratio of
extraplasmic spaces
•Initial decrease in plasma relative to the plasma
amount due to rapid spaces.
distribution phase, the
followed by slower
elimination phase
 Use of Vd
•Vd is useful as it can be Large Vd influences half life of the
used to calculate the drug as elimination depends on
amount of drug needed the amount of drug delivered to
to achieve a desired the liver or kidney which in turn
plasma concentration. depends on blood flow and
fraction of drug in the plasma.
•If a drug like digoxin has
a plasma concentration
of Ci and the desired If Vd is large, most drug is in the
level is Cii, the Clinician extraplasmic space and is
wants know how much unavailable for excretory organs.
should be given to bring
the circulating label to Any factor decreasing Vd can lead
Cii to an increase in half life and
extended duration of action. Large
Vd indicates sequestering of drug
Amount of drug needed in some organs or compartments.
(D) = Vd *(Cii-Ci)
Ci =initial concentration
Cii = final concentration
 Drug Metabolism
•Biotransformation of drugs, both occur, the major
•their biochemical modification
or degradation, by specialized
metabolites of most
enzyme systems. drugs are detoxification
products.
•Drug metabolism often converts •Drugs are almost all
lipophilic chemical compounds
into more readily excreted, water
xenobiotics (foreign).
soluble/polar products. •Other commonly used
organic materials are
• rate of administration and also xenobiotics, and are
particularly metabolism is an
important determinant of the
metabolized by the same
duration and intensity of the enzyme as drugs.
pharmacological action of drugs. •This is an opportunity
for interactions.
•metabolism can result in the
activation or deactivation of the
chemical(drug).
 Phases of METABOLISM
•Phase I and Phase II
reactions
Phase II reactions
•Phase I reactions a non synthetic • conjugation reactions
reactions may occur by oxidation. (e.g.with glucuronic
Types: acid sulfonation/sulfation,
glutathione or amino
Reduction hydrolysis, cyclization, and acids like glycine)
de-cyclization reactions.
Acetylation.
Dehydrogenation (non microsomal) •This is usually a form of
•May increase, decrease or detoxification and
not alter the drug pharmacological involves the interactions of
the polar functional groups
activity. of phase I metabolites to
•Most frequently catalyzed by produce the excretable
forms
cytochrome p450 system
(mixed function oxidases) •both occur, the major
•Drug binds to oxidized form of metabolites of most
drugs are detoxification
p450 introducing oxygen and products.
Coupled
to NADPH:p450 oxidative reductase.
Drug excretion
Bibliography and Readings
• Ritschel & Kearns: Handbook of Basic
Pharmacokinetics. (6th ed.).pages 1-12
• Harvey & Champe: Pharmacology (4th
ed.). Pages 1-16