Hacettepe University, Faculty of Pharmacy, Ankara, Turkey (S.S.);
and
School of Pharmacy and Pharmaceutical Sciences, University of
Manchester, Manchester, United Kingdom (M.R.)
The hepatic distribution kinetics of salicylic acid was determined
using a single-pass dual hepatic artery (HA) and portal vein (PV)
perfused in situ rat liver preparation. Bolus doses of
[14C]salicylic acid and of reference markers
([3H]-water and [14C]-sucrose) were
injected in a random order into either the HA or PV and then, after an
appropriate interval, into the alternate vessel. The hepatic outflow
profile of [14C]salicylic acid displayed a characteristic
sharp peak followed by a slower eluting tail, whereas sucrose and water
displayed unimodal outflow profiles. The biphasic outflow profile
indicates that the hepatic distribution of salicylic acid is not
instantaneous but is limited by a permeability barrier. The in situ
permeability surface area product for [14C]salicylic acid
was 3.35 ± 0.26 ml/min/g for PV and 7.45 ± 1.50 ml/min/g
for HA administration. Furthermore, theory dictates that hepatic uptake
is influenced by both perfusion and permeability if effective
permeability surface area product/blood flow ratio lies between the
values of 0.06 and 7.0. Our estimates (3.0 for venous output and 6.7 for arterial input) indicate that hepatic uptake of salicylic acid is
dependent on both perfusion and permeability. The volume terms were
calculated using two different methods, standard and specific.
Regardless of the compound and method, the volume of distribution after
arterial administration was larger than that after venous
administration. In addition, a volume of distribution approximately
twice that of the total aqueous space (i.e., HA, 2.23 ± 0.13 versus 1.10 ± 0.07 ml/g; PV, 1.72 ± 0.16 versus 0.68 ± 0.04 ml/g) implies that salicylic acid has a significant affinity
for hepatic tissue. A similar tissue-to-perfusate partition coefficient
associated with HA and PV input (5.40 ± 0.38 versus 6.48 ± 0.56) indicates that affinity of salicylic acid for hepatic tissue is
independent of the route of input.
 |
Introduction |
Hepatic elimination may be influenced by various
processes, including organ perfusion, binding to blood and tissue
components, cellular activity, and membrane permeability (Rowland and
Tozer, 1995
). In the liver, the primary barrier is at the cellular
membrane level because the vascular endothelial membrane, with its
large fenestrae, does not offer material resistance to the movement of
drug molecules. A cell membrane rate limitation in hepatic uptake is
most likely to be seen with polar molecules.
Most of the basic physiological concepts surrounding hepatic uptake
have been developed using the isolated perfused rat liver preparation,
mostly receiving single perfusion via the portal vein
(PV1;
Rowland and Evans, 1991). Yet, in vivo, the liver
receives two blood supplies via the hepatic artery (HA) as well as via
the PV. Although some investigators propose that these two blood
supplies mix before or within the sinusoids (Nakai et al., 1979;
Watanabe et al., 1994), the body of data supports the view that at
least part of the HA flow perfuses a specific arterial space (Field and
Andrews, 1968; Ahmad et al., 1984; Reichen, 1988; Kassissia et al.,
1994; Pang et al., 1994; Sahin and Rowland, 1998a).
Although there have been some studies comparing the hepatic
dispositional characteristics of various compounds between PV and HA in
the dual-perfused liver (Ahmad et al., 1984; Pang et al., 1994),
apparently no such studies have been reported for compounds showing
membrane permeability rate-limited uptake. The aim of the current study
was to address the latter issue, using salicylic acid, whose uptake had
been shown to be permeability rate-limited in the single PV perfused
rat liver (Hussein et al., 1994), as a model compound.
| |
Materials and Methods |
Salicylic acid (14C; 59 mCi/mmol) was obtained from
Amersham (Amersham, UK); 14C-sucrose (0.1 mCi/ml) and
3H-water (100 mCi/ml) were obtained from ICN Biomedicals,
Inc., (Costa Mesa, CA). Sodium salicylate and all other chemicals were of analytical grade and obtained commercially.
Perfusion Procedure.
