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Antimicrobial Agents and Chemotherapy, May 1998, p. 1146-1150, Vol. 42, No. 5
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Disposition of the Acyclic Nucleoside Phosphonate
(S)-9(3-Hydroxy-2-Phosphonylmethoxypropyl)Adenine
Martin K.
Bijsterbosch,1,*
Louis J. J. W.
Smeijsters,2 and
Theo J. C.
van
Berkel1
Division of Biopharmaceutics,
Leiden/Amsterdam Center for Drug Research, Leiden University, 2300 RA
Leiden,1 and
Institute of Infectious
Diseases and Immunology, Department of Parasitology and Tropical
Veterinary Medicine, Utrecht University, 3508 TD
Utrecht,2 The Netherlands
Received 10 July 1997/Returned for modification 14 October
1997/Accepted 10 February 1998
 |
ABSTRACT |
The acyclic nucleoside phosphonate
(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine
[(S)-HPMPA] has been shown to be active against
pathogens, like hepatitis B viruses and Plasmodium
parasites, that infect parenchymal liver cells. (S)-HPMPA
is therefore an interesting candidate drug for the treatment of these
infections. To establish effective therapeutic protocols for
(S)-HPMPA, it is essential that the kinetics of its hepatic
uptake be evaluated and that the role of the various liver cell types
be examined. In the present study, we investigated the disposition of
(S)-HPMPA and assessed its hepatic uptake. Rats were
intravenously injected with [3H](S)-HPMPA,
and after an initial rapid distribution phase (360 ± 53 ml/kg of
body weight), the radioactivity was cleared from the circulation with a
half-life of 11.7 ± 1.4 min. The tissue distribution of
[3H](S)-HPMPA was determined at 90 min after
injection (when >99% of the dose cleared). Most (57.0% ± 1.1%) of
the injected [3H](S)-HPMPA was excreted
unchanged in the urine. The radioactivity that was retained in the body
was almost completely recovered in the kidneys and the liver (68.4% ± 2.5% and 16.1% ± 0.4% of the radioactivity in the body,
respectively). The uptake of [3H](S)-HPMPA by
the liver occurred mainly by parenchymal cells (92.1% ± 3.4% of
total uptake by the liver). Kupffer cells and endothelial cells
accounted for only 6.1% ± 3.5% and 1.8% ± 0.8% of the total
uptake by the liver, respectively. Preinjection with probenecid reduced
the hepatic and renal uptake of [3H](S)-HPMPA
by approximately 75%, which points to a major role of a
probenecid-sensitive transporter in the uptake of (S)-HPMPA by both tissues. In conclusion, we show that inside the liver, (S)-HPMPA is mainly taken up by parenchymal liver cells.
However, the level of uptake by the kidneys is much higher, which leads to nephrotoxicity. An approach in which (S)-HPMPA is
coupled to carriers that are specifically taken up by parenchymal cells
may increase the effectiveness of the drug in the liver and reduce its
renal toxicity.
| |
INTRODUCTION |
Many efforts in the search for
effective antiviral agents have focused on the development of
nucleoside analogs that selectively affect viral DNA synthesis (1,
11, 12, 15). These analogs need to be phosphorylated to their
triphosphate derivatives to become biologically active. The
triphosphates affect viral replication either by inhibiting viral
replication enzymes (e.g., reverse transcriptase and viral DNA
polymerase) or by terminating viral DNA chain elongation. The
phosphorylation of antiviral nucleoside analogs to their triphosphate
derivatives is, in general, catalyzed by cellular kinases. To bypass
the first critical phosphorylation step, monophosphorylated nucleoside
analogs have been synthesized and tested for their antiviral
activities. Acyclic nucleoside phosphonate analogs have been found to
be particularly promising. A key feature of these compounds is that
their phosphonylmethyl ether group is resistant to the activities of
the esterases that dephosphorylate regular monophosphorylated
nucleosides. The compounds are, however, still readily phosphorylated
to the active derivatives by cellular enzymes (27). Acyclic
nucleoside phosphonates show broad-spectrum antiviral activity against
several RNA and DNA viruses (10). The spectra of the
antiviral activities of the nucleoside phosphonates vary largely and
depend on the nature of the base and the nature of the acyclic side
chains (11). The mechanisms of the antiviral actions of
these analogs are, however, not entirely clarified. It has been shown
that their active diphosphorylated derivatives can competitively
inhibit the DNA polymerase- and reverse transcriptase-catalyzed
incorporation of natural triphosphate nucleosides into DNA (16,
23). However, recent studies indicate that some of these analogs
can also act as alternative substrates, which leads to DNA chain
termination or a strongly reduced rate of DNA chain elongation
(19, 37). Additional mechanisms, however, cannot be
excluded. Studies with animals and patients indicate that acyclic
nucleoside phosphonates are therapeutically effective in vivo but that
renal toxicity is dose limiting (6, 27, 31).
