116
`
`Boume and Dlttert
`
`EXAMPLE. Calculate CP at quarter-hourly intervals for the first 24 hr of the kanamycin dosing
`regimen described in the first example in this subsection. The entry data are as follows:
`
`= 2.3 hr
`Half-life for elimination
`= 0.2 hr
`Half-life for absorption
`Fraction of body weight equal to volume of distribution = 0.27
`= 74 kg
`Subject weight
`= 1.0
`Fraction of the dose absorbed
`Loading dose (D0)
`= 800 mg
`Maintenance dose (do)
`= 800 mg
`= 6 hr
`Dosing interval (T)
`= 0.25 hr
`Time interval
`= 0-4
`Number of maintenance doses (n)
`
`The results of the calculation are shown in Fig. 15. Note that Cmax and Cm,n are identical with
`the values calculated in the aforementioned example.
`
`C. Dosage Regimen Adjustment In Renal Failure
`
`The influence of impaired renal or liver function on the rate of elimination of a drug was
`mentioned previously, and a method for predicting the half-life of kanamycin in patients with
`varying degrees of renal impairment was described earlier (see Sec. VI). If patients with im-
`
`36
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`Time (hours)
`
`15
`
`18
`
`21
`
`24
`
`Fig. 15 Plot of kanamycin plasma concentrations (circles) versus time following multiple IM injections,
`calculated with Eq. (56).
`
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`

`

`-
`
`Pharmacoklnetlcs
`
`117
`
`paired renal function are given a normal-dosing regimen of kanamycin, they will soon build
`up toxic plasma concentrations of the drug. However, they can be dosed safely and effectively
`by adjusting the dosing regimen in accordance with the predicted elimination half-life. Dosing
`regimen adjustment involves changing the dose or the dosing interval.
`
`Alteration of the Dosing Interval
`The kanamycin package insert recommends that a dose of 7.5 mg/kg be administered every
`three half-lives, and that for patients with impaired renal function, the half-life in hours can
`be estimated by multiplying the serum creatinine level (mg/100 ml) by 3 (see also Sec. VI).
`Thus the dosing interval for a renal patient should be nine times serum creatinine level (mg/
`100 ml).
`
`EXAMPLE. A patient (74 kg) has a serum creatinine level of 6 mg/100 ml (elimination half(cid:173)
`life = 18 hr); therefore, the dosing regimen would be 7.5 mg/kg IM every 54 hr. Figure 16
`shows the results of this dosing regimen in terms of the plasma concentrations of kanamycin
`produced in the renal patient (solid line) and a normal patient (dashed line). In both cases, the
`Cmax values are below the MTC of 35 µg/ml, but the Cm'" values fall below the MEC of 10
`µg/ml (Sec. IX.A).
`For the normal patient, the time during which the plasma concentrations are below 10 µg/
`ml is only about 4 hr for each dosing interval; but for the renal patient, this time extends to
`about 18 hr. This gives the renal patient inadequate therapy for long time periods and can
`foster the development of strains of bacteria that are resistant to kanamycin.
`
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`60
`Time (hours)
`
`100
`
`120
`
`140
`
`Fig. 16 Plot of kanamycin plasma concentration versus time following multiple IM injections in a
`normal patient (dashed line) and a renal
`
`creatinine level (mg/100 ml) (altered-d
`
`2
`
`2
`
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`

`

`118
`
`Bourne and Dlttert
`
`Alteration of the Dose
`In a previous example the "maintenance dose every half-life" regimen was proposed for kana(cid:173)
`mycin because it maintained plasma concentrations between the MTC and MEC. The same
`regimen could be employed for IM injections of kanamycin in renal patients, but the logistical
`problems that arise in the clinic when the maintenance doses must be given at odd time intervals
`(e.g., 18 hr) make this regimen somewhat impractical. It would be much better if the maintenance
`doses could be administered at the same time other medication is given (i.e., every 4, 8, or 12 hr).
