BIOAVAILABILITY AND

BIOEQUIVALENCE

1
 BIOAVAILABILITY AND BIOEQUIVALENCE
Bioavailability : the rate and extent reaches the systemic
circulation
Bioequivalent: when two drug products given by the same route
containing same amount of the same drug exhibit invivo the same
rate and extent of absorption, they may be termed bioequivalent.
Bioequivalency: bioequivalence is a measure of the degree of
the sameness in the biological activity for a test product compare
to a standard.
 the rate and extent of absorption of the test drug do not show a
significant difference from the rate and extent of absorption of the
reference drug when administered at the same molar dose.
Bioequivalence may sometimes be demonstrated using an in-
vitro bioequivalence standard, especially when such an in-vitro
test has been correlated with human in-vivo bioavailability data.
In other situations, bioequivalence may sometimes be
demonstrated through comparative clinical trials or
pharmacodynamic studies. 2
 Purpose of Bioavailability Studies: Bioavailability studies are
performed for both approved active drug ingredients and
therapeutic moieties not yet approved for marketing by the
FDA.
 New formulations of active drug ingredients must be approved
by the FDA before marketing.
 In approving a drug product for marketing, the FDA ensures
that the drug product is safe and effective for its labeled
indications for use.
 Moreover, the drug product must meet all applicable standards
of identity, strength, quality, and purity.
 In-vivo bioavailability studies - performed for new formulations
of active drug -full NDA approval, then approved for marketing.
 studies is to determine the bioavailability and to characterize
the pharmacokinetics of the new formulation, new dosage form,
or new salt or ester relative to a reference formulation.
 In summary, clinical studies are useful in determining the safety
and efficacy of drug products. 3
 AUC-The area under the drug concentration–time curve (AUC)
is used as a measure of the total amount of unaltered drug that
reaches the systemic circulation.

4
 Relative Availability: Relative (apparent) availability is the
availability of the drug from a drug product as compared to a
recognized standard.
 The relative availability of two drug products given at the same
dosage level and by the same route of administration can be
obtained using the following equation:
Relative Availability = [AUC]A / [AUC]B
 Where drug product B is the recognized reference standard.
This fraction may be multiplied by 100 to give percent relative
availability.
 Urinary drug excretion data may also be used to measure
relative availability, as long as the total amount of intact drug
excreted in the urine is collected. The percent relative
availability using urinary excretion data can be determined as
follows:
Percent relative availability =[Du]∞A / [Du]∞B x 100
5
 Where [D u]∞ is the total amount of drug excreted in the urine.
 Absolute Availability: The absolute availability of drug is the
systemic availability of a drug after extravascular administration
(eg, oral, rectal, transdermal, subcutaneous) compared to IV
dosing.
 Absolute availability after oral drug administration using plasma
data can be determined as follows:
absolute availability = [AUC]PO dosePO / [AUC]IV doseIV
 Absolute availability, F, may be expressed as a fraction or as a
percent by multiplying F x 100.
 Absolute availability using urinary drug excretion data can be
determined by the following:
absolute availability =[Du]∞PO dosePO / [Du]∞IV dose IV x 100
 The absolute bioavailability is also equal to F, the fraction of the
dose that is bioavailable.
 Absolute availability - expressed as a percent, ie, F = 1, or
100%. For drugs given intravascularly, such as by IV bolus
injection, F = 1 because all of the drug is completely absorbed.
 For all extravascular routes of administration, such as the oral
route (PO), the absolute bioavailability F may not exceed 100%
(F > 1), where PO is the oral route or any other extravascular6
route of drug administration.
 Assessment and comparison of bioavailability
 Direct and indirect methods may be used to assess drug
bioavailability.
 The in-vivo bioavailability of a drug product is demonstrated by
the rate and extent of drug absorption, as determined by
comparison of measured parameters, eg, concentration of the
active drug ingredient in the blood, cumulative urinary excretion
rates, or pharmacological effects.