The S enantiomer of
9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine
[(S)-HPMPA] is of particular interest for the therapy of liver-associated disease. It has been shown that it is highly effective
against human and duck hepatitis B viruses in cultured cells (38,
39). Furthermore, it has been shown in vivo with mice that
(S)-HPMPA is active against the liver stage of the rodent parasite Plasmodium berghei (a murine model for human
malaria). It prevents the development of a blood-stage infection and
thus the severe symptoms of malaria (32). Both pathogens
(i.e., hepatitis B viruses and Plasmodium parasites) infect
parenchymal liver cells. To establish an effective therapeutic protocol
for (S)-HPMPA for the treatment of these infections, it is
essential that the kinetics of its uptake by the liver be evaluated and
that the roles of the various types of liver cells be examined.
Furthermore, these parameters need to be related to the dose-limiting
renal uptake.
| |
MATERIALS AND METHODS |
Reagents.
(S)-HPMPA was kindly provided by E. de
Clercq (Rega Institute, Leuven, Belgium).
[2,8-3H](S)-HPMPA (14 Ci/mmol) was purchased
from Moravek Biochemicals, Brea, Calif. The radiochemical purity was
regularly checked by thin-layer chromatography (TLC; the solvent was
n-butanol-acetone-water-ammonia; 40:35:20:5) and by
high-performance liquid chromatography (HPLC; see below) and was found
to be >95%. Probenecid was obtained from Sigma, St. Louis, Mo.
Emulsifier Safe and Hionic Fluor scintillation cocktails and
Soluene-350 were from Packard, Downers Grove, Ill. All other reagents
were of analytical grade. TLC plates (preformed 0.2-mm-thick layers of
Silica 60-F254 on aluminum sheets) were obtained from
Merck, Darmstadt, Germany.
Analysis by HPLC.
Analysis of the radiochemical purity of
[3H](S)-HPMPA and assessment of plasma and
urine samples for the presence of radiolabeled (S)-HPMPA
were performed by HPLC with a Partisil SAX-10 anion-exhange column and
a Nucleosil 100/C18 reverse-phase column (both columns were
purchased from Alltech, Deerfield, Ill.). Fractions were collected and
assayed for radioactivity. The Partisil SAX-10 column (25.0 by 0.46 cm)
was eluted at a flow rate of 1 ml/min. After application of the
samples, the column was eluted with 10 ml of 10 mM
NH4H2PO4, followed by a linear
gradient of 10 to 1,000 mM NH4H2PO4
(30 min). The retention time of (S)-HPMPA under these conditions was approximately 2.5 min. The Nucleosil 100/C18
column (25.0 by 0.46 cm) was eluted isocratically for 75 min at a flow rate of 0.4 ml/min with a mobile phase consisting of 5 mM
tetrabutylammonium-dihydrogenphosphate, 50 mM
KH2PO4, and 5% (vol/vol) acetonitrile. The
retention time of (S)-HPMPA under these conditions was
approximately 15.0 min. Both assays had an excellent log-linear
correlation between peak areas and the amounts of the
(S)-HPMPA standards in the range of 0.1 to 10 µg
(r2 > 0.99). The sensitivities of both assays
for unlableled (S)-HPMPA were 0.1 µg (sensitivities for
[3H](S)-HPMPA, 5 pg). The between-day
variation for both assays was <10%. Urine samples and stock solutions
of [3H](S)-HPMPA were injected directly into
the HPLC system after filtration over a 0.22-µm-pore-size filter
(Millipore, Bedford, Mass.). Plasma samples were extracted as follows.