The single-pass dual-perfused in situ rat liver preparation used male
Sprague-Dawley rats (318 ± 11 g; wet liver weight 13.5 ± 0.7 g; n = 7). Krebs-bicarbonate solution
containing 5 mg/liter sodium salicylate was used as the perfusion
medium. The surgical procedure was the same as that described
previously (Sahin and Rowland, 1998b). Briefly, after induction of
anesthesia, the bile duct was cannulated and loose ligatures were
placed around the PV, ensuring exclusion of the HA. The gastroduodenal
artery and branches of the celiac artery (i.e., the left gastric and
splenic arteries) were tied very close to their junctions. Initially, the PV was cannulated with a 16-gauge (Argyle Medicut, o.d. 1.7 × 45 mm) catheter and the perfusion started at a flow rate of 12 ml/min.
The thoracic vena cava was cannulated through the right atrium for the
collection of the outflow perfusate. The HA was cannulated indirectly
through the celiac artery using a 18-gauge (Argyle Medicut, o.d.
1.3 × 45 mm) or 20-gauge (Argyle Medicut, o.d. 1.1 × 45 mm)
catheter and the second perfusion was started at a flow rate of 3 ml/min. All operative procedures were completed within 20 to 30 min
without interruption of flow to the liver. Viability of the perfused
liver was assessed from measurement of bile flow, perfusate recovery,
hepatic arterial pressure, and from gross appearance.
Injection Preparations.
Two tracer markers (i.e., either [14C]salicylic acid and
3H-water, or [14C]sucrose and
3H-water) were injected together as a bolus (50 µl) in
saline; doses used were [14C]salicylic acid, 0.31 µCi;
14C-sucrose, 0.16 µCi; and 3H-water, 0.74 µCi.
Experimental Procedure.
All of the experiments were performed after at least a 20-min initial
stabilization period. Salicylic acid (14C) and reference
markers (14C-sucrose, tritiated water) were administered as
a bolus in a random order either into the HA or PV, and then into the
alternate vessel, separated by an appropriate time interval based on
prior washout information. Immediately after an injection, the total effluent was automatically collected at 2-s intervals for 2 min, using
a motor-driven carousel, and thereafter at increasing time intervals,
for an additional 3 to 6 min. The activities of 3H and
14C were determined simultaneously in 200 µl of outflow
perfusate, after the addition of 5 ml of scintillation fluid, with the
results expressed in dpm.
Data Analysis.
The frequency output [f(t), 1/s] of the injected radiolabeled
material at the midpoint time of the sampling interval was calculated using the following equation:
|
(1)
|
where C(t) is the concentration of radioactivity,
Q is the total perfusate flow (ml/s), and D is
the injected dose (in dpm). The delay in the nonhepatic region of the
experimental system (i.e., PV, 2.40 ± 0.03 s; HA, 2.27 ± 0.06 s; n = 6; mean ± S.E.) was simply
subtracted from the midtime of the sampling interval. The moments of
the frequency outflow against midtime profiles were estimated by
numerical integration, and then the parameters related with these
moments (e.g., VH, CV2) were
calculated using the following equations:
|
(2)
|
|
(3)
|
|
(4)
|
where AUC is the area under the concentration versus time
profile; MTT is the mean transit time, which is the average time taken
for a molecule to pass through the organ; and VTT is variance of
transit times, which is a measure of temporal spreading or dispersion
of transit times within the organ. These equations assume that solute
is not eliminated and total perfusate flow rate (Q) is constant throughout.
The normalized variance (CV2) is given by
|
(5)
|
CV2 is a dimensionless parameter and has been used
as a measure of relative dispersion of drug within the liver (Roberts
et al., 1988).
The recovery (F) is defined as:
|
(6)
|
The volume of distribution (VH) is
estimated using two different methods, namely, the standard and
specific methods. The standard method is given by:
|
(7)
|
In the specific method, total hepatic aqueous space
is considered to consist of a common and a specific space. The common space is perfused by both arterial and venous flows, whereas the specific space receives a fraction of the arterial blood (Sahin and
Rowland, 1998a). Furthermore, the common and specific spaces are
parallel to each other, and solute or solvent exchange does not take
place between these spaces. The volume terms associated with each input
are given by the following equations:
after the venous injection:
|
(8)
|
|
(9)
|
where VC is the volume of distribution
of the common space, MTTC is the MTT after the
PV injection operating in a dual perfusion mode,
QC is the flow rate to the common space,
QHA and QPV are the HA
and PV flow rates, respectively, and f3 is the fraction of
QHA perfusing the specific hepatic arterial
space. The fraction of HA flow to the common space (1 
f3) was taken as 0.83 (Sahin and Rowland, 1998a):
after the arterial injection (Sahin and Rowland, 1998a):
|
(10)
|
|
(11)
|
so that
|
(12)
|
Rearrangement of eq. 12 yields
![V<SUB>sa</SUB>=Q<SUB><SC>ha</SC></SUB> · [MTT<SUB><SC>ha</SC></SUB>−(1−f<SUB>3</SUB>) · MTT<SUB><SC>c</SC></SUB>]](/content/vol27/issue3/fulltext/373/img013.gif)
|
(13)
|
Finally
|
(14)
|
where Vsa is the volume of the specific arterial
space, and VHA is the volume of distribution
after HA input.
