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`Copyright 1974. All nghts reserved
`
`BIOA V AILABILITY OF DRUGS
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`+6579
`
`FROM FORMULATIONS AFTER
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`ORAL ADMINISTRATION
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`L. F Chasseaud and T. Taylor
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`Huntingdon, England
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`Department of Metabolism and Pharmacokinetics, Huntingdon Research Centre,
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`An administered drug can elicit only the pharmacologic response for which it was
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`developed, provided that sufficient concentrations of drug reach and are available
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`to the receptors. Determination of the likely availability of the active drug to the
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`receptors is the basis ofbioavailability testing. Drugs that are chemically equivalent
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`may not be therapeutically equivalent because of differences in dosage form. Cer­
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`tainly, the more potent the pharmacologic action of the drug, the more imperative
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`is the need for bioavailability testing (1), but only recently has such testing gained
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`acceptance as a worthwhile and necessary adjunct (2-4) to the gamut of tests to
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`which new and existing drugs are subjected.
`Among the multiplicity of terms coined in recent years, that ofbioavailability has
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`been the subject of much discussion and considerable misunderstanding. Bioavaila­
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`bility, or biologic availability, has been usefully reviewed or discussed by several
`(5-16).
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`authors Confusion has arisen, however, over interchange of the terms bi­
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`ologic availability (bioavailability), physiologic availability, generic equivalence, and
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`therapeutic equivalence, all of which have been used to define essentially the same
`events.
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`which in this decade has become the preferred term, de­
`Bioavailability,
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`scribes the extent to which and the rate at which the active drug reaches the systemic
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`circulation, and ultimately the receptors or sites of action at concentrations that are
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`effective, and thereby defines the efficiency of the dosage formulation as an extravas­
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`cular drug delivery system. Because it is generally impossible to measure receptor
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`drug concentrations, these are measured in the circulation, venous or arterial, from
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`which the receptors receive their supply. Alternatively, urinary concentrations of
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`the active drug or a characteristic metabolite can be measured (13, 17, 18). There
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`is no guarantee, however, that a drug reaching the systemic circulation will also
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`reach the receptors in adequate concentrations. Sometimes the response of the
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`receptors to the drug may be quantified in controlled clinical trials, for example, the
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`35
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`Annu. Rev. Pharmacol. 1974.14:35-46. Downloaded from www.annualreviews.org
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`36 CHASSEAUD & TAYLOR
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`lowering of blood sugar by hypoglycemics (19, 20), the excretion of electrolytes after
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`administration of diuretics (21), or the anticoagulant effects of certain coumarins
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`(22), but it is important to know whether the intensity of the pharmacologic effect
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`in a particular case is a function of drug concentration in the body.
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`V ARIA nONS IN BIOA V AILABILITY
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`In reality, because the drug has to cross several membranes, exist in numerous
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`physiologic environments, and be sUbjected to tissue uptake, biotransformation, and
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`excretion (18, 23-26), much of an administered dose never reaches the receptors.
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`So that patients are provided with drug formulations that are physically and chemi­
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`cally stable, pharmaceutically reliable, and aesthetically acceptable, drugs are pre­
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`pared in various physical forms with a number of other ingredients which may
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`influence their bioavailability. To be absorbed from the gastrointestinal tract, the
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`drug must be presented in a soluble form to the site of absorption; for example, an
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`administered tablet must disintegrate and the particles must dissolve in the gastroin­
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`testinal milieu before absorption can occur. Different dosage forms of drugs may
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`thus provide varying amounts of the drug for absorption and thereby cause differ­
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`ences in the onset, extent, and duration of pharmacologic effect. These differences
`m odified bioavailability
`and be due to the physi­
`may derive from physiologically
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`ology or path logy of the patient and/or his genetic makeup (27), or alternatively
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`from dosage form-modified bioavailability and be due to the methods of manufac­
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`ture or to the physicochemical properties of the drug (13) (Table I). This review
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`is mainly concerned with the latter category. For these reasons (Table I). in vitro
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`tests which do not take into account some of these factors cannot be presumed to
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`predict in vivo drug availability. The in vitro system must be compared against the
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`in vivo case (28) for every formulation type, and in vitro systems are generally only
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`for in vivo of suitable formulations useful for quality control or for the selection
`testing.