 For drug products - measurements intended to reflect the rate
and extent to which the active ingredient or active moiety
becomes available at the site of action.
 The design of the bioavailability study depends on the
objectives of the study,
- the ability to analyze the drug (and metabolites) in biological
fluids,
- the pharmacodynamic of the drug substance,
- the route of drug administration, and the nature of the drug
product.
 Pharmacokinetic and/or pharmacodynamic parameters as well
as clinical observations and in-vitro studies may be used to 7
determine drug bioavailability from a drug product.
 Plasma Drug Concentration
 Measurement of drug concentrations in blood, plasma, or
serum after drug administration is the most direct and objective
way to determine systemic drug bioavailability.
 By appropriate blood sampling, an accurate description of the
plasma drug concentration–time profile of the therapeutically
active drug substances can be obtained using a validated drug
assay.
 t max. The time of peak plasma concentration, t max, corresponds
to the time required to reach maximum drug concentration after
drug administration.
 At t max, peak drug absorption occurs and the rate of drug
absorption exactly equals the rate of drug elimination.
 Drug absorption still continues after t max is reached, but at a
slower rate.
 When comparing drug products, t max can be used as an
approximate indication of drug absorption rate.
 The value for tmax will become smaller (indicating less time
required to reach peak plasma concentration) as the absorption
rate for the drug becomes more rapid. 8
 C max. The peak plasma drug concentration, C max,
represents the maximum plasma drug concentration obtained
after oral administration of drug.
 For many drugs, a relationship is found between the
pharmacodynamic drug effect and the plasma drug
concentration.
 C max provides indications that the drug is sufficiently
systemically absorbed to provide a therapeutic response.
 In addition, C max provides warning of possibly toxic levels of
drug.
 The units of C max are concentration units (eg, mg/mL, ng/mL).
Although not a unit for rate, C max is often used in
bioequivalence studies as a surrogate measure for the rate of
drug bioavailability.
 AUC. The area under the plasma level–time curve, AUC, is a
measurement of the extent of drug bioavailability.
 The AUC reflects the total amount of active drug that reaches
the systemic circulation. 9
 The AUC is the area under the drug plasma level–time curve
from t = 0 to t = ∞, and is equal to the amount of unchanged
drug reaching the general circulation divided by the clearance.
[AUC]∞o = ∫∞o Cp dt
[AUC]∞o = FDO/ clearance = FDO/ kVD
- Where F = fraction of dose absorbed,
-D0 = dose,
-k = elimination rate constant, and
-VD = volume of distribution.
 The AUC is independent of the route of administration and
processes of drug elimination as long as the elimination
processes do not change. The AUC can be determined by a
numerical integration procedure, such as the trapezoidal rule
method. The units for AUC are concentration time (eg, μg
hr/mL).
 For many drugs, the AUC is directly proportional to dose. For
example, if a single dose of a drug is increased from 250 to
1000 mg, the AUC will also show a fourfold increase (and).
 the AUC is not directly proportional to the administered dose10for
all dosage levels.
 as the dosage of drug is increased, one of the pathways for drug
elimination may become saturated. Drug elimination includes the
processes of metabolism and excretion.
 Drug metabolism is an enzyme-dependent process.
 drugs salicylate, phenytoin- continued increase of the dose causes
saturation of one of the enzyme pathways for drug metabolism
and consequent prolongation of the elimination half-life.
 Urinary Drug Excretion Data: Urinary drug excretion data is an
indirect method for estimating bioavailability.
 D∞u. The cumulative amount of drug excreted in the urine,
D∞u, is related directly to the total amount of drug absorbed.
Experimentally, urine samples are collected periodically after
administration of a drug product. Each urine specimen is analyzed
for free drug using a specific assay. A graph is constructed that
relates the cumulative drug excreted to the collection-time interval.
 drug is almost completely eliminated, the plasma concentration
approaches zero and the maximum amount of drug excreted in
the urine, D∞u, is obtained.