Aliquots of 0.2 ml of plasma were mixed with 1.8 ml of ice-cold
methanol. After 5 min of shaking at room temperature, insoluble
material was removed by centrifugation (5 min at 16,000 × g). The pellet was washed with an additional 1.0 ml of
methanol. The combined supernatants were lyophilized, and the residue
was dissolved in 0.5 ml of phosphate-buffered saline (10 mM sodium
phosphate buffer [pH 7.4] containing 0.15 M NaCl). After filtration
over a 0.22-µm-pore-size filter, the samples were injected into the
HPLC system. The overall recovery by the extraction and HPLC procedure
[assessed by including 10 µg of an (S)-HPMPA standard in
the serum samples] was >80%.
Determination of clearance from plasma and distribution in
tissue.
Male Wistar rats (weight, between 200 and 350 g) were
used. The animals were anesthetized by intraperitoneal injection of 12 to 20 mg of sodium pentobarbital. To determine the clearance from
plasma, the abdomen was opened and
[3H](S)-HPMPA dissolved in phosphate-buffered
saline was injected via the vena penis. Blood samples of 0.2 to 0.3 ml
were taken from the inferior vena cava at 0.75, 1.5, 5.0, 12.5, 20.0, 27.5, 35.0, and 42.5 min after injection. The samples were collected in
heparinized tubes and were centrifuged at 16,000 × g
for 2 min. The plasma was assayed for radioactivity. The total amount of radioactivity in plasma was calculated by the following equation: plasma volume (in milliliters) = (0.0219 × body weight [in
grams]) + 2.66 (4). Uptake of
[3H](S)-HPMPA by tissues was determined by
excision of the tissues followed by determination of the
tissue-associated radioactivity. Urine was collected from the bladder
at sampling times up to 90 min after injection or from a metabolic cage
at longer times after injection.
Pharmacokinetic analysis.
The clearance of intravenously
injected [3H](S)-HPMPA from plasma was
analyzed by a nonlinear regression program (GraphPad; ISI Software, San
Diego, Calif.). The data were best fit by a two-compartment model. The
distribution volume (V) was calculated by extrapolation of
the elimination curve to time zero. The half-life of elimination
(t1/2) was calculated from the elimination rate constant (kel) by the formula
t1/2 = 0.693/kel. The
total body clearance (CL) was calculated by the formula CL = V × kel.
Determination of the distribution over liver cell types.
Rats were anesthetized and injected with radiolabeled
(S)-HPMPA as described above. Sixty minutes later, the vena
porta was canulated and the liver was perfused with
Ca2+-free Hanks' balanced salt solution containing 10 mM
HEPES (pH 7.4; 8°C) at a flow rate of 14 ml/min. After 8 min, a
lobule was tied off for determination of the total uptake by the liver.
Then, the liver was perfused with 0.05% (wt/vol) collagenase in
Hanks' balanced salt solution containing 10 mM HEPES (pH 7.4), and
parenchymal, Kupffer, and endothelial cells were isolated as previously
described in detail (25). The cell fractions were assayed
for radioactivity and protein (by the method of Lowry et al.
[22] by using bovine serum albumin as the standard).
The contribution of each cell type to the total uptake by the liver
could subsequently be calculated from their contributions to the total
liver protein (92.5, 2.5, and 3.3% for parenchymal, Kupffer, and
endothelial cells, respectively [25]). As found with
other ligands (4, 25), no significant amounts of
radioactivity were lost from the cells during the isolation procedure.
This was checked in each experiment by comparing the calculated uptake
by the liver (i.e., the sum of the contributions of the various cell
types) with the value actually measured in the liver lobule.
Determination of radioactivity.
Radioactivity was counted in
a Packard Tri-Carb 1500 liquid scintillation counter with Emulsifier
Safe or Hionic Fluor scintillation cocktails. TLC scrapings were first
dissolved in 5 M NaOH at 75°C. Tissue samples were processed with a
Packard 306 Sample Oxidizer. Some tissues (e.g., bone) were dissolved
in 10 M NaOH at 95°C.
| |
RESULTS |
Clearance of [3H](S)-HPMPA from
plasma.
