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Introduction |
Historically, the concept of bioavailability is
closely, if not exclusively, associated with dosage form performance.
This is because the drug entity has been defined and its absorption and
disposition characteristics per se are fixed. Recently, the application of bioavailability principles and techniques has been extended to include animal studies in the selection of potential drug
candidates for development. In particular, poor oral bioavailability is
increasingly an issue in the drug discovery process. In situations where different chemical entities are under investigation, dosage form
performance is just one of the possible contributing factors to poor
oral bioavailability. Other possibilities include diminished access for
absorption because of chemical degradation, physical inactivation, and
insufficient contact time in transit through the gastrointestinal
tract; poor permeability across the gastrointestinal mucosa; and
elimination during the first passage through the gut wall and the
liver. Reliable estimates of the relative importance of these causative
factors are essential as guides to chemical modifications aimed to
optimize oral bioavailability.
There is a body of literature on the subject of presystemic events and
first-pass elimination and their evaluation in vivo (1-32).
However, existing strategies and methods do not possess the flexibility
and versatility that current applications demand. The main drawbacks
are that key variables are incompletely resolved and parameter
estimates are often confounded by simplifying assumptions attendant to
their solution. The liver has been most extensively studied, and its
contribution to oral bioavailability is well defined. The isolation and
quantitation of the remaining components are problematic and usually
predicated on assumptions such as the dose being completely absorbed
unchanged, biotransformation not occurring in the gut wall; the liver
being the only drug metabolizing organ; etc. While such qualifying
assumptions may be appropriate in specific situations, they detract
from the general applicability of a method. The purpose of this
communication is to consider supplemental strategies in search of wider
applicability.
Theoretical
The bioavailability of an administered substance is that fraction
of the dose that reaches the general circulation unchanged. The general
circulation is defined experimentally by the sampling site, usually a
blood vessel in the peripheral circulation. Fig. 1 is a schematic representation of drug
movement after oral ingestion. As the drug passes down the
gastrointestinal tract, part of the dose may not be available for
absorption because of chemical degradation, physical inactivation
through binding or complexation, microbial biotransformation, etc. Of
that which is absorbed at x, some may be metabolized in
transit through the gut wall. Unchanged drug that reaches the hepatic
portal vein p may be extracted by the liver by way of
biotransformation or biliary excretion. Finally, further elimination
may occur between the hepatic vein h and the site of
measurement, say a peripheral vein j or a peripheral artery a.
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Fig. 1.
Schematic representation of drug movement in
the body.
Lower case letter mark sites of possible interest: Absorption sites
x; the hepatic portal vein p; the hepatic vein
h; peripheral veins i, j,
k, l; peripheral arteries a; the
mesenteric artery m; and arterial supply n to venous
effluent at j.
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Thus, the bioavailability F
of an orally administered dose is
comprised of the individual fractions that survive the various barriers
encountered by the drug during its first passage from the gut lumen to
the sampling site (15, 27), viz.,
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(1)
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where FX is the fraction absorbed (i.e. net
transport of unchanged drug into and around the absorptive cells of the
gastrointestinal tract), FG is the fraction that is not
metabolized in a single passage through the gut wall, FH is
the fraction that is not extracted during the first passage through the
liver, and FS is the fraction that survives post-hepatic
elimination en route to the sampling site. By definition,
therefore, nonabsorption and lumenal elimination are represented by the
quantity (1 
FX).
Eq. 1 formally defines oral bioavailability and its component parts. In
practice, however, explicit knowledge of FS is seldom sought. Hence, the more familiar definition of oral bioavailability, F,
is that given by eq. 2.
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(2)
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The difference between eqs. 1 and 2 is in the point of reference,
i.e. how one defines the general circulation. Whereas F refers to that fraction of an oral that reaches the sampling site unchanged, F is effectively a measure of drug availability to the
hepatic venous circulation. Experimentally, different sites of drug
administration are indicated in the determination of total body
clearance (33-35).
Experimental strategies will be developed to isolate and quantify the
individual components shown on the right-hand side of eq. 1. Each case
involves the grouping of experiments in which the sites of
administration and measurement are systematically varied to yield
estimates of the desired parameters (1, 13, 14, 19). Experimental
designs will evolve from the familiar to the more esoteric in search of
greater precision and efficiency. Assumptions are that total body
clearance is independent of concentration and constant between
treatments. Moreover, individual components of body clearance,
especially those of primary interest, e.g. gut wall and
liver, need to be invariant between treatments.