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 dDu/dt. The rate of drug excretion. Because most drugs are
eliminated by a first-order rate process, the rate of drug
excretion is dependent on the first-order elimination rate
constant k and the concentration of drug in the plasma Cp.
 In , the maximum rate of drug excretion, (dDu/dt)max, is at point
B, whereas the minimum rate of drug excretion is at points A
and C. Thus, a graph comparing the rate of drug excretion with
respect to time should be similar in shape as the plasma level–
time curve for that drug.
 t ∞. The total time for the drug to be excreted. In and , the slope
of the curve segment A–B is related to the rate of drug
absorption, whereas point C is related to the total time required
after drug administration for the drug to be absorbed and
completely excreted t = ∞.
 Acute Pharmacodynamic Effect: In some cases, the
quantitative measurement of drug is not available, an acute
pharmacodynamic effect such as an effect on pupil diameter,
heart rate, blood pressure-can be used as an index of drug
bioavailability. 12
 An acute pharmacodynamic effect, such as an effect on forced
expiratory volume, FEV1 (inhaled bronchodilators) or skin
blanching (topical corticosteroids) can be used as an index of
drug bioavailability.
 In this case, the acute pharmacodynamic effect is measured
over a period of time after administration of the drug product.
 Measurements of the pharmacodynamic effect should be made
with sufficient frequency to permit a reasonable estimate for a
time period at least three times the half-life of the drug.
 This approach may be particularly applicable to dosage forms
that are not intended to deliver the active moiety to the
bloodstream for systemic distribution.
 The use of an acute pharmacodynamic effect to determine
bioavailability generally requires demonstration of a dose–
response curve.
 Bioavailability is determined by characterization of the dose–
response curve.
 For bioequivalence determination, pharmacodynamic
parameters including the total area under the acute
pharmacodynamic effect–time curve, peak pharmacodynamic
effect, and time for peak pharmacodynamic effect are obtained 13
 The onset time and duration of the pharmacokinetic effect may
also be included in the analysis of the data.
 The use of pharmacodynamic endpoints for the determination
of bioavailability and bioequivalence is much more variable than
the measurement of plasma or urine drug concentrations.
 Clinical Observations: Well-controlled clinical trials in humans
establish the safety and effectiveness of drug products and may
be used to determine bioavailability.
 However, the clinical trials approach is the least accurate, least
sensitive, and least reproducible of the general approaches for
determining in-vivo bioavailability.
 The FDA considers this approach only when analytical methods
and pharmacodynamic methods are not available to permit use
of one of the approaches described above.
 Comparative clinical studies have been used to establish
bioequivalence for topical antifungal drug products (eg,
ketoconazole) and for topical acne preparations.
 For dosage forms intended to deliver the active moiety to the
bloodstream for systemic distribution, this approach may be
considered acceptable only when analytical methods cannot be
developed to permit use of one of the other approaches 14
 In-Vitro Studies: Drug dissolution studies may under certain
conditions give an indication of drug bioavailability. Ideally, the
in-vitro drug dissolution rate should correlate with in-vivo drug
bioavailability.
 Dissolution studies are often performed on several test
formulations of the same drug.
 The test formulation that demonstrates the most rapid rate of
drug dissolution in vitro will generally have the most rapid rate
of drug bioavailability in vivo.
 Bioequivalence Studies: Differences in the predicted clinical
response or an adverse event may be due to differences in the
pharmacokinetic and/or pharmacodynamic behavior of the drug
among individuals
 Bioequivalent drug products that have the same systemic drug
bioavailability will have the same predictable drug response.
However, variable clinical responses among individuals that are
unrelated to bioavailability may be due to differences in the
pharmacodynamics of the drug.
 Differences in pharmacodynamics, ie, the relationship between
the drug and the receptor site, may be due to differences in
receptor sensitivity to the drug. 15
 Various factors affecting pharmacodynamic drug behavior may
include age, drug tolerance, drug interactions, and unknown
pathophysiologic factors.