To study the clearance of (S)-HPMPA from
plasma, rats received a bolus injection of
[3H](S)-HPMPA and the radioactivity in blood
plasma was monitored. The administered amount, 5 mg/kg of body weight,
is in the range of doses of acyclic nucleoside phosphonates that have
been found to be effective in vivo (14, 22, 28, 30). Figure
1 shows that after an initial rapid
distribution phase (distribution volume, 360 ± 53 ml/kg of body
weight), radioactivity was cleared from the circulation with a
half-life of 11.7 ± 1.4 min (means ± standard errors of the
means [SEMs] for six rats). The total body clearance was 20.9 ± 1.8 ml/min per kg of body weight. Analysis by reverse-phase HPLC and
anion-exchange HPLC performed with plasma samples taken up to 60 min
after injection indicated that >90% of the radioactivity in the
plasma samples represented unchanged (S)-HPMPA.
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FIG. 1.
Clearance of intravenously injected
[3H](S)-HPMPA from plasma. Rats were
intravenously injected with [3H](S)-HPMPA at a
dose of 5 mg/kg of body weight. At the indicated times, blood samples
were taken and the plasma was assayed for radioactivity. Values are
means ± SEMs for six rats.
|
|
Disposition of [3H](S)-HPMPA.
To
study the contribution of various tissues to the clearance of
(S)-HPMPA from the circulation, rats were injected with
[3H](S)-HPMPA, and at 90 min after injection
the distribution of radioactivity over the tissues was examined. In
addition, urine was collected. Table 1
shows that most of the radioactivity (57.0% ± 1.1% of the dose) was
found in the urine. Analysis by reverse-phase HPLC and anion-exchange
HPLC indicated that >95% of the radioactivity in the urine
represented unchanged (S)-HPMPA. In the body, most of the
radioactivity was recovered in the kidneys and liver (29.4% ± 0.8%
and 6.9% ± 0.3% of the dose, respectively). The amounts of
radioactivity in the tissues were also calculated as a percentage of
the amount of radioactivity recovered from the body. Table 1 shows that
kidneys and liver accounted for 68.4% ± 2.5% and 16.1% ± 0.4% of
the radioactivity from the body, respectively. The small amount of
remaining label was evenly distributed over the body. The relative
specific radioactivity of the kidneys was by far the highest. It was
more than 25-fold higher than the relative specific radioactivity of
the liver and even more than 250-fold higher than that of any other
tissue.
The kinetics of the renal and hepatic uptake of (
S)-HPMPA
and its urinary excretion was studied by injecting rats with
[
3H](
S)-HPMPA and monitoring the accumulation
of radioactivity in
the liver, kidneys, and urine (Fig.
2). Radioactivity accumulated
rapidly in
the liver and kidneys, reaching maximal values after
60 min. The amount
of radioactivity in the urine reached its maximum
at 90 min after
injection.
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FIG. 2.
Accumulation of intravenously injected
[3H](S)-HPMPA in the liver, kidney, and urine.
Rats were intravenously injected with
[3H](S)-HPMPA at a dose of 5 mg/kg of body
weight. At the indicated times, the amounts of radioactivity in the
liver ( ), kidney ( ), and urine ( ) were determined. Values are
means ± SEMs for three to four rats.
|
|
Role of liver cells in the uptake of (S)-HPMPA.
The liver contains three highly metabolically active cell types:
Kupffer cells, endothelial cells, and parenchymal cells. To identify
the cell type(s) responsible for the hepatic uptake of
(S)-HPMPA, rats were injected with
[3H](S)-HPMPA. Sixty minutes later,
parenchymal, endothelial, and Kupffer cells were isolated from the
liver and assayed for radioactivity. The results are presented in Fig.
3. The parenchymal cells were found to be
the main site of uptake. These cells accounted for 92.1% ± 3.4% of
the total uptake by the liver, whereas endothelial cells and Kupffer
cells accounted for only 1.8% ± 0.8% and 6.1% ± 3.5% of the total
uptake by the liver, respectively.
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FIG. 3.
Distribution of intravenously injected
[3H](S)-HPMPA over liver cell types. Rats were
injected with [3H](S)-HPMPA at a dose of 5 mg/kg of body weight. Sixty minutes later, parenchymal cells (PC),
endothelial cells (EC), and Kupffer cells (KC) were isolated, and the
association of radioactivity to each cell type was determined. Uptake
by each cell type is expressed as the relative contribution to the
total uptake by the liver. These values were calculated from the level
of uptake per milligram of cell protein and the contribution of each
cell type to the total liver protein (25). Values are
means ± SEMs for three rats.
|
|
Mechanism of hepatic and renal uptake of
(S)-HPMPA.