`
`(13)
`Table I Factors affecting
`bioavailability
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`Dosage form
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`Physiologic
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`Particle size, Polymorphic form,
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`Time of Age, Sex, Physical state of patient,
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`administration, Stomach emptying,
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`Solvation, Hydration, Chemical form,
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`pH, Solubility characteristics,
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`Intestinal motility, food. Other drugs,
`Disease
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`formulation adjuvants, Manufacturin
`g
`method
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`PARAMETERS OF BIOA V AILABILITY
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`The bioavailability of a drug is characterized by two important parameters: the area
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`under the blood concentration-time relationship and the peak height of this relation­
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`ship together with its time of occurrence. Figure I illustrates the plasma concentra­
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`tion-time relationships for a hypothetical drug which needs to attain a minimum
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`Annu. Rev. Pharmacol. 1974.14:35-46. Downloaded from www.annualreviews.org
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`OF DRUGS 37
`BIOAVAILABILITY
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`concentration in the plasma to be pharmacologically active. Above the maximum
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`safe concentration, a drug such as digoxin (29) causes toxicity. Inspection of the
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`relationships shows that a formulation producing curve I is ineffective, that produc­
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`ing curve II is active and the preferred dosage form, and that producing curve III
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`is active but also leads to toxicity. Similarity of the areas under all three curves in
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`Figure I docs not necessarily indicate that the drug will be therapeutically effective
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`in all cases. As a criteria of bioavailability, therefore, both parameters should be
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`considered. Rates of bioavailability are likely to be important for drugs with a low
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`therapeutic index, sparingly soluble drugs, drugs that are destroyed in the gastroin­
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`testinal tract or are actively absorbed, or when adequate drug concentrations are
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`required rapidly, as with antibiotics, analgesics, coronary vasodilators, and hypo­
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`glycemics. Differences in bioavailability are, however, equivalent to differences in
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`dosage. Suitable reduction in dosage for formulation III and increase in dosage for
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`formulation I should produce a therapeutic and nontoxic response (Figure I ). If
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`bioavailability is estimated from urinary excretion data, suitable parameters are the
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`cumulative excretion of drug (or metabolite) in the urine and the maximum excre­
`tion rate and time of its occurrence.
`
`I
`
`"
`
`.g '"
`.::
`"
`OJ
`U
`c::
`o
`U
`
`Toxic
`
`Therapeu
`tic
`
`Ineffective
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`ESTIMA TION OF BIOA V AILABILITY
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`Time
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`Earlier methods of estimating bioavailabiJity were qualitative, such as monitoring
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`the disintegration of formulations in the gastrointestinal tract (30-32). Disintegra­
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`tion of a formulation or indeed the dissolution of its contents does not provide
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`absolute proof of absorption. The concept of bioavailability was introduced in 1945
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`(33) during studies of the relative absorption of vitamins from pharmaceutical
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`preparations and was estimated by comparing the fraction of a dose from a test
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`formulation, and that from an aqueous solution, excreted in the urine during a fixed
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`time. An aqueous solution was considered to present the drug in an ideal form for
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`absorption. More generally, bioavaiIability may be measured as the ratio
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`Bioavailability
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`amount of drug absorbed from test formulation
`X 100%
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`amount of drug absorbed from reference formulation
`
`Annu. Rev. Pharmacol. 1974.14:35-46. Downloaded from www.annualreviews.org
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`38 CHASSEAUD & TAYLOR
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`where the reference formulation is one from which the drug is readily absorbed, or,
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`preferably, is known to be clinically effective. So measured, bioavailability is a
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`statement of relative absorption, not of amount absorbed.