Estimation of Permeability-Surface Area Product (PS).
Estimates of the PS have been reported for diazepam (Diaz-Garcia et
al., 1992) and salicylic acid (Hussein et al., 1994) by fitting the
two-compartment dispersion model to hepatic outflow data. This fitting
procedure is complex and time-consuming in comparison to two recently
proposed model-independent approaches for the estimation of the PS
value (Wu et al., 1993; Chou, 1995). Although these two methods evolved
from the same origin (from the CV2 of the two-compartment
dispersion model defined by Yano et al. (1989) for noneliminated
substances), the one proposed by Wu et al. (1993) assumes that no
metabolism or protein binding occurs in the organ, whereas the other
makes no such assumption. In the present study, the method of Chou
(1995) was adopted for the estimation of the PS value of
[14C]salicylic acid, namely:
|
(15)
|
where fuB is the unbound fraction in the
perfusate, MTTHB and
CV2HB are mean transit time and
normalized variance for the extracellular marker (sucrose), and
MTTH and
CV2H are the corresponding values
for the test substance (salicylic acid). The influx (k12)
and efflux (k21) first-order rate constants across the
hepatocellular membrane can be evaluated from the
fuB·PS value (Chou, 1995); that is
|
(16)
|
|
(17)
|
The apparent tissue-perfusate partition
coefficient (Kp) was estimated from the ratio of the influx
and efflux rate constants (Yano et al., 1989).
|
(18)
|
In addition, an estimate of the intracellular unbound fraction
(fuC) was obtained using the relationship
between the rate constants and volumes of distribution (Hussein et al., 1994); it is given by
|
(19)
|
where VCV is defined as the aqueous
cellular volume and is calculated as the difference between the
distribution volumes of water and sucrose (VB),
an extracellular marker. This calculation assumes that salicylic acid
distributes into the total water space of the liver and that the influx
and efflux PS values are equal i.e., PSin = PSout (Hussein et al., 1994).
Data are presented as mean ± S.E. and compared using a paired or
unpaired Student's t test. A p value less than
.05 was considered significant.
| |
Results |
Outflow Profiles.
In the presence of sodium salicylate (5 mg/l) in the perfusate,
representative frequency outflow versus midtime profiles of [14C]salicylic acid and the two reference markers
(14C-sucrose and 3H-water) after bolus
administrations into the HA and PV are depicted in Fig. 1, A and
B, respectively. Regardless of the route
of entry, sucrose and water displayed unimodal outflow profiles.
Irrespective of the marker, the outflow profiles after arterial
administration were flatter than after PV administration (e.g.,
fmax: for sucrose, HA, 0.051 ± 0.003 and PV,
0.092 ± 0.008 1/s; and for water, HA, 0.018 ± 0.001 and PV,
0.030 ± 0.002 1/s).
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|
Fig. 1.
Semilogarithmic plots of fractional rate of
efflux of 14C-sucrose ( ), 3H-water ( )
and [14C]salicylic acid ( ) after injection into the
hepatic artery (A) and portal vein (B) of a representative dual
perfused rat liver.
|
|
In contrast to the reference markers, the hepatic outflow profiles of
[14C]salicylic acid were clearly multiphasic (Fig.
2). This multiphasic profile was
characterized by a sharp peak followed by a slow eluting flat tail. In
addition, apart from a slightly diminished first peak after HA
injection (e.g., fmax, HA: 0.011 ± 0.001 and PV: 0.016 ± 0.002 1/s, tmax: 5.80 ± 0.31 versus
7.50 ± 0.75 s), arterial and venous injections produced very
similar outflow profiles.
View larger version (14K):
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|
Fig. 2.
Linear plots of fractional rate of efflux of
[14C]salicylic acid after injections into the hepatic
artery () and portal vein () of a representative rat liver
operating in the dual perfusion mode.
|
|
Moment Analysis.