 The bioavailability of a drug may be more reproducible among
fasted individuals in controlled studies who take the drug on an
empty stomach.
 When the drug is used on a daily basis, however, the nature of
an individual's diet and lifestyle may affect the plasma drug
levels because of variable absorption in the presence of food or
even a change in the metabolic clearance of the drug.
 reported that patients on a high-carbohydrate diet have a much
longer elimination half-life of theophylline, due to the reduced
metabolic clearance of the drug (t 1/2, 18.1 hours), compared to
patients on normal diets (t 1/2 = 6.76 hours).
 Theophylline complete bioavailable
 The higher plasma drug concentration resulting from a
carbohydrate diet may subject the patient to a higher risk of
drug intoxication with theophylline.
 The effect of food on the availability of theophylline has been
reported by the FDA concerning the risk of higher theophylline
plasma concentrations from a 24-hour sustained-release drug 16
 Bases for Determining Bioequivalence: Bioequivalence is
established if the in-vivo bioavailability of a test drug product
(usually the generic product) does not differ significantly in the
product's rate and extent of drug absorption, as determined by
comparison of measured parameters (eg, concentration of the
active drug ingredient in the blood, urinary excretion rates, or
pharmacodynamic effects), from that of the reference listed
drug (usually the brand-name product) when administered at
the same molar dose of the active moiety under similar
experimental conditions, either single dose or multiple dose.
 Drug Products with Possible Bioavailability and
Bioequivalence Problems:
 Lack of bioavailability or bioequivalence may be suspected
when evidence from well-controlled clinical trials or controlled
observations in patients of various marketed drug products do
not give comparable therapeutic effects. These drug products
need to be evaluated either in vitro or invivo.

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 In addition, during the development of a drug product, certain
biopharmaceutical properties of the active drug substance or
the formulation of the drug product may indicate that the drug
may have variable bioavailability and/or a bioequivalence
problem. Some of these biopharmaceutic properties include:
physicochemical evidences
 1. The active drug ingredient has low solubility in water (eg,
less than 5 mg/mL).
 2. The dissolution rate of one or more such products is slow
(eg, less than 50% in 30 minutes when tested with a general
method specified by the FDA).
 3. The particle size and/or surface area of the active drug
ingredient is critical in determining its bioavailability.
 4. Certain structural forms of the active drug ingredient (eg,
polymorphic forms, solvates, complexes, and crystal
modifications) dissolve poorly, thus affecting absorption.
 5. Drug products that have a high ratio of excipients to active
ingredients (eg, greater than 5:1).
 6. Specific inactive ingredients (eg, hydrophilic or hydrophobic
excipients and lubricants) either may be required for absorption
of the active drug ingredient or therapeutic moiety or may 18
 Pharmacokinetic evidence
 The active drug ingredient, is absorbed in large part in a
particular segment of the GI tract or is absorbed from a
localized site.
 The degree of absorption of the active drug ingredient,
therapeutic moiety, or its precursor is poor (eg, less than 50%,
ordinarily in comparison to an intravenous dose), even when it
is administered in pure form (eg, in solution).
 There is rapid metabolism of the therapeutic moiety in the
intestinal wall or liver during the absorption process (first-order
metabolism), so that the rate of absorption is unusually
important in the therapeutic effect and/or toxicity of the drug
product.
The therapeutic moiety is rapidly metabolized or excreted, so that
rapid dissolution and absorption are required for effectiveness.
The active drug ingredient or therapeutic moiety is unstable in
specific portions of the GI tract and requires special coatings or
formulations (eg, buffers, enteric coatings, and film coatings) to
ensure adequate absorption.
The drug product is subject to dose-dependent kinetics in or near
the therapeutic range, and the rate and extent of absorption are 19
 Design and Evaluation of Bioequivalence Studies:
Bioequivalence studies are performed to compare the
bioavailability of the generic drug product to the brand-name
product.