Measurement in the Peripheral Circulation Only.
Let's begin with the evaluation of bioavailability as defined by eq.
2. The amount of drug that reaches general circulation after an oral
dose, Dpo, is
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(3)
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where AUC is the area under the plasma, serum, or blood drug
concentration curve from time zero to time infinity; the superscript refers to the route of drug administration, the subscript j
denotes a venous sampling site; and CL is the total body clearance that is usually determined in a separate experiment, such that
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(4)
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where Div,i refers to an intravenous dose of
drug administered to a peripheral vein i. Combining eqs.
2-4, one obtains
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(5)
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Similarly, the bioavailability of an intravenous dose of drug
administered to the portal vein, Div,p, can be
represented by eq. 6.
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(6)
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which, when divided into eq. 5, yields
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(7)
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To resolve FX FG, it would be necessary to
effect an independent estimate of FX or FG. It
is generally recognized that absorption of xenobiotics occurs mainly in
the intestines, especially the upper part of the small intestine. It
follows, therefore, that the intestinal wall contributes most
prominently to gut-wall metabolism. Accordingly, an intra-arterial dose
of drug to the superior (cranial) mesenteric artery,
Dia,m, should yield an estimate of FG
FH. That is to say,
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(8)
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Dividing eq. 8 into eq. 5,
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(9)
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Finally, from eqs. 7 and 9,
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(10)
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The experimental determination of FS should nominally
include an intravenous dose to the hepatic vein,
Div,h, as the test treatment. However,
Div,i is not a suitable reference in the
determination of total body clearance. This is because the first-pass
effects encountered by Div,i are virtually
identical to those operating on Div,h such that
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(11)
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Peripheral venous sites of administration other than i
are similarly unsuitable.
One way to avoid this dispositional overlap is to administer the drug
intra-arterially at site n in fig.
1 such that
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(12)
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where CL is total body clearance as defined by the site of
administration n and the site of measurement j
(27, 33); n is the arterial supply to the organ or tissue
for which j is the venous effluent. For now, let's assume
that no drug elimination occurs between n and j.
Under these circumstances, the product of CL and
AUCjDiv,h is the amount of drug
that reaches the sampling site following Div,h.
Hence,
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(13)
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Combining eqs. 11 and 13,
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(14)
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Eq. 14 is experimentally preferable to eq. 13 in that a peripheral
vein is more accessible than the hepatic vein. Moreover, the evaluation
of FS would entail only one additional treatment, Dia,n, rather than two, Dia,n
and Div,h.
Total body clearance, CL or CL, may be calculated from serum, plasma,
or blood concentration data as long as the same medium is used
consistently in bioavailability assessment.
For clarity, ensuing discussions will dispense with FS, the
assessment of which can always be amended with an additional
experiment. Furthermore, since all peripheral veins are interchangeable
as sites of administration, the site qualifiers for Div are
no longer necessary and will be dropped. The Div,p
designation is retained for drug administration to the hepatic portal
vein, however. Whereas peripheral veins appear to be equivalent as
sites of administration, they are not interchangeable as sampling sites. Conversely, peripheral sampling sites on the arterial side are
equivalent, but administration to each artery engenders a unique
first-pass effect. Therefore, data used to extract pharmacokinetic parameters should come from samples taken from a common venous sampling
site. Data derived from samples taken from peripheral arteries are not
similarly constrained. For this reason, subsequent developments will
designate an artery a as the peripheral sampling site.
Measurements in the Portal and Peripheral Circulation.
Concomitant measurements in the portal and peripheral blood provide a
new dimension in experimental design. Suppose the gastrointestinal tract were subjected to a continuous perfusion at a constant rate of a drug solution of fixed composition. At steady state, blood concentrations Css at individual sampling sites become time
invariant. Fig. 2 depicts steady-state
concentrations at sampling sites of possible interest for a drug that
is capable of being absorbed and the eliminating organs for which
include the gut wall and the liver. The rate of drug delivery, R, from
the gut lumen to the portal circulation can be estimated (23) by
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(15)
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where Qp is the blood flow rate in the hepatic
portal vein, Css,p is the observed concentration in
portal blood at steady state, and
Css,
is that part of Css,p represented by drug returning from the
general circulation. The difference between Css,p
and Css,, therefore, represents
new contributions from the gut lumen. The relationship between
Css,p and
Css, can be visualized by rolling
fig. 2 back on itself to form a cylinder wherein vertical bars
representing "gut wall" and "liver" on the far right coincide
with their counterparts on the left. In this alignment,
Css,p and
Css, appear in the same column
representing the portal vein.