`For bioavailability studies, healthy volunteers are preferred to patients because
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`states may influence drug bioavailability (34) or elimination (35). SUbjects
`disease
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`should be selected on the basis of a satisfactory medical examination, normal renal
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`and hepatic function, and freedom from a history of renal, hepatic, gastrointestinal,
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`and endocrine disorders or from a known sensitivity to drugs. Female subjects
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`should be selected only if they are unlikely to be pregnant during or for some time
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`after the studies. The very thin or obese should be excluded so that wide intersubject
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`variations in apparent volumes of distribution are avoided. The use of subjects aged
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`between 18 and 50 years reduces anomalous age-dependent responses (36,37). Since
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`commonly occur, a sufficient large intra-and intersubject variations in absorption
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`number of subjects, usually 6 to 20, should be used to permit a satisfactory statistical
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`analysis of the data (18, 38-40), and to demonstrate equivalence, a larger number
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`may be necessary. The subjects should give their informed consent and should not
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`be taking other drugs. Equal doses of test and reference formulations should be
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`administered, as plasma concentrations or clearances may not be linearly related to
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`the dose (41, 42). Experimental designs (43) are commonly of a complete crossover
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`type, where every subject receives each formulation according to a random treat­
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`ment schedule (38). The intensity of the pharmacologic effect of a drug is often
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`nonlinearly related to the logarithm of the administered dose (23) and the therapeu­
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`tic consequences of changes in dose due to modification of bioavailability may be
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`more serious at lower doses. For this reason acceptable limits ofbioavailability must
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`be established for each drug at or near the expected therapeutic dose (13).
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`Bioavailability is usually estimated from a statistical comparison of either average
`drug concentrations
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`in the blood (18) or areas to infinite time under the drug
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`concentration-time relationships in the blood after administration of single doses of
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`both test and reference formulations. The duration of sampling is relatively short
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`and improvements in methodology allow accurate determinations of very low drug
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`concentrations. In single-dose studies, sufficient blood samples should be withdrawn
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`to describe adequately the critical phases of the concentration-time relationship:
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`(a) absorption which allows at least a qualitative comparison of the rates of avail­
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`ability, (b) time of occurrence of maximal concentrations. and (c) the decline of
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`concentrations during the elimination phase. During the latter phase, drug concen­
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`trations may fall to very low levels, and inadequate analytical procedures
`could
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`introduce errors into the calculation of areas to infinite time. The precision of the
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`analytical method should be known and the level of sensitivity should exceed the
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`expected peak blood concentration by at least twentyfold. Total areas under the
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`concentration-time curves are usually measured by the trapezoidal rule (44) up to
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`the last sampling time, and the remaining area to infinite time is calculated from
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`the concentration at that time and the observed rate constant for drug elimination
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`from plasma (45). The calculated areas may be normalized (13, 18,45,46) to correct
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`for intra-and intersubject variations in dose, body weight, and the apparent elimina-
`
`Annu. Rev. Pharmacol. 1974.14:35-46. Downloaded from www.annualreviews.org
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`Page 4
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`OF DRUGS 39
`BIOAVAILABILITY
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`tion (biological) half-life of the drug. This allows bioavailabilities estimated in
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`studies performed at different times with different subject panels to be validly
`compared.
`Under some circumstances it may be preferable to estimate bioavailability during
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`a sequence of multiple doses, so that experimental conditions resemble the clinical
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`situation (13, 18). After multiple dosing, blood concentrations are greater and more
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`easily measured, but experimental control is more complex. In multiple dose studies,
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`biovailability can be estimated, after attainment of steady state conditions, by com­
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`parison of the areas under the blood concentration-time curves during a complete
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`dosage interval or by comparison of maximal and minimal concentrations reached
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`during the dosage interval. This obviates the need for calculation of areas to infinite
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`time, which may be a prime source of error in single-dose studies.