 Statistical techniques should be of sufficient sensitivity to detect
differences in rate and extent of absorption that are not
attributable to subject variability.
 Once bioequivalence is established, it is likely that both the
generic and brand-name dosage forms will produce the same
therapeutic effect.
 Design: The design and evaluation of well-controlled
bioequivalence studies require cooperative input from
pharmacokineticists, statisticians, clinicians, bioanalytical
chemists, and others.
 The basic design for a bioequivalence study is determined by
(1) the scientific questions to be answered,
 (2) the nature of the reference material and the dosage form to
be tested,
 (3) the availability of analytical methods, and
 (4) benefit–risk and ethical considerations with regard to testing
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in humans.
 For bioequivalence studies, the test and reference drug
formulations must contain the pharmaceutical equivalent drug
in the same dose strength, in similar dosage forms (eg,
immediate release or controlled release), and be given by the
same route of administration.
 Both a single-dose and/or a multiple-dose (steady-state) study
may be required.
 Before beginning the study, the Institutional Review Board
(IRB) of the clinical facility in which the study is to be performed
must approve the study.
 The IRB is responsible for safeguarding the rights and welfare
of human subjects.
 The basic guiding principle in performing studies is do not do
unnecessary human research.
 Generally, the study is performed in normal, healthy male and
female volunteers who have given informed consent to be in
the study.
 Critically ill patients are not included in an in-vivo bioavailability
study.
 Patient selection is made according to certain established
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criteria for inclusion into, or exclusion from, the study.
 For example, the study might exclude any volunteers who have
known allergies to the drug, are overweight, or have taken any
medication within a specified period (often 1 week) prior to the
study.
 Smokers are often included in these studies.
 The subjects are generally fasted for 10 to 12 hours (overnight)
prior to drug administration and may continue to fast for a 2- to
4-hour period after dosing.
 Analytical Methods: The analytical method used in an in-vivo
bioavailability or bioequivalence study to measure the
concentration of the active drug ingredient or therapeutic
moiety, or its active metabolite(s), in body fluids or excretory
products, or the method used to measure an acute
pharmacological effect, must be demonstrated to be accurate
and of sufficient sensitivity to measure, with appropriate
precision, the actual concentration of the active drug ingredient
or therapeutic moiety, or its active metabolite(s), achieved in
the body.
 For bioavailability studies, both the parent drug and its major22
 Reference Standard: For bioequivalence studies, one
formulation of the drug is chosen as a reference standard
against which all other formulations of the drug are compared.
 The reference drug product should be administered by the
same route as the comparison formulations unless an
alternative route or additional route is needed to answer
specific pharmacokinetic questions.
 For example, if an active drug is poorly bioavailable after oral
administration, the drug may be compared to an oral solution or
an intravenous injection.
 Moreover, in-vitro comparative dissolution or drug-release
studies under various specified conditions are usually
performed for both test and reference products before
performing the in-vivo bioequivalence study.

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 Extended-Release Formulations: The purpose of an in-vivo
bioavailability study involving an extended-release drug product
is to determine if
 (1) the drug product meets the controlled-release claims made
for it,
 (2) the bioavailability profile established for the drug product
rules out the occurrence of any dose dumping,
 (3) the drug product's steady-state performance is equivalent to
that of a currently marketed non-extended-release formulation,
and
 (4) the drug product's formulation provides consistent
pharmacokinetic performance between individual dosage units.
 A comparison bioavailability study is used for the development
of a new extended release drug product in which the reference
drug product may be either a solution or suspension of the
active ingredient or a currently marketed non-controlled release
drug product such as a tablet or capsule.
 For example, the bioavailability of a non-controlled-release
(immediate-release) drug product given at a dose of 25 mg
every 8 hours is compared to an extended-release product
containing 75 mg of the same drug given once daily. 24
 Combination Drug Products
 Generally, the purpose of an in-vivo bioavailability study
involving a combination drug product containing more than one
active drug substance is to determine.
 if the rate and extent of absorption of each active drug
ingredient in the combination drug product is equivalent to the
rate and extent of absorption of each active drug ingredient
administered concurrently in separate single-ingredient
preparations.