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Fig. 2.
Schematic diagram of steady-state
concentrations, Css, at sites of interest during a
continuous perfusion of drug solution to the gastrointestinal tract at
a constant rate.
Lower case letter designation have the same meaning as in fig. 1.
"Css,x" is the effective steady-state
concentration at the absorption site x. See text for the
definition of Css,.
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By analogy to eq. 15, the total amount of drug that reaches the portal
circulation from the gut following a single oral dose is
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(16)
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AUCDpo is not an
experimentally observable entity, but its value can be deduced from the
corresponding area measured in samples taken from a peripheral blood
vessel, say, AUCaDpo.
From an intravenous dose, one obtains
AUCaDiv and
AUCpDiv. Since there is no lumenal source
of drug after an intravenous dose,
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(17)
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Furthermore, in a linear system with constant clearance
between treatments, the ratio of AUC to
AUCa is invariant regardless of the route of administration and numerically equal to that following an iv dose; i.e.
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(18)
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Combining eqs. 16-18,
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(19)
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Given that
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(20)
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dividing eq. 19 into eq. 20 yields
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(21)
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Similarly, the amount of drug that reaches the portal circulation
after a dose to the mesenteric artery is
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(22)
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which, when combined with eqs. 17 and 18, yields
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(23)
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Finally, dividing eq. 23 into eq. 19, one obtains
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(24)
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Simultaneous measurement in the portal vein and a peripheral
artery eliminates the need for an iv,p treatment. There are, however,
twice as many measurements in the remaining treatments. In addition,
the application of eqs. 21 and 23 requires explicit knowledge of the
blood flow rate in the portal vein; implicit in eq. 24 is the
assumption of constant Qp between treatments. Depending how
precisely one needs to separate the parameters FX, FG, and FH, one can either measure
Qp directly (35-38) or rely on literature values (39).
With Qp defined as blood flow rate, drug concentrations in
whole blood should be used in eqs. 21 and 23.
Simultaneous Measurement of Drug and Metabolite.
Let's define Fmi as the bioavailability of a specific
metabolite mi after oral administration of the parent drug,
viz.
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(25)
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where Mi is the dose administered as mi
and AUCmi is the area under the mi
concentration curve from time zero to time infinity. Other superscripts
and subscripts have the same meaning as before. Molar equivalents of
drug and metabolite should be used throughout to account for the
difference in their molecular weight.
Similarly, FX,mi,
FG,mi, and FH,mi are,
respectively, the fraction that is absorbed as mi from the
lumen following an oral dose of drug, the fraction that reaches the
portal vein as mi following a single passage of drug
through the gut wall, and the fraction that reaches the hepatic vein as
mi following a single passage of drug through the liver.
Finally, FmiMi,
FX,miMi,
FG,miMi, and
FH,miMi are to
mi following metabolite mi administration as F,
FX, FG, and FH are, respectively,
to drug following drug administration.
The quantity Fmi is comprised of mi that
is derived from parent drug that reached the general circulation
initially as drug and mi that reaches the sampling site for
the first time as mi per se. That fraction of
the total body clearance of drug that is available as mi is
fmi. The bioavailability of drug after an oral dose
Dpo is F. Hence, the systemic source of
Fmi is fmi F. The nonsystemic component of Fmi is the sum of the bioavailability of
mi that is formed in the gut lumen,
FX,mi
FG,miMi
FH,miMi, and
mi that is formed and survived during first passage of the parent through the gut wall and liver. The latter is composed of
mi molecules that are formed in the liver and survived,
FX FG FH,mi, and
mi molecules in the portal circulation that survived a
single passage through the liver, FX
FG,mi
FH,miMi. Thus,
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(26)
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The fraction fmi of drug clearance that is
bioavailable as mi is given by eq. 27.
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(27)
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Therefore,
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(28)
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By analogy to eqs. 25 and 26, the bioavailability of
mi after a dose of drug to the mesenteric artery is given
by eq. 29.