`The same loading dose (in milligrams per kilogram) can be given to all patients regardless
`of their renal function because the loading dose is determined by the volume of distribution
`(or body weight) and not by the rate of elimination. However, if a normal-dosing interval is
`used, the amount of drug eliminated over one interval (T) will be much less for a patient with
`renal failure than for a patient with normal renal function. As a result, the maintenance doses
`must be reduced to replace only that amount of drug lost during the preceding dosing interval.
`EXAMPLE. The dosing regimen recommended for normal adults in the kanamycin package
`insert is 7.5 mg/kg every 12 hr. The insert also states that the half-life of kanamycin in a
`normal adult is about 4 hr. What should the 12-hr maintenance dose be for the individual in
`the previous example?
`For a person whose half-life is 18 hr (k.1 = 0.0385 hr- 1
`), the amount remaining at the end
`of a 12-hr-dosing interval is
`k.it
`Ao
`log A =
`2.30
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`0-+---------
`20
`40
`0
`
`Time (hours)
`
`fig. 17 Plot of kanamycin plasma concentration versus time following multiple IM injections in a
`normal patient (dashed line) and a patient with renal impairment (solid line) calculated with Eq. (56) and
`maintenance dose = amount lost over
`
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`

`

`Pharmacoklneflcs
`
`7.5
`log -
`A
`
`=
`
`0.0385 X 12
`2.30
`
`A = 4.72 mg/kg
`
`The amount lost over the 12-hr interval is
`
`7.5 mg/kg - 4.72 mg/kg = 2.78 mg/kg
`
`119
`
`Therefore, the maintenance dose= 2.78 mg/kg every 12 hr. The loading dose (same as normal)
`= 7.5 mg/kg.
`The results of this dosing regimen in terms of plasma concentrations are shown as a solid
`line in Fig. 17. The dashed line in Fig. 17 shows the plasma concentrations that would be
`produced in a normal patient on a normal-dosing regimen (7.5 mg/kg every 12 hr). Figure 17
`shows that the administration of 2.8 mg/kg maintenance doses every 12 hr to the aforemen(cid:173)
`tioned renal patient is a convenient dosing regimen that produces Cm10 plasma levels above the
`MEC and Cmax plasma levels below the MTC.
`
`REFERENCES
`
`4.
`
`1. R. E. Notari, Biopharmaceutics and Clinical PharmacokinetLcs: An Introduction, 4th Ed., Marcel
`Dekker, New York, 1987.
`2. M. Gibaldi and D. Perrier, Pharmacokinetics, 2nd Ed., Marcel Dekker, New York, 1982.
`J. G. Wagner, Fundamentals of Clinical Pharmacokinetics, Drug Intelligence Publications, Hamilton,
`3.
`IL, 1975.
`J. G. Wagner, Biopharmaceutics and Relevant Pharmacokinetics, Drug Intelligence Publications,
`Hamilton, IL, 1971.
`5. G. A. Partmann, Phannacokinetics, in Current Concepts in the Pharmaceutical Sciences: Biophar(cid:173)
`maceuticals (J. Swarbrick, ed.), Lea & Febiger, Philadelphia, 1970.
`6. W. J. Westlake, The design and analysis of comparative blood-level trials, in Current Concepts in
`the Pharmaceutical Sciences: Dosage Form Design and Bioavailability (J. Swarbrick, ed.), Lea &
`Febiger, Philadelphia, 1973.
`
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`

`5
`
`The Effect of Route of Administration and
`Distribution on Drug Action
`
`Svein llJie and Leslie z. Benet
`University of California, San Francisco, California
`
`I. THE DOSE-EFFICACY SCHEME
`
`When a health practitioner administers (or ''inputs") a dose of drug to a patient, usually the
`ultimate goal is solely directed to the usefulness of the drug under abnormal conditions. That
`is, the drug must be efficacious and must be delivered to its site of action in an individual
`experiencing a particular physiological anomaly or pathological state. Pharmaceutical scientists,
`on the other hand, concentrate their attention to solving problems inherent in drug delivery to
`deliver the optimal dose to the site(s) of action.