Table 1 presents the results of moment
analysis for 14C-sucrose, 3H-water, and
[14C]salicylic acid. Regardless of the compounds, the
recovery of injected material was over 90%. The mean transit times,
and hence the volumes of distribution VH,
increased from sucrose to salicylic acid whether they were administered
into the HA or PV. Irrespective of the marker, the mean transit times
(s) after HA injection were longer than that after PV
injection-sucrose: 21.6 ± 2.3 versus 12.7 ± 1.2 (p < .05); water: 60.4 ± 4.2 versus 37.0 ± 2.4 (p < .01); salicylic acid
121.1 ± 3.6 versus 92.4 ± 5.7 (p < .05). Also, regardless of the method used, the HA estimates for the
volume of distribution were significantly larger than those of the PV
estimates (Table 1). Although the relative spreading (CV2)
of [14C]salicylic acid was very similar whether
administered into the HA or PV, the corresponding values for sucrose
and tritiated water were larger after arterial than venous input
(p < .01).
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|
TABLE 1
Mean (±S.E.) statistical moment analysis parameters for
14C-sucrose, 3H-water and [14C]salicylic acid
in the dual perfused rat liver
|
|
Membrane Permeability.
Values of the PS of salicylic acid (given that
fuB = 1 in the absence of albumin) are
summarized in Table 2. The estimated PS
value for salicylic acid after the HA administration was approximately
twice that of the corresponding value after PV injection (PS, ml/min/g
liver; HA: 7.45 ± 1.50 and PV: 3.35 ± 0.26;
p < .01). Although influx (k12) and efflux
(k21) first-order rate constants across the hepatocellular
membrane were larger after arterial than venous injections (Table 2),
the difference between these rate constants was not significant.
Regardless of the injection site, the tissue-perfusate partition
coefficients (KP) for
[14C]salicylic acid were comparable (i.e., HA, 5.40 ± 0.38; PV, 6.48 ± 0.56). Furthermore, the estimated unbound
fractions of [14C]salicylic acid in the cells,
fuC, were almost identical whether injected
into the HA or PV (i.e., HA, 0.36 ± 0.02; PV, 0.31 ± 0.03).
The ratio of effective permeability-surface area product to blood flow
(PS/Q) was 3.0 for PV injection and 6.7 for HA injection.
| |
Discussion |
Choice of the Compound.
In the present study, salicylic acid was chosen as the model compound
because it is a small, relatively polar molecule displaying low
permeability across the hepatocyte membrane (Hussein et al., 1994) and
it binds to cellular constituents of liver cells (Yoshikawa et al.,
1984). Although the distribution kinetics of salicylic acid have been
investigated under various conditions, including flow rate and
concentration in the single (PV) perfused rat liver (Hussein et al.,
1994), no information is available with regard to route of hepatic
input, the subject of this study in the dual perfused rat liver.
Additionally, sucrose and water were chosen as reference markers
because they represent the asymptotes with regard to hepatocyte
permeability. Sucrose is completely excluded from the hepatocytes (zero
permeability, Alpini et al., 1986), whereas water has free access to
the hepatocytes. Accordingly, they occupy the extracellular and total
aqueous spaces, respectively.
Salicylic acid is metabolized in man and animals to salicyluric acid,
salicyl phenolic, and acyl glucuronides, gentisic acid and gentisuric
acid. In man and rat, the main metabolite is the glycine conjugate,
salicyluric acid. Available data suggest that salicyluric acid and
salicyl phenolic glucuronide can be reversibly metabolized back to
salicylic acid (Morris, 1990). Nevertheless, more recent reports
support the idea that salicylic acid is not metabolized (Hussein et
al., 1994; Shetty et al., 1994) or is minimally metabolized by the
liver during single pass (i.e., 20 min after infusion, in a
recirculating mode, the percentage of metabolites in the perfusate is
only about 4%; Laznicek and Laznickova, 1994). The same was assumed to
hold in the present study. Therefore, measured total
14C-radioactivity was taken to represent
[14C]salicylic acid.
Outflow Profiles.