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(29)
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The fraction of Dpo that is absorbed as drug is
FX, such that
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(30)
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The product of eqs. 29 and 30 is, therefore,
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(31)
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The difference between eq. 31 and eq. 28 is the contribution of
first-pass metabolism to the bioavailability of mi from an oral dose of drug, viz.
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(32)
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The two terms on the left-hand side of eq. 32 represent the
respective contributions of mi formed in the liver and the
gut wall. Separate estimates for each can be effected by administering drug to the portal vein, following which the bioavailability of mi is given by eq. 33.
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(33)
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Since
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(34)
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the product of eqs. 33 and 34 is
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(35)
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Subtracting eq. 28 from eq. 35 and then eq. 36 from eq. 32, one
gets
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(36)
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and
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(37)
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Finally, the bioavailability of lumenally formed mi is
the difference between eq. 26 and eq. 31, viz.
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(38)
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The key expressions are eqs. 25, 28, 32, and 38. They indicate
that the overall bioavailability Fmi can be separated
into its lumenal, first-pass, and systemic components through the
simultaneous measurement of drug and mi following
Dpo, Dia,m, Div, and
Miiv. The gut-wall and hepatic contributions to
first-pass drug elimination and mi bioavailability can be
separated from each other by the addition of Div,p.
Further resolution is possible through the additional treatments of
Mipo, Miia,m, and
Miiv,p to obtain estimates of mi
formation in the lumen and bioavailability across the gut wall and
liver. Assumptions that pertain to mi disposition are the
same as those for drug, i.e. clearances are independent of
concentration and constant between treatments. Reversibility in the
biotransformation of drug and mi to each other is not
excluded conceptually but may require some change in form to
accommodate the definition of clearance (40).
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Discussion |
Experimental strategies have been outlined to isolate and quantify
the individual elements that contribute to the bioavailability of drug
and metabolite after an oral dose of drug. They represent an
integration of and extensions to existing methods (1, 7, 15, 17, 19,
23, 25, 29, 32). Depending on the kind of information being sought,
experiments may involve drug and metabolite administration orally,
intravenously to the hepatic portal vein and a peripheral vein, and
intra-arterially to the mesenteric artery followed by the measurement
of drug and metabolite in blood samples taken from the hepatic portal
vein, a peripheral vein, and a peripheral artery. Assumptions are
linear pharmacokinetics and constant clearance between treatments.
Questions encountered in the selection of compounds with optimal oral
bioavailability for further development as a potential drug are
different from those in support of clinical evaluation of a selected
compound in man or other target animals. Instead of whether the
bioavailability of a compound has been adversely affected by
formulation or whether the intended effect of the formulation to
enhance or modulate has been achieved, one is more likely to be
interested in the factors affecting oral bioavailability and their
respective contributions to the observed value. In drug discovery,
therefore, it would be highly desirable to be able to separate and
quantify lumenal events from systemic ones and permeability issues from
first-pass effects for individual compounds under investigation.
Coincidentally, there is also greater flexibility in experiment design
in the preclinical evaluation of drug candidates.
Heretofore, estimates of fraction absorbed have been based on the
assumption of no gut-wall metabolism or on nonspecific measures such as
drug-related substances recovered in the urine or AUC of total
radioactivity. Such estimates are not useful in the resolution of
FXFG into its components. On the other hand,
drug administration to the arterial supply of the gut provides an
opportunity to assess metabolism by the gut-walls free from the
confounding effects of gastrointestinal absorption. First choice among
such arteries is the superior (cranial) mesenteric because it has the
widest coverage of absorptive surfaces along the gut. To the extent
that a reasonable estimate of FG can be effected, the
magnitude of the corresponding FX provides useful direction
for new compound synthesis. For example, a high value of FX
would indicate good membrane permeability while a low value suggests
poor net transport or significant lumenal loss, 1-FX. The
relative magnitudes of FX and FGFH
would distinguish transport problems from first-pass elimination.
Because experimental parameters are often dependent on the method for
their determination, they can be defined more precisely after the fact.
The assessment of oral bioavailability and its components is typical.