`The general pathway a drug takes from residence in a dosage form until its clinical utility
`is depicted in Fig. 1. Ideally, the drug should be placed directly at the site of action, as
`illustrated by the stippled arrow in Fig. 1, to maximize the effect and minimize
`relating to unwanted responses at sites other than the target tissue. However, deliv
`to the site of action is more often than not, impractical or not possible. Instead, we have to
`settle for the most convenient routes of delivery. This is illustrated by the solid arrows in Fig.
`1. That is, the drug is placed directly in the vascular systems or in close proximity to some
`biological membrane through which the drug can traverse to reach body fluids or the vascular
`system. The delivery system is generally designed to release the drug in a manner that is
`conducive to this passage through the membrane. Previous chapters have discussed how drug
`delivery systems may be optimized in terms of dissolution in the fluids surrounding the
`membrane to allow the desired rate of passage through the membrane. Subsequent chapters
`will deal with specific drug d
`passed
`through the membrane and i
`eneral
`distribution of the drug will take place throughout the biological system. As pointed 01,1t in
`Chapter 3, the degree of dilution (referred to as the apparent volume of distribution) will dictate
`the initial concentration of drug in the general circulation, as sampled from a peripheral vein.
`Usually, the dose of the drug administered to the patient was chosen to give sufficiently high
`
`5
`
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`156
`
`Ste and Benet
`
`DISTRIBUTION
`
`l (cid:141)
`
`Desired
`Effect
`
`Fig. 1 A schematic representation of the dose-efficacy relationship for a drug.
`
`blood levels so that an adequate quantity of the drug would reach the site of action. The rate
`of input needed to achieve adequate levels of the drug at the site of action is influenced not
`only by the distribution and general elimination in the body, but may also be modified by the
`loss processes that are unique to a specific route of administration. This chapter will deal
`primarily with the distribution and loss processes that result uniquely from the physiological
`parameters inherent in the use of a particular route of administration.
`Unfortunately, no drug is yet so specific that it interacts with only the target site in the
`target tissue, and will not give rise to hyperclinical activity. Too much drug at the wrong place
`or too high a concentration at the right place may result in unwanted or toxic effects. Thus the
`practitioner must determine the usefulness of any dose of a drug from a particular drug delivery
`system by balancing the efficacy achieved from the clinical effect against the to
`observed.
`Most drug delivery systems achieve the required drug levels at the site of action as a result
`of attaining adequate blood levels in the general circulation (see Fig. 1, solid arrows). This
`process is followed because of the ease with which present drug delivery systems can "input"
`drugs into the general circulation and the inherent difficulties in delivering the drug selectively
`to a relatively inaccessible site (e.g., pituitary gland). In addition, for many compounds, the
`exact site of action is still unknown. However, when the site of drug action is sufficiently
`defined, Fig. 1 illustrates the advantage of delivering the drug directly to the site of action. By
`direct administration to the active site, a lower dose could be used to achieve the clinical effect
`because the drug no longer is diluted or eliminated en route. As a result, drug concentrations
`e levels
`at unwanted sites of action
`at the site of action might be attained much more rapidly, since the process of distribution
`throughout the entire body could be avoided. One should not forget that, in addition to the
`obvious clinical advantage of direct administration, there is also an economical one. By deliv(cid:173)
`ering the drug to the site of action, the amount of drug needed is much smaller than by more
`traditional delivery methods. This
`ant
`
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`J ,f
`
`Effect of Administration Route and Distribution
`
`157
`
`compounds that can be very expensive. Much work is currently being carried out in an attempt
`to achieve such a selectiveness as that described in Fig. 1.