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`Estimates of bioavailability from urinary excretion data require complete collec­
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`tion of the urine for at least seven drug half-lives, and control of urinary pH may
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`be necessary for certain drugs, such as weak bases (47). Loss of a single sample could
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`invalidate the estimation of bioavailability from measurement of cumulative excre­
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`tion data, and rates of urinary excretion may not correspond to rates of gastrointesti­
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`nal absorption. This method is advantageous because the subjects need not undergo
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`numerous venepunctures for blood withdrawal, and drug analysis is simpler, but it
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`should not be used when the drug is extensively biotransformed and less than 20%
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`is excreted in the urine unchanged or as a characteristic metabolite.
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`All the experimental data obtained should be analyzed by the appropriate statisti­
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`cal procedures (40) with due regard for the methodology used. It should be esti­
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`mated what differences need to occur between formulations before these are
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`statistically significant.
`Seven methods of estimating bioavailability have been described by Wagner &
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`Nelson (48), some of which differ only in the mathematical treatment of the experi­
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`mental data. Wagner (18) has critically appraised the assumptions involved.
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`FACTORS AFFECTING BIOA V AILABILITY
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`Since absorption occurs only after the drug is in solution, orally administered drugs
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`in solid form must first dissolve in the gastrointestinal fluids. The rate at which
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`dissolution occurs is an important determinant of bioavailability and is dependent
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`on several factors. Drugs administered in solid form as capsules or tablets need to
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`disaggregate so that dissolution may occur more readily.
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`in]
`IDrug
`Lcapsule
`IDrug in]
`�ablet
`
`Dispersion
`...
`Solid
`Drug
`drug
`in
`Dissolution
`Absorption
`•
`•
`Disintegration
`particles
`solution
`•
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`Annu. Rev. Pharmacol. 1974.14:35-46. Downloaded from www.annualreviews.org
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`40 CHASSEAUD & TAYLOR
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`Particle Size
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`The greater the surface area of drug in contact with the gastrointestinal fluids, the
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`in particle size, there is an
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`more rapid the dissolution rate. Thus with decrease
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`increase in dissolution rate (49, 50). The bioavailabilities of spironolactone (51) and
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`phenacetin (52) are improved by a reduction in particle size. However, particle size
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`reduction provides more opportunity for particle interaction, which may sometimes
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`lead to aggregation. Nitrofurantoin, in high concentrations, causes gastric irritation
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`and nausea when taken orally and it is thus preferable to present this drug to the
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`tract as larger, slower-dissolving crystals (53, 54).
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`gastrointestinal
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`Diffusion from the Dosage Form
`The rate of bioavailability of a drug is enhanced if the rate of diffusion from the
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`dosage form is increased either by use of a more soluble drug form or by alteration
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`of the microenvironment surrounding the drug particle (8, 12). Administration of
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`soluble salts of penicillin V resulted in higher blood levels of antibiotic than were
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`obtained with the less soluble free acid (55, 56). The rates of absorption of different
`(57).
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`aspirin formulations correlated with their solubility characteristics
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`Crystalline Form
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`Some drugs such as barbiturates (58) exist in several crystalline forms of differing
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`solubilities and other physical properties (59, 60) with resultant differences in bi­
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`(61). The amorphous is more sol up Ie than the crystalline form.
`oavailability
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`Hydration
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`The hydration state of a drug influences its solubility, and the anhydrous form is
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`usually more soluble. Anhydrous ampicillin has a greater extent of bioavailability
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`in dogs and man than the less soluble trihydrate (62).
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`Formulation Ingredients
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`which can influence the bioavailability of
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`Some of the agents added to formulations
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`the drug include fillers, binders, disintegration aids, lubricants, surfactants, and
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`suspending agents. Hydrophobic lubricants such as magnesium stearate prevented
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`thereby adequate contact between the gastrointestinal fluids and the drug solids,
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`slowing dissolution, whereas the hydrophilic sodium laurylsulfate produced the
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`opposite effect (63). Surfactants may alter the rate and extent of absorption of certain
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`drugs (64). Absorption of phenacetin was apparently enhanced by Tween 80 (52).