The definition of F is dependent on the choice of reference for the
determination of body clearance and the sampling site. Insofar as
FH can be determined under well-defined experimental
conditions, FXFG is precisely defined by the
ratio F/FH. Conversely, by sampling hepatic portal blood,
one can estimate FXFG directly and define
FH as F/FXFG. By definition,
FXFG is clearly the net effect of drug
absorption and first-pass gut-wall metabolism. However, the
experimental separation and quantitation of FX and
FG are seldom, if ever, attempted. Most of the reported strategies are based on the assumption that the drug is either completely absorbed (8, 12, 15-18, 25, 27, 28) or not metabolized in
the gut wall (7, 8, 12, 15, 31). In effect,
FXFG has been experimentally defined either as
drug absorption or gut-wall metabolism. Similarly, the experimental
evaluation of FX and FG by dose administration
to a mesenteric artery are subject to a different set of design
constraints and dependencies. In subsequent discussion, it may be
useful to treat bioavailability F and its components as net transport
and survival to their respective experimentally defined reference
points. By considering the formal definitions of each parameter and
their possible dependencies on method, one may be better able to
interpret the results. For example, would a molecule be registered as
part of FX, FG, or FH if it enters
an enterocyte as drug, is conjugated there, and is deconjugated in the
liver? What about a molecule that is absorbed in the stomach and is
metabolized in the liver?
To the extent that the superior mesenteric vein is only one of the
tributaries feeding the hepatic portal circulation, the proposed
treatment of dosing to the superior mesenteric artery does not
completely capture metabolic activities of the entire gut wall. Among
the unrepresented regions are the stomach and the upper portion of the
rectum. However, absorption must take place through these tissues for
the metabolic activities therein to manifest. In consideration of
factors such as tissue permeability, effective surface area, dwell
time, and fecal impaction, contribution of the rectum to drug
absorption after an oral dose is usually thought to be negligible while
that of the stomach is about 10%; the remainder is attributed to the
intestines, particularly the upper part of the small intestine
(41-43). Since only a fraction of that which is absorbed through the
stomach wall contributes to the overall bioavailability, the error
associated with its neglect seems acceptably small. In situations where
another segment of the gut is deemed to contribute more significantly
than the small intestine, the site of administration should then be the artery supplying that segment. Dosing simultaneously to two or more
loci may be more encompassing but is conceptually less desirable than
dosing only to the region mostly responsible for metabolism in the gut
wall. This is because such an undertaking would engender the need to
apportion the relative contribution of each segment a
priori. The consequences of incomplete coverage, albeit by design, is that estimates of the fraction absorbed FX are somewhat
biased on the high side to the extent that FG is
underestimated. This is because their product
FXFG is unaffected by the nature of the experimental approximation. Drug molecules that are absorbed from the
lower rectum directly into the inferior vena cava would also positively
bias estimates of FX. This source of error is probably insignificant after an oral dose but may be significant after rectal
administration or in situations when drug is absorbed directly into the
lymphatic system.
In addition, there may be situations in which not all of the metabolic
activity extant in the intestinal epithelium is accessible to drug
entering from the serosal side. This would result in an overestimate of
FG and a corresponding underestimation of FX. Inasmuch as the product of FX and FG is
unaffected, the decrement in FX would appear as a
corresponding increase in the fraction of the dose metabolized in the
gut lumen. For example, a qualitative difference in biotransformation
after oral and parenteral routes of administration may indicate that
the enzyme system responsible for the orally-specific metabolite is not
accessible to substrate delivered from the serosal side of the gut or
that said metabolite is formed in the lumen and absorbed as such. Few
attempts have been made to distinguish between the alternatives. In
isolated intestinal segments, absence of conjugates in the effluent
after the administration of phenol (44) and isoprenaline (20) to the
arterial supply may indicate lack of penetration by these substrates.
On the other hand, the presence of only nonconjugated metabolites of
testosterone (44) in the effluent suggests transport into enterocytes
but not to the relevant phase II enzymes therein. Indirectly, substrate
permeability into enterocytes from the systemic circulation may be
inferred from studies on the inductive and inhibitory effects of
xenobiotics on intestinal enzymes following inhalation or parenteral
administration. Substances presumably polycyclic aromatic hydrocarbons
from cigarette smoke (45) and intraperitonially administered
dexamethasone (46) and some combination of phenobarbital,
polyhalogenated biphenyls, and organochlorine pesticides (47) seem to
have ready access to enterocytes while erythromycin (48) apparently
does not. In view of the paucity and inconclusive nature of the
evidence, the possibility of limited access should be considered in the
design and interpretation of experiments. If one suspects incomplete
access, comparative turnover rates in gut-wall homogenates
vs. lumenal contents may be revealing. Also, high rates of
metabolism in gut-wall homogenates may be incompatible with high
estimates of FG. Finally, as a practical matter, an
acceptably high estimate of FX or an unacceptably low estimate of FXFG may be sufficiently decisive
despite misapportionment.