 The reference material in such a bioavailability study should be
two or more currently marketed, single-ingredient drug
products, each of which contains one of the active drug
ingredients in the combination drug product.
 The FDA may, for valid scientific reasons, specify that the
reference material be a combination drug product that is the
subject of an approved NDA.
 Study Designs: For many drug products, the FDA, Division of
Bioequivalence, Office of Generic Drugs, provides guidance for
the performance of in-vitro dissolution and in-vivo
bioequivalence studies.
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 Currently, three different studies may be required for solid oral
 (1) a fasting study, (2) a food intervention study, and/or
(3) a multiple-dose (steady-state) study.
 Fasting Study: Bioequivalence studies are usually evaluated by a
single-dose, two-period, two-treatment, two-sequence, open-label,
randomized crossover design comparing equal doses of the test and
reference products in fasted, adult, healthy subjects.
 This study is required for all immediate-release and modified-release
oral dosage forms. Both male and female subjects may be used in
the study.
 Blood sampling (zero time) the dose and at appropriate intervals after
the dose to obtain an adequate -the plasma drug concentration–time
profile.
 The subjects should be in the fasting state (overnight fast of at least
10 hours) before drug administration and should continue to fast for
up to 4 hours after dosing.
 No other medication is normally given to the subject for at least 1
week prior to the study.
 In some cases, a parallel design may be more appropriate for certain
drug products, containing a drug with a very long elimination half-life.
 A replicate design -used for high intrasubject variability.

26
 Food Intervention Study: Co-administration of food with an
oral drug product may affect the bioavailability of the drug.
 Food intervention or food effect studies are generally conducted
using meal conditions that are expected to provide the greatest
effects on GI physiology so that systemic drug availability is
maximally affected.
 The test meal is a high-fat (approximately 50% of total caloric
content of the meal) and high-calorie (approximately 800–1000
calories) meal.
 A typical test meal is two eggs fried in butter, two strips of
bacon, two slices of toast with butter, 4 ounces of brown
potatoes, and 8 ounces of milk.
 This test meal derives approximately 150, 250, and 500–600
calories from protein, carbohydrate, and fat, respectively.
 Bioavailability studies might also examine the affects of other
foods and special vehicles such as apple juice.
 Following an overnight fast of at least 10 hours, subjects are
given the recommended meal 30 minutes before dosing. 27
 No food is allowed for at least 4 hours post dose.
 Multiple-Dose (Steady-State) Study: In a few cases, a
multiple-dose, steady-state, randomized, two-treatment, two-
way crossover study comparing equal doses of the test and
reference products may be performed in adult, healthy subjects.
 Blood sampling is performed similarly to the single-dose study.
 Crossover Designs: A complete crossover design is usually
employed, in which each subject receives the test drug product
and the reference product.
 Examples of Latin-square crossover designs for a
bioequivalence study in human volunteers, comparing three
different drug formulations (A, B, C) or four different drug
formulations (A, B, C, D), are described in and .
 The Latin-square design plans the clinical trial so that each
subject receives each drug product only once, with adequate
time between medications for the elimination of the drug from
the body.
 In this design, each subject is his own control, and subject-to-
subject variation is reduced.
 Moreover, variation due to sequence, period, and treatment
(formulation) are reduced, so that all patients do not receive the
28
same drug product on the same day and in the same order.
 Possible carryover effects from any particular drug product are minimized by
changing the sequence or order in which the drug products are given to the subject.
 Thus, drug product B may be followed by drug product A, D, or C.
 After each subject receives a drug product, blood samples are collected at
appropriate time intervals so that a valid blood drug level–time curve is obtained.
 The time intervals should be spaced so that the peak blood concentration, the total
area under the curve, and the absorption and elimination phases of the curve may
be well described.