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`Pharmaceutical or Dosage Form
`The compressed tablet provides a low surface area for dissolution and must first
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`disintegrate
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`(65). Coated tablets, particularly enteric coated types, may release the
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`drug unevenly. The rate of dispersion of drug particles from a capsule
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`influences the
`of the drug, but in general
`a reliable
`bioavailability
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`a capsule is considered dosage
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`form. Drugs with a short biological half-life are sometimes formulated as sustained­
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`or timed-release products (44), but care is necessary since failure of the formulation
`
`Annu. Rev. Pharmacol. 1974.14:35-46. Downloaded from www.annualreviews.org
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`BIOAVAILABILITY OF DRUGS 41
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`could result in toxic levels of drug (66). The expected relative bioavailabilities from
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`various dosage forms are shown in Table 2.
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`Table 2 Dosage forms for oral administration (8)
`
`Increasing
`
`release rate of drug 1 Aqueous solutions
`
`and syrups
`Suspensions
`Powders
`Capsules
`Tablets
`Coated tablets
`
`Compressed tablets are the most widely used form of oral medication, and an
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`accepted laboratory standard measurement of drug release from the tablet has been
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`the disintegration test which merely measures physical breakup of the tablet. This
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`test does not predict drug bioavailability in vivo (65, 67, 68) although it can be
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`assumed that a tablet formulation failing to disintegrate within about 30 min would
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`provide only slowly available drug.
`The dissolution rate test provides a means of ranking various solid dosage forms
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`lity (18, in vitro and, although the results may correlate with in vivo bioavailabi
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`69-72), measured dissolution rates can be affected by test conditions (73. 74). Levy
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`(67) compared various commercial aspirin tablets and found that absorption from
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`the gastrointestinal tract correlated with dissolution but not disintegration rate data.
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`In vitro techniques must always be suspect because they do not compensate for the
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`and circulatory systems that charactize the biological case.
`nervous
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`Gastrointestinal Conditions
`
`Absorption of drugs may be affected by the physiologic status (disease, pH. peristal­
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`sis) of the gastrointestinal tract. Administration of laxatives, such as MgS04, may
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`cause dilution of the intestinal contents and enhance intestinal motility, thereby
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`reducing the time available for drug absorption. A pH-dependent dissolution stage
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`precedes tetracycline absorption in man (75). and simultaneous administration with
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`antacids or milk reduces absorption, because these contain divalent metal ions
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`of (76-78). Administration which form a poorly absorbed chelate with tetracycline
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`drugs with food usually reduces or delays absorption (79). Aspirin (80), dicloxacillin
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`(81). and penicillin V (56) were absorbed best by fasting subjects. However, absorp­
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`tion of griseofulvin was least in fasting subjects and was enhanced by meals with
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`a high fat content (82). Dietary components influence the absorption of par aceta mol
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`(83) and acetaminophen (84). Drugs that are unstable in acid media are formulated
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`for safe passage through the stomach with an enteric coating (18. 85). Such coatings
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`are pH sensitive and may prematurely disintegrate in the stomach if antacids are
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`taken simultaneously. The action of sustained-or timed-release products formulated
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`
`
`
`with organic solvent-sensitive coatings may be undesirably enhanced by concomi­
`(12).
`
`tant intake of alcoholic beverages
`
`Annu. Rev. Pharmacol. 1974.14:35-46. Downloaded from www.annualreviews.org
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`42 CHASSEAUD & TAYLOR
`
`Drug Interactions
`
`Drug interactions occurring in the gastrointestinal tract, such as lincomycin and
`
`
`
`
`
`
`
`
`
`kaolin-pectin (38), may be considered as pharmaceutical incompatabilities and
`
`
`
`
`
`avoided by consideration of the relevant physicochemical properties of the formula­
`
`
`
`
`tion ingredients. Drug interactions in the body or during absorption, however, occur
`
`
`
`
`
`by modification of absorption, distribution, biotransformation, excretion, and action
`
`
`
`
`
`at receptor sites (86-92) and are a consequence of polypharmacy. Examples include
`
`
`displacement of protein-bound drugs by other drugs (12, 25, 93-97) and enzyme
`
`
`
`
`induction (88, 98, 99). Age, nutrition, and pathological states are other important
`
`
`determinants of drug interactions (100).