Available evidence seems to suggest that systemic access to
drug-metabolizing enzymes in enterocytes is compound specific (25).
Complete access leads the best estimate of FG and the highest resolution among FX, FG, and
FH. At the other end of the spectrum, total inaccessibility
would result in no resolution between FG and its neighbors
FX and FH. Nonetheless, dose administration to
the mesenteric artery, Dia,m, is the preferred
treatment in situations in which the primary objective is to assess the
relative contribution of nonabsorption vs. first-pass
elimination. In the worst case, one would obtain a valid estimate of
FH as if the dose had been administered to the hepatic
portal vein. Except in the worst case, the result should be closer to
the target than that following the alternative treatment
Div,p.
In the assessment of FS by eqs. 13 or 14,
Dia,n should best be administered by infusion
rather than as a bolus. This is to maximize the opportunities for
representative sampling at site j and to ensure thereby a
competent estimate of CL. The assumption that the organ spanning sites
n and j should be noneliminating was dictated by
eq. 1, wherein the general circulation was defined by the sampling site
j. If this assumed condition were not satisfied, the
application of eq. 13 or 14 would result in a different estimate of
post-hepatic elimination, say FS, that is numerically
larger than FS. In effect, the reference point has again
been changed such that general circulation is now synonymous with the
arterial supply. Although seldom indicated, the decrement between
FS and FS can be restored by assessing the
extraction ratio across sites n and j.
Alternative experimental strategies have been described for the
determination of FS or, more generally, first-pass effects across organs (49-52). Different combinations of sites of
administration and measurement may result in estimates that are
independently valid but differ because of their point of reference. In
any event, the implementation of experimental strategies that require
total accountability at the site of administration should be undertaken with care (19, 27, 53-56).
Simultaneous sampling in the portal and peripheral circulation
represents an alternative experimental strategy wherein the reference
point shifts from a peripheral site to the portal vein. The prominent
role of the portal measurements is evident by comparing eq. 16 to eq.
19 and eq. 22 to eq. 23. They clearly show the subordinate nature of
the peripheral samples which are used mainly to effect estimates of
AUC. An intravenous dose is
needed in the estimation of
AUC. By design this treatment
is to emulate only drug molecules returning to the portal vein from the
general circulation. Sampling in a peripheral artery ensures the
registration of drug molecules from the intravenous dose prior to their
entry to the portal circulation for the first time. Similarly, drug
molecules that enter the portal vein via the enterohepatic
circulation are not entering for the first time and, therefore, should
register as part of AUC as
well. To fully account for the effects of enterohepatic circulation the
sampling scheme should be adequate to effect competent measures of
AUCa and AUCp. Overall, there are no apparent
strategic advantages or experimental expediencies associated with
simultaneous measurements in the portal circulation.
There is renewed interest in the use of the portal-to-peripheral
concentration gradient as a measure of intestinal absorption (41-45).
Notwithstanding the confounding effects of gut-wall metabolism, the
validity of this approach depends on how closely the drug concentration
profile measured in a peripheral blood vessel resembles that which is
occurring at . Fig. 2 shows that
steady-state concentrations at peripheral sampling sites i, j,
k, and a may differ from each other and from the
expected value at for one drug at a fixed
rate of input. The relative magnitudes at these same sites will differ
from drug to drug since they depend on where drug elimination occurs
and the relative contributions of each eliminating organ. After a
single oral dose of drug, the difference in concentration between
p and varies with time and is
proportional to the time course of change in drug input to the portal
circulation; it starts at zero at time zero, goes through a series of
finite values, and returns to zero eventually. Differences in
concentration between p and peripheral sites i, j,
k, or a must undergo similar changes with time but not
coincidently with each other. Also unlike the differences between those
at and , they
are not necessarily zero in the absence of input from the gut and,
therefore, generally not proportional to the drug input profile. The
remoteness with which concentrations at a peripheral site can emulate
those at suggests that the valid use of
portal-to-peripheral concentration gradients per se would be
limited. Empirically, applicability is limited to situations in which
AUC's measured in the portal vein and the peripheral site after an iv
dose are equal. In other words, differences in drug concentration
between the portal and the peripheral blood are not indicative of
ongoing absorption except in highly specialized situations,
e.g. the drug is metabolically inert. They are especially
inappropriate as indices of comparative absorption across compounds.