 Latin-Square Crossover Design for a Bioequivalence Study of Three Drug Products
in Six Human Volunteers

subject Study period-1 Study period-2 Study period-3

1 A B C
2 B C A
3 C A B
4 A C B
5 C B A 29
30
 Preabsorptive hydrolysis and metabolism:
 The principle sites of the chemical or biochemical conversion of
a drug in the gut lumen are the stomach (acid), small intestine
(esterases and other enzymes), and distal small intestine and
colon (gut bacteria).
 These conversions can take place in parallel with or precede
drug absorption and result in reduced availability.
 Some drugs are not chemically stable at the low pH of the
stomach; examples include penicillin G, methicillin,
erythromycin, and digoxin.
 After oral administration, they are subject to acid hydrolysis in
the stomach to form inactive products; less than 100% of the
administered dose is available for absorption.
 These problems can be predicted from invitro chemical stability
studies.
 The availability of drugs subject to acid hydrolysis in the
stomach is a function of the rate of dissolution and the
residence time of the drug in the stomach.
 Minimizing the dissolution of the drug in the stomach leads to
increased availability. Factors that promote gastric emptying 31or
increase gastric pH also result in improved bioavailability.
32
 The importance of enzymatic hydrolysis in the fluids of
small intestine in determining the availability of drugs
is unknown.
 Esterases, principle degrade drugs like aspirin or ester
prodrugs like pivampicillin or chloramphenicol
palmitate before or in competition with the absorption
process.
 In general, however, the gut wall likely to be a more
important site for the enzymatic hydrolysis of esters
than is the gut lumen. Pivampicillin subject to
hydrolysis in the fluids of small intestine, this surely
must represents only a small fraction of the dose
because the blood levels of ampicillin are much higher
after a dose of the prodrug than after an equivalent
dose of ampicillin.
 This means that a significant fraction of the
pivampicillin dose must be absorbed (penetrate the
gut wall) as such and thereby evade preabsorptive 33
metabolism.
 Many different kinds of microorganisms are normal residents of
the lower intestine.
 These bacteria, which constitute the intestinal microflora, carry
out a variety of metabolic process, but they are particularly
adept at reduction, including the reduction of double bonds, azo
groups, aldehydes, ketones and alcohols.
 Most drugs are absorbed before reaching the ileum and are
subject to metabolism by intestinal microorganisms.
 On the other hand a substantial fraction of an oral dose of
slowly absorbed drugs or a drug given in a prolonged release
dosage form may reach the lower intestine.
 When this occurs, preabsorptive metabolism by intestinal
microflora may affect the availability of drug. This situation
applied to digoxin.
 Certain antibiotics, including tetracycline and erythromycin alter
the bacterial flora and decrease the inactivation of digoxin.
Steady-state serum level in some patients increase 2 fold
during oral antibiotic treatment, presenting the risk of toxicity.
34
 Presystemic metabolism: After oral administration, a drug
must pass sequentially from the intestinal lumen, through the
gut wall, then through the liver before reaching the systemic
circulation.
 This sequence is the anatomic requirement because blood
perfusing the entire length of the gastrointestinal tract with the
exception of the buccal cavity and lower rectum, drains in to
liver by way of the hepatic portal vein.
 Since the gut wall and the liver are sites of drug metabolism, a
fraction of the amount absorbed may be eliminated
(metabolized) before reaching the blood stream.
 Therefore, an oral dose of a drug may be completely absorbed
but incompletely valuable to the systemic circulation because of
presystemic or first pass metabolism in the gut wall or liver.
 The detection requires only that systemic availability is less
than the fraction of the dose absorbed.
 The fraction absorbed determined by urinary data by using
radio active. Understanding of the hepatic first pass effect is
often useful in differentiating the sites of presystemic
elimination; we will first consider the liver as the site of
presystemic metabolism. 35
 Hepatic presystemic metabolism: The liver is the most
important site of presystemic elimination because of its high
level of drug metabolizing enzymes, its ability to rapidly
metabolize many kinds of drug molecules, and its unique
anatomic location.