`
`InRuence of Route of Administration
`
`Most orally administered drugs are absorbed into the hepatic portal system where
`
`
`
`
`
`
`
`
`extensive biotransformation may result in only a small proportion of the original
`
`
`
`
`
`drug reaching the peripheral circulation. Attempts to estimate the extent of absorp­
`
`
`tion by comparison of the areas under plasma concentration-time curves obtained
`
`
`
`after oral and intravenous administration are thus invalidated by this "pass effect"
`
`
`
`of the liver (101-104), as plasma clearances vary according to the route of adminis­
`
`
`
`
`tration. Extensive biotransformation during passage through the gastrointestinal
`
`
`
`
`epithelium may also reduce the bioavailability of an orally administered drug (105).
`
`
`
`
`Despite some intersubject variations, an increase in dosage in the ratio 1: 1.5: 2-
`
`
`
`
`
`3:3-4:3-5 was thought necessary to obtain similar blood concentrations of pentazo­
`
`
`
`
`cine after intravenous, intramuscular, oral (solution), rectal, and oral (tablet)
`
`
`
`
`administration respectively (106). Plasma concentrations were erratic after rectal
`
`
`
`
`administration of aspirin (107) when absorption would be limited by the rate of drug
`
`
`
`diffusion through a viscous medium. The nature of the suppository base would
`
`
`strongly influence bioavailability.
`
`GENERIC PRODUCTS
`
`Nonproprietary preparations are chemically equivalent if they contain the same
`
`
`
`
`
`active
`
`
`
`drug and they would be therapeutically equivalent if they produced the same
`
`
`
`
`
`
`biological response. Chemically equivalent formulations from different manufactur­
`
`
`
`ers, referred to as generic products, often differ widely in their methods of manufac­
`
`
`
`
`
`ture and content of pharmacologically inert ingredients. In recent years, controversy
`
`
`
`
`has arisen over the possible extent to which such generic products mayor may not
`
`
`
`be therapeutically equivalent. The problem is one of bioavailability (5, 11, 16, 18).
`
`
`
`
`Controlled studies in man on twelve commercial drug products showed inequiva­
`
`
`
`lence in ten cases (18) in either the rate or extent of bioavailability. Differences in
`
`
`
`
`the therapeutic equivalence of some formulations has been noted in clinical practice
`
`
`(11, 108, 109), but it is not entirely clear that formulation effects are alone responsi­
`
`
`
`
`ble, especially in cases where therapeutic efficacy is not directly related to drug
`
`
`
`
`concentrations in the blood (110) or where the clinical response is subjective. Pre­
`
`
`scott & Nimmo (11) ranked normal individuals as fast and slow absorbers of
`
`
`
`
`paracetamol and showed that plasma concentrations were similar after ingestion of
`
`Annu. Rev. Pharmacol. 1974.14:35-46. Downloaded from www.annualreviews.org
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`BIOA V AILABILITY OF DRUGS 43
`
`by the former but not the latter
`and plain tablet a suspension, effervescent tablet,
`
`
`
`subjects, which suggests
`
`of some products may only arise in
`that the inequivalence
`
`certain subjects.
`Maximal plasma concentrations and rates of absorption of chloramphenicol
`
`
`
`
`
`
`
`differed after administrations offour different formulations to human subjects (Ill).