There are many situations in which one would be interested in the
bioavailability of a metabolite in addition to or instead of the drug.
For example, in the evaluation of prodrugs, bioavailability of the drug
is germane. In this context, F is a measure of the bioavailability of
the prodrug after prodrug administration while Fmi is
the bioavailability of drug after prodrug administration. On another
occasion one may wish to know how much of the administered drug reaches
the general circulation as an active metabolite. The experimental
strategy for metabolite bioavailability assessment is the same as that
for drug. Drug bioavailability involves the accounting of a single
sequence of events in which drug molecules move serially through the
gut lumen, the gastrointestinal mucosa, the gut wall, and the liver.
Drug molecules that survive each tissue are a continuing source of
metabolite while metabolite formed in each tissue must survive the
remaining tissues sequentially to be counted. Metabolite
bioavailability, therefore, consists of the tracking of parallel
sequences representing the serial survival of drug and metabolite.
Since there are no constraints on the relationship between drug and
metabolite, i.e. primary or nth generation, the
same strategy applies for any other metabolite. Furthermore, more than
one metabolite can be studied simultaneously. For example, the
bioavailability of metabolites mi and mj after drug administration would nominally entail one additional treatment Mjiv and analyzing all samples for drug, mi
and mj. How the results should be analyzed to yield the
appropriate parameters would depend on the relationship between
mi and mj. If they are products of parallel and
mutually exclusive metabolic pathways, the components of mj
bioavailability would be represented by expressions analogous to eqs.
25, 28, 32, and 38. Where mi is an obligatory precursor of mj, the serial survival of drug and mi across
each tissue must be accounted for in the bioavailability of
mj while eqs. 25, 28, 32 and 38 remain valid for
mi. Where mi is one of the sources of mj, or vice versa, additional branch points must
be included to account for the survival of mi and
mj across each tissue in addition to their direct
descendence from the parent drug. Insofar as their applicability
extends to precursor-product relationships, the proposed strategies are
not limited to bioavailability assessment but should be generally
useful in the in vivo evaluation of sites of drug metabolism
and metabolite formation.
Most of the analytical expressions of interest involve area comparisons
after two or more different treatments. Experimental designs can be
made more efficient, therefore, by the concomitant administration of
different isotope-labeled drug or metabolite by different routes.
Whereas four separate administrations are needed to resolve and
estimate FH, FG, and FX by eqs. 6,
10, and 9, respectively, only two treatments would suffice by giving
two different labels concomitantly in each. Alternatively, the
concomitant administration of an intravenous dose with each of the
other three routes not only reduces the total number of treatments but
also dispenses with the assumption of constant total body clearance between treatments. In paradigms involving simultaneous measurements in
the portal and peripheral circulation, concomitant administration of a
labeled dose intravenously ensures a competent estimate of AUC free from assumptions of
constant clearance and components thereof. Furthermore, drug and
metabolites can be administered simultaneously by one route
concomitantly with differently labeled drug and metabolites by another.
The number of compounds that can be co-administered by each route and
the diversity of the isotope labels needed therein depend on one's
ability to distinguish and quantify drug and metabolite(s) unequivocally by source.
While it is desirable to have experimental strategies and procedures in
place to effect estimates for the individual components of
bioavailability, their routine application in toto is seldom indicated. On a given occasion, primary interest is usually limited to
one or two elements. The following sequence of events is only intended
to be illustrative. An otherwise ideal compound is poorly bioavailable
when given orally. By administering a dose to the mesenteric artery,
one learns the problem is poor absorption not extensive first-pass
elimination. Drug bioavailability remains poor after oral
administration of a prodrug. By administering the prodrug
intravenously, one learns that the oral bioavailability of the prodrug
is excellent but biotransformation to drug is poor. The process
continues. By posing questions precisely, each iteration seldom
requires more than one or two additional experiments.
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Abstract
Introduction