`
`11. PHYSIOLOGICAL CONSIDERATIONS FOR THE VARIOUS
`ROUTES AND PATHWAYS OF DRUG INPUT
`
`A. Drug Input at or Close to the Site of Action
`
`Figure 2 illustrates a number of sites where drug delivery systems have historically been used
`to input drug directly to its site of action [1,2]. Various classic dosage forms were developed
`to take advantage of these input sites: eye, ear, and nose drops; inhalation, oral, topical, and
`vaginal aerosols; topical solutions, creams, and ointments; and rectal solutions, enemas, and
`suppositories. Each of the sites for local drug administration requires specific formulation to
`allow the drug to remain at the site of application for a sufficient length of time to allow the
`drug to penetrate through the particular membrane(s) so that it can reach the actual site of
`action adjacent to the site of application. For example, some ophthalmic preparations may be
`given to elicit a superficial anti-infective effect, such as treatment of an inflammation of the
`conjuctiva. Thus, only topical effects are desired, and there is no need for the drug to penetrate
`into the eyeball. Formulation of such products would be quite different than formulation of a
`drug delivery system for which the drug must be absorbed into the interior of the eye to produce
`
`sublingual
`
`Fig. 2 Various routes and pathways by which a drug may be "input" into the body. The position of
`one lung is distorted to emphasize that the lungs are in an excellent position for cleansing the blood. The
`diagram is especially useful in explaining the first-pass effect following oral dosing, for which drug
`absorbed from the small intestine or st
`t
`to metabolism or biliary excretion befo
`
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`158
`
`IZJie and Benet
`
`a response, such as miotics, mydriatics, anti-inflammatory drugs that act in the anterior segment
`of the eye, and, occasionally, drugs for treatment of infections. A detailed description of the
`factors involved in the development of such ophthalmic preparations, as well as the particular
`physiological characteristics of the eye, will be presented in Chapter 15. Similar types of design
`problems arise for many of the other sites that are traditionally treated by direct local appli(cid:173)
`cation. One of the most difficult problems facing the formulator is that the behavior of the
`diseased tissue may be different from that for healthy individuals, and it may also change over
`the course of treatment. For example, diseased skin is often more permeable than healthy skin;
`therefore, the drug may disappear faster from the site of administration than desired, and the
`effect will be less than expected. Should the formulation be designed to accommodate this
`phenomenon, one must be mindful of the fact that as the pathological condition improves, the
`absorption may also change.
`Although the classic dosage forms mentioned earlier can be used to put drug directly into
`the site of action, many of them have a degree of "messiness" that prevents good patient
`acceptance and adherence. Not only is there an initial psychological barrier that must be over(cid:173)
`come, but the general public has an aversion to taking drugs by routes other than oral. There
`is, in addition, a general dislike for sticky creams, drippy drops, greasy ointments, and the
`like. Over the last two decades much work has been directed toward developing more accept(cid:173)
`able delivery systems than the traditional ones. Emphasis has been placed on long-acting drug
`delivery systems that may be more convenient, since they would only require self-administra(cid:173)
`tion once a week or possibly at even longer intervals.
`A large number of new devices have been developed, and new ones are constantly being
`investigated. Plastic disks for placement in the eye (similar to a contact lens) that slowly release
`drug into the humoral fluid; drug-impregnated plastic rings or loops that when placed in the
`uterus will release controlled amounts of contraceptive agents; bioadhesive tablets or disks that
`can be placed buccally, nasally, or vaginally for local release; hydrogels for slow release in
`the eye are examples of such new delivery systems that input drug directly to the site of action.
`In a more ambitious move, many groups have also embarked on site-specific delivery to
`less accessible sites than those given in Fig. 2. Although numerous experimental systems have
`been designed, few have reached the clinical stage. The simplest and most direct method when
`a specific target organ can be located is cannulation (direct access port). A catheter is placed
`in an appropriate artery or vein. If a vein is used, the catheter has to reach the organ, or
`otherwise the drug will be flowing away from the target tissue, be diluted with b
`rest of the body, and be not different than a systematic intravenous administrati
`can also be placed in the peritoneum, the bladder, and in the cerebrospinal fluid. A drug can
`now be administered directly into the desired tissues at a rate that can be well controlled.
`Although catheter delivery is a direct method, it is limited in that it is essentially restricted to
`inpatient use. Use of implants in the desired tissue, or a drug carrier (e.g., liposomes, nano(cid:173)
`particles, and such) that will either home in on the desired tissue by specific receptors, or
`release their content at the desired site by an external stimulus ( e.g., magnetic fields, light,
`current), are drug systems currently being explored for target-specific delivery.