Visual comparison of the outflow profiles for sucrose, water, and
salicylic acid indicates that distribution of salicylic acid, unlike
water, is not instantaneous in the liver but is limited by a
permeability barrier. The multiphasic profile of salicylic acid has
been previously investigated by Ichikawa et al. (1992) and more
recently by Hussein et al. (1994) in the single (PV) perfused rat
liver. The current study extends this knowledge to the dual perfused
liver. The similarity in the outflow profiles of salicylic acid
obtained after HA and PV injections indicates that distribution of
salicylic acid is minimally affected by the route of input. Regardless
of the route of administration, the rapidly eluting peak of
[14C]salicylic acid emerged almost at the same time as
sucrose, indicating that a certain fraction of salicylic acid, the
throughput component, emerges without ever entering the hepatocytes on
transit through the liver, essentially due to poor permeability. The
fraction of throughput component increases with an increase in the flow rate (i.e., 4% for 15 ml/min and 12% for 30 ml/min; Hussein et al.,
1994). In contrast, the more slowly eluting fraction of the outflow
profile, referred to as the "returning component" (Goresky, 1983)
represents the fraction of [14C]salicylic acid that has
entered the hepatocytes and returned to the vascular space, delayed by
intracellular binding and limited permeability (Hussein et al., 1994).
Moment Analysis.
Preliminary experiments indicated that presence of salicylate in the
perfusate has no effect on the distribution kinetics of sucrose and
water. Nevertheless, this was not the case for labeled salicylic acid;
MTT was decreased and the recovery of the administered dose was
increased with the addition of salicylate to the perfusate. With regard
to [14C]salicylic acid, a longer MTT and, hence, larger
VH than for sucrose clearly indicates that
salicylic acid is not confined to the extracellular space of the liver.
In addition, a VH approximately twice that of
the total aqueous space suggests that salicylic acid has affinity for
hepatic tissue. These results are in accordance with the results of
those in the in situ single (PV) perfused rat liver preparation
(Hussein et al., 1994). The VH values estimated
using the standard and specific methods support the idea that the
volume estimates are dependent upon the method used and could be
misleading. Although PV estimates were minimally affected by the choice
of the method, this effect was dramatic for HA estimates.
Membrane Permeability and Tissue Binding.
The extent of distribution of a compound into an organ (i.e., liver)
can be rate-limited by either perfusion or permeability (Rowland and
Tozer, 1995). Recently an attempt has been made to correlate
hepatocellular permeability with physicochemical properties (e.g., logD
(n-octanol: pH 7.4 aqueous buffer; Chou et al., 1995) for variety of
compounds studied in the isolated rat liver. It was concluded that for
compounds that have logD values greater than 0, the uptake is flow
limited either if the perfusate contains no binding protein or binding
of compound in the perfusate is negligible. On the other hand, the
uptake is limited by permeability irrespective of degree of binding
when the logD value of a compound is less than 3. If the logD value
lies between these limits, as in the case of salicylic acid which has a
logD value of 2.17 (Chou et al., 1995), hepatic uptake is anticipated
to be governed by both flow rate and magnitude of permeability. This
expectation is supported by considering the relative effective
permeability-surface area (fuB·PS), flow rate
(Q) and the dispersion number (DN), a
dimensionless parameter used as a measure of relative axial spreading
of a solute within the liver. Unlike permeability, the general
similarity of DN estimated for a variety of
substances (0.2-0.5) of differing physicochemical properties indicates
that this parameter characterizes the hepatic microvascular morphology
rather than that of a drug (Rowland and Evans, 1991).
Theory dictates that hepatic uptake is influenced by both perfusion and
permeability if fuB.PS/Q lies within the following bounds (Chou et al., 1995)
|
(20)
|
For a noneliminated substance such as salicylic acid,
DN can be estimated from CV2
through the relationship DN = CV2/2
(Roberts et al., 1988). This yields a value of
DN of 0.42 to 0.44, given that CV2 = 0.84-0.88 (Table 1). Thus, for equation 20 to hold,
fuB-PS/Q must lie between 0.056 and 7.0, which
is the case in the perfusate experiments being 3.0 for PV input and 6.7 for HA input. Although these high values suggest a tendency to a
perfusion rate-limitation in the perfusate experiments in the absence
of binding protein, with salicylic acid bound to circulating albumin in
plasma (fuB = 0.11 in the presence of 4.9%
bovine serum albumin; Ichikawa et al., 1992),
fuB·PS/Q is about 0.33 and 0.74 (for PV and
HA respectively), suggesting that in vivo hepatic uptake is dependent
on both perfusion and permeability. Notwithstanding, these values for
salicylic acid are sufficiently high that distribution equilibrium
between the liver and circulating drug will be rapid (in minutes)
compared with the overall elimination of drug from the body, which
takes many hours (t1/2 = 10 h after i.v. injection of
173 mg/kg salicylic acid; Hirate et al., 1989). Also, with permeability
much greater than intrinsic clearance (PS 
CLint), at
equilibrium, the unbound concentration within the hepatocyte is
expected to be essentially the same as that in perfusing blood.