`
`in another study (112) when fourteen
`
`
`Less pronounced differences were observed
`different
`
`
`
`
`formulations as capsules, tablets, and suspensions were administered
`
`
`
`
`orally. These differences were unlikely to have been caused by intersubject variations
`
`
`
`in rates of absorption or biotransformation. In both studies the rate ofbioavailability
`
`
`
`
`was related to the in vitro dissolution time; those preparations providing the lowest
`
`
`
`
`
`plas�a concentrations showed the slowest dissolution rates. Differences in either
`
`
`
`rate or extent of bioavailability of generic products have been shown for digoxin
`
`
`
`(113, 114), ampicillin (115), phenylbutazone (116), warfarin (117), a combination
`
`(118), sulfonamides (119, 120), and tetracyclines
`of trimethoprim-sulfamethoxazole
`
`
`
`
`no differences were found between several products containing
`(121-124), although
`
`
`(125) and sulfamethizole (126). Six preparations
`phenylbutazone
`
`of isoniazid were
`(127) and in vivo bioavailability
`
`shown to be therapeutically equivalent
`paralleled
`
`
`
`
`
`in vitro tests. The bioavailability of triple sulfa from 20 generic products was similar
`
`
`
`(128), although the drugs were more slowly absorbed from the formulations than
`
`
`
`from aqueous solutions, and there was no in vivo correlation with widely varying
`
`
`
`
`rates. Of generic products, formulations continue to attract
`dissolution
`digoxin
`
`much interest (136-139).
`While in vitro tests provide
`a means of ranking formulations, the available evi­
`
`
`
`dence (18) challenges
`
`
`
`the usefulness oftests in vitro to predict bioavailability in vivo
`
`
`(73, 129-132). Efforts are being made to design in vitro tests capable of predicting
`
`
`
`
`
`the in vivo performance of generic products (73, 133-135), but in vivo studies are
`
`
`
`
`currently the only reliable way of ascertaining whether drugs are available from
`their formulations
`of a therapeutic response.
`
`for absorption and production
`Al­
`
`
`
`
`though drug formulation has been studied extensively in vitro, the extent of generic
`
`
`
`and its clinical significance is at present unknown but may be expected
`inequivalence
`
`
`
`to have more relevance to drugs of poor water solubility, as known examples of
`
`
`
`inequivalence seem to reflect the dissolution rather than the disintegration rates of
`
`
`
`
`the products. The relative importance of equivalence is also linked to the disease
`
`
`
`
`being treated. A criticism of most bioavailability studies that detect differences
`do not define the extent (if any) to
`
`
`between generic products is that these studies
`
`which a particular inequivalence the well being of the patient.
`endangers
`
`
`Literature Cited
`I. Castle, W. B., Astwood, E. B., Finland,
`M., Keefer, C. S. 1969. J. Am. Med
`Assoc. 208:1171-72
`2. Drug Res. Rep. September 2, 1970. p.
`11
`3. Food Drug Cosmetic Law Rep. Janu­
`ary 15, 1973. No. 518
`4. Hayes, T. A. 1971. Drug Cosmet. fnd.
`109:44ff
`
`5. Pharmacology 1973. 8:17-215
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`6. Barr, W. H. 1969. Drug fnr Bull. 3:
`27-45
`7. Academy of Pharmaceutical Sciences.
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`1970. J. Am. Pharm. Assoc. NSlO:I07-
`116
`8. Levy, G. 1970. In Prescription
`Phar­
`macy, ed. J. B. Sprowls Jr., 36-102.
`
`Phiiadelphia:Lippincott. 2nd ed. 662 pp.
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`Annu. Rev. Pharmacol. 1974.14:35-46. Downloaded from www.annualreviews.org
`
` Access provided by Atlanta University Center on 02/05/18. For personal use only.
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`Page 9
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`44 CHASSEAUD & TAYLOR
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`9. Schneller, G. H. 1970. Am. J Hasp.
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`34. Bates, J. H., Schultz, J. c., Abernathy,
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`Pharm. 27:487-88
`R. S. 1965. CJin. Res. 13:77
`10. Wagner, J. G. 1971. Drug InteII. CJin.