`Although the method of direct delivery is a very attractive one, it also has its regulatory
`ate dif(cid:173)
`problems. Benet [1] has no
`ficulties because the manu
`hat can
`measure drug concentration at the site of action. For example, the extent and rate of availability
`of an orally administered drug can easily be assessed by measuring blood levels, whereas for
`a drug input into a site of action, significant blood levels would indicate distribution away
`from that site. Frequently, signifi n
`e of
`action (such as a topical preparati
`cts
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`r
`
`Effect of Administration Route and Distribution
`
`159
`
`on intestinal flora) indicate either a poor drug delivery system or substantial overdosing. For
`this class of drug delivery systems, clinical efficacy necessarily has to serve as the best meas(cid:173)
`urement of drug availability and dosage form efficacy.
`
`B. Drug Input Into the Systemic Circulation
`
`The overwhelming majority of existing drugs are, however, given by general routes; that is,
`by routes that do not deliver the drug directly to the site of action. These modes of drug input
`rely on a passive delivery of drug through distribution by the vascular system. The most
`commonly accepted method is oral administration. As will be discussed later, oral administra(cid:173)
`tion is not ideal, as one needs to be concerned about whether the drug can be destroyed in the
`stomach, in the gastrointestinal fluid, in its passage through the gut wall, through the liver, or
`simply not be absorbed in time before it is expelled from the gastrointestinal tract. Several
`alternative routes of delivery are being used or are being developed to diminish these potential
`losses. The advantages and problems inherent in the individual routes of administration will
`now be discussed.
`
`Parenteral Administration: Intravascular
`Of the routes of input depicted in Fig. 2, intravenous (IV) administration yields one of the
`fastest and most complete drug availabilities. However, intra-arterial injections might be em(cid:173)
`ployed when an even faster and more complete input of drug to a particular organ is desired.
`By administering the drug through an artery, the total drug delivered will enter the organ or
`tissue to which the artery flows. Intravenously administered drug will first be diluted in the
`venous system as the venous blood is pooled in the superior and inferior vena cava. It then
`enters the heart, and is subsequently pumped to the lung before it can enter the arterial system
`and reach the target organ(s). In addition, the fraction of the drug reaching a desired site is
`dependent on the fraction of the arterial blood flow reaching that site. Additional drug can
`reach the target tissue only by being recirculated from the other organs. In comparison with
`intra-arterial administration, IV administration reaches the target slower, and initially at a lower
`concentration. Although intra-arterial injections appear superior, they are infrequently used
`because they are considered much more dangerous than IV administration. Intra-arterial ad(cid:173)
`ministration has been associated with patient discomfort, bleeding, and thrombosis.
`In addition to the dilution factor resulting from mixing with larger volumes of
`intravenous administration, one also needs to consider the possibility of temporary or
`loss of drug during its passage through the lung. The position of the lungs in Fig. 2 has been
`distorted to emphasize the point that the lungs are in an excellent strategic position for cleansing
`the blood, since all of the blood passes through the lungs several times a minute. Apart from
`their respiratory function and the removal of carbon dioxide from the pulmonary circulation,
`the lungs serve other important cleansing mechanisms, such as filtering emboli and circulating
`leukocytes, as well as excretion of volatile substances. The lungs also have metabolic capacity
`[3] and may serve as a metabolic site for certain drugs [4] or as an excretory route for com(cid:173)
`pounds with a high vapor pressure. The lungs can also act as a good temporary storage site
`ssues,
`for a number of drugs, especia
`as well as serving a filtering f
`ction.
`Accumulation of lipophilic compounds and filtering of any compounds in solid form can be
`viewed as a temporary clearing or dilution of the drug, as it will eventually leach back into
`the vascular system. Thus the lung serves as a dampening or clearing device, that is not present
`following intra-arterial injection. Drugs given by the IV route may, therefore, not necessarily
`be completely available to the site
`e
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`160
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`tlJie and Benet
`
`eliminated by the lung before entering into the general circulation [5). This might be called a
`"lung first-pass effect."