The mean PS estimate of [14C]salicylic acid after PV
administration (3.35 ± 0.26 ml/min/g liver) is in good agreement
with the previous results obtained both in isolated hepatocytes in
vitro (6.4 ml/min/g liver; Ichikawa et al., 1992) and the single PV perfused in situ liver (4.6 ml/min/g liver; Hussein et al., 1994). Although the PS value for [14C]salicylic acid after
arterial administration (7.45 ± 1.50 ml/min/g liver) was similar
to that determined from in vitro hepatocytes studies by Ichikawa et al.
(1992), no such data are available in the in situ liver preparation. In
the presence of albumin, due to binding to this protein, a substantial
decrease in the PS value of salicylic acid has been reported both in
the isolated hepatocytes and in situ liver preparation (e.g., 1.5 ml/min/g liver for isolated hepatocytes and 1.6 ml/min/g liver for the in situ rat liver; Miyauchi et al., 1993). In addition, Hirate et al.
(1989) observed that the disposition characteristics of salicylic acid
are markedly altered in the presence of low plasma protein
concentration (i.e., analbuminemic versus control rats) due to
reduction in the protein binding of salicylic acid.
Low recovery of the [14C]salicylic acid (i.e., 59% for
HA and 69% for PV) obtained in the absence of salicylic acid in the
perfusate during preliminary experiments was attributed to the binding
to hepatic tissue rather than elimination of the compound. This idea was supported by displacement of some [14C]salicylic acid
after subsequent bolus injection of unlabeled material (i.e., 9-12%
of injected dose for HA and 6% of injected dose for PV over a period
of 1-2 min). Additionally, regardless of both route of input and
salicylate in the perfusate, alteration of both fractional recovery and
displacement of [14C]salicylic acid with sodium
salicylate in the bolus give support to the idea that binding to tissue
is reversible and saturable. Moreover, a Kp value of
approximately 6 also suggests that salicylic acid has an affinity to
hepatic tissue whether delivered via the HA or PV. This value of
Kp is in agreement that in the in situ rat liver perfused
via the PV (about 6; Hussein et al., 1994) and also with in vivo values
(e.g., 6.4 after a dose of 10 mg/kg) estimated by Hussein et al.
(1994), based on the data supplied by Hirate et al. (1989). The
concentration-dependent characteristics of Kp (i.e., a
decrease with an increase in the concentration of salicylate in the
perfusate; Hussein et al., 1994) is indicative of saturable tissue binding.
An absence of binding protein in the perfusate (fu = 1) offers an
opportunity to investigate the extent of [14C]salicylic
acid binding within the hepatic tissue (i.e., 1 fuc). The presence of salicylate in the perfusate results
in a concentration-dependent decrease in the hepatic tissue binding of
[14C]salicylic acid (e.g. fuc values are
0.37, 0.59, and 0.93 at 0, 100, and 200 mg/l, respectively; Hussein et
al., 1994). In the present study, intracellular binding characteristics
of salicylic acid are unaffected by route of administration and the
values of fuc are in a good agreement with the literature
data (Hussein et al., 1994).
In summary, the present study demonstrates that the distribution
kinetics of salicylic acid is influenced by route of administration. Nevertheless, its hepatic uptake process is independent of the site of
administration and governed by both flow rate and cellular permeability
located at the level of hepatocytes. Also, the larger in situ PS seen
after HA input is probably attributable to the presence of the specific
arterial space and associated hepatocytes. Additionally, an alternative
method to the standard method is proposed for the estimation of volume
of distribution of compounds in the dual perfused liver. Thus, using
the water content of the liver obtained by desiccation as the reference
(i.e., 0.72 ± 0.01 ml/g liver; Sahin and Rowland, 1998a), the
specific method for tritiated water proved superior to the standard
method, especially after arterial administration (0.79 ± 0.04 versus 1.10 ± 0.07, ml/g liver; Table 1).
We thank the Turkish Government for a studentship (S.S.);
research supported by a grant from the Wellcome Trust.
Abbreviations used are:
HA, hepatic artery;
PV, portal vein;
PS, permeability-surface area product.
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Abstract
Introduction