 A large number of drugs subject to considerable hepatic first
pass metabolism; examples include β-blockers (propanolol and
metoprolol), analgesics (propoxyphene, meperidine, and
pentazocine) and antidepressants (imipramine and
nortryptyline).
 Hepatic presystemic metabolism is most easily understood
when the liver is the sole organ of drug elimination. Under these
conditions, the clearance of a drug, as determined after
intravenous administration from the ratio of dose to area (AUC),
is equal to hepatic clearance (ClH), which is given by
ClH = QHERH
 Where QH is hepatic blood flow and ERH is the hepatic
extraction ratio. Hepatic blood flow in man ranges from about36
1.5L/min.
 hepatic extraction ratio may range from 0 to 1, depending on
livers ability to metabolize the drug. The maximum clearance of
drug eliminated exclusively by hepatic metabolism is equal to
hepatic blood flow, this occurs when ERH = 1.0.
 The fraction of drug eliminated from portal blood during
absorption is given by the extraction ratio. ERH ; the remainder
(1 - ERH) escapes in to systemic circulation, and is then cleared
from the circulation by the liver. If a fraction (f) of the oral dose
(Do) is absorbed and then subjected to hepatic presystemic
metabolism, the AUC after oral administration (AUCo) is given
by:
AUCo = fDo(1 - ERH)/ QH ERH
 Since QHERH is equal to hepatic clearance, which, under these
conditions, is given by the ratio of intravenous dose (DIV) to
area
AUCo / AUCIV = fDo (1 - ERH)/DIV.
 The ratio of areas after oral and intravenous administration of
an equal dose of a drug = its systemic availability (F). If we 37
 Which shows that systemic availability depends on hepatic
extraction ratio? Drugs with low extraction ratio such as
antipyrine, warfarin and tolbutamide under goes little
presystemic metabolism.
 An estimate of the hepatic extraction ratio may be made by
determining the clearance of the drug after intravenous
administration and comparing this value to a mean value for
liver blood flow.
ERH = ClH/QH.
 Presystemic metabolism after oral administration of a drug
results in the formation of a bolus of metabolites during the first
pass through the liver.
 Higher peak levels of metabolites after oral administration of a
drug with a high hepatic extraction ratio is observed than after a
parenteral administration.

38
 Gut wall presystemic metabolism:
 presystemic metabolism in the gut wall and liver can be
differentiated in animals by comparing drug concentration after
oral and intraportal administrations to assess the contribution of
gut wall and after intraportal and intravenous administration to
asses the contribution of liver.
 Changes in metabolite excretion pattern provide indirect
evidence for gut wall metabolism. Intravenous isoproterinol is
excreted largely unchanged in man.
 On the other hand the sulfate conjugate accounts for 80% of
the drug in urine after oral administration.
 No sulfate conjugate is found after intravenous administration.
The results suggest that presystemic metabolism of
isoproterinol in man is confined to the mucosal surface of the
gut wall.


39
 Albuterol (salbutamol), a potent β-adrenergic agonist used
widely in the treatment of bronchial asthma is subject to
substantial presystemic metabolism after oral administration.
 After IV administration the plasma clearance was 480ml /min
elimination half life was 4 hrs, urinary excretion of unchanged
albuterol was 64% and sulfate metabolite was 12%, after oral
administration systemic availability was 50%, urinary excretion
of unchanged drug and metabolite was 32 and 48%.
 Oral albuterol has low bioavailability; it is well absorbed from
the GI tract.
 The fraction of dose of albuterol eliminated on first pass could
be accounted for entirely as sulfate conjugate form mainly in
the gut wall.
 gut wall metabolism is inferred when the degree of presystemic
metabolism of drug exceeds the hepatic extraction ratio.

40