`The foregoing concepts may be visualized by referring to Fig. 3. In this figure one can
`readily see the difference between intra-arterial and intravenous administration of drugs. Let
`us assume that compartment n is the target tissue. Administration into any vein (i.e., into any
`of the efferent arrows on the left-hand side of the figure) would lead the drug to the heart and,
`from there, to the lung. Drug that enters the lung can leave by only one of two routes, as
`illustrated in Fig. 4: by the blood that leaves the lung, or by being eliminated. The result is
`that there is a competition between the two routes for the drug, and the greater the ability of
`the lung to eliminate the drug in comparison with the pulmonary blood flow, the more drug;
`will be extracted. If we assume that the pulmonary blood flow is Qp and that the intrins1 ...
`elimination clearance of the organ is CL,01, and no plasma protein binding occurs (Cu = Cau,),
`then the extraction ratio can be expressed as
`
`(1)
`
`£ =
`
`CL1n1
`Caul CL1n1
`=
`(Caul CL1n1) + (Caul Qp) Clint + Qp
`In perfusion models, as depicted in Fig. 3, it is assumed that distribution into and out of the
`organ is perfusion rate-limited such that drug in the organ is in equilibrium with drug concen(cid:173)
`tration in the emergent blood (6). The intrinsic clearance of an organ is different from the
`value we normally think of as the clearance of the organ. The clearance of the organ is defined·
`as the rate of loss in relation to the incoming concentration, whereas the intrinsic clearance is
`defined as the rate of loss in relation to the organ concentration (or exiting concentration). In
`addition, it is also clear that, of the drug that escapes elimination in the lung, only a small
`fraction goes to compartment n, the rest is distributed to other organs. Drugs that enter these
`organs will be exposed to elimination in these organs and must necessarily recirculate through
`the heart and lungs before they again have the opportunity to reach compartment n.
`
`Parenteral Administration: Depot
`The other parenteral routes depicted in Fig. 2, intramuscular (IM) and subcutaneous (SC)
`injections, may also be considered in terms of Fig. 3. Drug absorbed from the IM and SC sites
`into the venous blood will return to the heart and pass through the lungs before being distributed
`to the rest of the body. However, there will be an initial lag between the time when the drug
`is injected and when it enters the circulation. Thus, the kinetics for drugs adminis
`parenteral routes would be expected to show a decreased rate of availability
`show a decreased extent of availability in comparison with intravenous administration, if loss
`processes take place at the site of injection. For example, we could consider that drug is now
`injected directly into compartment m in Fig. 3 and that this compartment is the muscle. The
`rate at which the drug leaves the muscle will depend primarily on blood flow in relation to
`the size (apparent volume of distribution) of the organ.
`Evans and co-workers [7] measured resting human muscle blood flow through the gluteus
`maximus, vastus lateralis, and deltoid muscles. Deltoid muscle blood flow was significantly
`greater than gluteus muscle blood flow, with vastus being intermediate. Because the two sites
`e might
`most commonly used for
`expect to see differences in
`docaine
`is one drug that has been investigated for its effect in response to the site of injection [8,9).
`Deltoid injection gave higher peak levels than lateral thigh injection which, in turn, gave higher
`levels than gluteal injection. Schwartz et al. [9] demonstrated that therapeutic plasma levels
`for a particular lidocaine dose were reached only when the deltoid injection site was used.
`the
`Evans et al. [7] concluded, ''T
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`Effect of Administration Route and Distribution
`
`161
`
`..