`35. Dettli, L., Spring, P., Ryter, S. 1971.
`Pharm. 5: 115-28
`Acta. Pharmacol. Toxicol. 29, Supp!.
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`II. Prescott, L. F., Nimmo, J. 1971. Acta
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`Pharmacal. Taxicol. 39, Supp!. 3:288-
`36. Bender, A. D. 1964. J Am. Geriat. Soc.
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`37. Mann, Jr., D. E. 1965. J. Pharm. Sci.
`12. Cadwallader, D. E. 1971. Biophar­
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`maceutics
`and Drug Interactions.
`New
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`Jersey: Roche Lab. 140 pp.
`38. Wagner, J. G. 1966. Can. J Pharm. Sci.
`
`
`c/in. 13. Ritschel, W. A. 1972. Drug Intell.
`1:55-68
`39. Harris, L. E. 1971. Drug Cosmet. Ind.
`Pharm. 6:246-56
`14. Kaplan, S. A. 1972. Drug Metab. Rev.
`109:48ff
`1:15-34
`W. 1971. Drug
`40. Roberts, C. D., Sloboda,
`15. Smith, R. N. 1972. Lancet ii:528-30
`Cosmet. Ind. 109:50ff
`
`16. Florence, A. T. May 20, 1972. Pharm.
`41. Levy, G. 1968. In Importance of Fun­
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`J,456-63
`damental Principles in Drug Evalu­
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`17. Baldridge, J. L. 1969. Bull. Parenteral
`ation, ed. D. H. Tedeschi, R. E.
`Drug Assoc. 23:40-47
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`Tedeschi, 141-72. New York:Raven.
`18. Wagner, 1. G. 1971. Biopharmaceutics
`
`480 pp.
`M. 1971. Ann. NY Acad. Sci.
`and Relevant Pharmacokinetics.
`Ham­
`42. Gibaldi,
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`ilton, I II.: Drug Intell. Pub!. 357 pp.
`179:19-31
`43. Cochran, W. G., Cox, G. M. 1957. Ex­
`19. Nelson, E., Knoeche!, E. L., Hamlin,
`W. E., Wagner, 1. G. 1962. J Pharm.
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`perimental Designs. New York: Wiley.
`Sci. 51:509-14
`2nd ed. 611 pp.
`44. Notari, R. E. 1971. Biapharmaceutics...
`20. Varley, A. B. 1968. J Am. Moo. Assoc.
`and Pharmacokinetics.
`New York:
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`21. Tannenbaum, P. J., Rosen, E., Flana­
`Dekker. 307 pp.
`gan, T., Crosley A. P. Jr. 1968. Clin.
`45. Wagner, J. G. 1967. J. Pharm. Sci. 56:
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`Pharmacol. Therap. 9:598-604
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`46. Ritschel, W. A. 1970. Drug Intell. CJin.
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`22. Nagashima, R., O'Reilly, R. A., Levy,
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`Pharm. 4:332-47
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`G. 1969. CJin. Pharmacol. Therap. 10:
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`47. Beckett, A. H. 1966. Dansk. Tidsskr.
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`Farm. 40: 197-203
`23. Barr, W. H. 1968. Am. J Pharm. Ed.
`48. Wagner, J. G., Nelson, E. 1964. J.
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`Pharm. Sci. 53:1392-1403
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`24. Goldstein, A., Aronow, L., Kalman, S.
`M. 1968. Principles
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`49. Wagner, J. G. 1962. Antibiotica et
`of Drug Action.
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`New York:Harper & Row. 848 pp.
`J. H. 1968. J Pharm. Sci. 57:
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`25. Chasseaud, L. F. 1970. Foreign Com­
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`52. Prescott, L. F., Steel, R. F., Ferrier, W.
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`macology, Basic Principles in Thera­
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`54. Conklin, J. D., Hailey, F. J. 1969. CJin.
`28. Morrison, A. B., Campbell, J. A. 1965.
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`J. Pharm. Sci. 54:1-8
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