`
`·~
`
`~
`
`.~
`
`Compartment 1
`~ Lung
`
`CL1
`"
`
`-
`
`CL
`t
`
`2
`
`.....-
`
`C½
`
`-
`
`Right
`Heart
`
`Left
`Heart
`
`Compartment 2
`Mesenteric Tissues
`
`-
`
`t
`
`-
`
`--
`
`t
`
`Compartment 3
`Liver
`
`- - t
`
`1 --
`-
`,
`
`-
`
`-
`-
`
`Compartment m
`
`CL
`m
`
`Compartment m+ 1
`
`Compartment n
`
`t
`
`"
`
`-
`
`--
`
`-
`
`Fig. 3 The body depicted as a physiological perfusion model. Compartment m must be co
`a summation of the individual tissues that metabolize the drug and compartment m + 1 th
`noneliminating tissues.
`
`Fig. 4 Flow model of an eliminating organ. The drug enters the body by the organ blood flow, CLi.
`and is immediately mixed in the organ. The drug leaves the organ by either being eliminated (CLi.,Cu)
`or by the exiting blood flow.
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`162
`
`l2.lie and Benet
`
`plasma level achieved and that the deltoid muscle should be used to achieve therapeutic blood
`levels as rapidly as possible.'' Likewise, if a sustained or a prolonged release is desired, this
`would more readily be achieved by injection into a lower blood flow muscle, such as the
`gluteus.
`Loss processes may also account for a decrease in the extent of availability following an
`IM injection. This can be visualized by assuming that the dose is injected into compartment
`m, which, as depicted in Fig. 3, is capable of eliminating the drug. As shown in Fig. 4, the
`drug can leave the tissue only by one of two routes, either by the blood leaving the organ, or
`by being eliminated by metabolism in the muscle. In addition, the drug that leaves the site of
`administration will also be subject to the additional distribution and elimination in the lung,
`similar to intravenous administration. In other words, drug given by intramuscular administra(cid:173)
`tion may be not only further delayed in its distribution to the target organ, but may also show
`a decreased extent of distribution to the organ, in comparison with the intravenous dose. For
`example, degradation can take place in the muscle, as shown by Doluisio et al. [10) for am(cid:173)
`picillin. These workers found that only 77-78% of an IM dose of ampicillin sodium solution
`was absorbed, as compared with the IV solution. The most likely explanation is that the drug
`may have been decomposed chemically or enzymatically at the injection site. In addition,
`temporary losses may also occur. For example, intramuscular doses of phenytoin result in a
`marked decreased rate and extent of absorption in comparison with IV or oral doses. Wilensky
`and Lowden [11] demonstrated that this could be due to precipitation of the drug as crystals
`in the muscle. Although these crystals eventually dissolve, the drug is essentially lost during
`a normal dosing interval.
`
`Oral Administration
`First-Pass Effect. Metabolism in the Gastrointestinal Fluids and Membranes. When a dos(cid:173)
`age form is administered by the oral route, drug particles come in contact with varying pH
`solutions, different enzymes, mucus, gut flora, and bile, all of which may contribute to de(cid:173)
`creasing the extent of availability by degradation, binding, or sequestering mechanisms. These
`factors, as well as the possiblity of drug metabolism in the intestinal membrane itself, have
`been well covered in Chapter 2 and will not be discussed here.
`Hepatic Metabolism: Linear Systems. As depicted in both Figs. 2 and 3, drug that is
`absorbed from the gastrointestinal tract must pass through the liver before reaching the sam(cid:173)
`pleable circulation and the rest of the body. Thus, if a drug is metabolized in the liver or
`excreted into the bile, some of the active drug absorbed from the gastrointestin
`inactivated by hepatic processes before the drug can reach the general circu
`distributed to its site(s) of action. An exception would be if the liver itself were the target
`organ, as we then would have to contend with only losses in the gastrointestinal tract and in
`the gut wall before reaching the site of action.
`For many drugs, the fraction of the dose eliminated on the first pass through the liver is
`substantial. The fraction eliminated is often referred to as the hepatic extraction ratio, desig(cid:173)
`nated herein as EH. Many drugs are known or suspected to have a high hepatic extraction ratio.
`A short list of some of the better-known compounds is given in Table 1. The hepatic first-pass
`phenomenon is not restricted to any particular pharmacological or chemical group of drug
`substances and the forego
`culation
`The available fraction
`will, therefore, be governed by