To study the mechanism of the renal and
hepatic uptake of (S)-HPMPA, rats were preinjected with
probenecid before injection of radiolabeled (S)-HPMPA.
Probenecid is an inhibitor of organic anion transport, and it has been
found that it protects against the nephrotoxicity induced by acyclic
nucleoside analogs (28). Figure
4 indicates that pretreatment of rats
with probenecid substantially reduced (by >75%) the accumulation of
[3H](S)-HPMPA in both the kidneys and the
liver. The amount of [3H](S)-HPMPA that was
not taken up by the kidneys and the liver was quantitatively recovered
in the urine. These findings indicate that a probenecid-sensitive
transporter plays a major role in the uptake of (S)-HPMPA by
both the kidneys and the liver.
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FIG. 4.
Effect of probenecid on the accumulation of
[3H](S)-HPMPA in the kidneys, liver, and
urine. Rats were intravenously injected with
[3H](S)-HPMPA at a dose of 5 mg/kg of body
weight. Thirty minutes prior to injection, the animals received
probenecid (1 mmol/kg of body weight) intraperitoneally. Controls
received an equal volume of solvent (phosphate-buffered saline). At 90 min after the injection of [3H](S)-HPMPA, the
amounts of radioactivity in the kidneys, liver, and urine were
determined. Differences with respect to the controls were tested for
significance by Wilcoxon's two-sample test (35). Values are
means ± SEMs for three to four rats. *, P < 0.05.
|
|
| |
DISCUSSION |
We show in the present study that after intravenous injection into
rats, the acyclic nucleoside phosphonate (S)-HPMPA is
rapidly cleared from the circulation. Excretion into the urine was
found to be the major route of elimination. Most of the
(S)-HPMPA that was retained in the body was recovered in the
kidneys. The renal clearance, calculated from the total body clearance
and the contribution of the kidneys to the clearance, was 18.1 ± 1.5 ml/min per kg of body weight. This value exceeds the values
reported for the glomerular filtration rate in rats (6 to 8 ml/min per
kg), but it is close to those reported for the renal blood plasma flow (20 to 28 ml/min per kg) (13, 20). The key role of the
kidneys in the dispostion of (S)-HPMPA was also observed for
other acyclic nucleoside phosphonates. It has been found in earlier
studies with 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and
(S)-HPMPA that these analogs are extensively excreted in the
urine and that significant amounts of these analogs accumulate in the
kidneys (9, 24). The high level of accumulation in the
kidneys [in the case of (S)-HPMPA, 25 to 250 times higher
levels in the kidneys than in other tissues] probably explains the
nephrotoxicity of acyclic nucleoside phosphonates (6, 28,
31). The liver displayed the second highest level of accumulation
of the acyclic nucleoside phosphonate, and it was found that virtually
all liver-associated (S)-HPMPA was present in parenchymal
cells. The accumulation of (S)-HPMPA in other tissues was
negligible.
Acyclic nucleoside phosphonates need to be internalized to become
pharmacologically active. The mechanisms of internalization of these
compounds have so far not been fully clarified. Some studies have been
performed with cells in culture. Depending on the cell line and the
compound investigated, different mechanisms have been found. A study
with Vero cells indicated that the uptake of (S)-HPMPA by
these cells proceeds via fluid-phase endocytosis (8).
Examination of the uptake of PMEA by HeLa cells, on the other hand,
provided evidence for the involvement of a specific cellular protein
(7). The uptake of PMEA by these cells appeared to be
strictly structure specific, because it could be inhibited only by
itself but not by closely related side chain-substituted compounds,
including (S)-HPMPA. The present in vivo results indicate that uptake of (S)-HPMPA by the two organs mainly involved
in clearance of (S)-HPMPA, the kidneys and the liver, occurs
via a probenecid-sensitive transporter. Both renal proximal tubular cells and parenchymal liver cells are equipped with multiple transport systems that are capable of taking up organic anions, some of which are
susceptible to inhibition by probenecid (29, 33, 34, 36).
These systems mediate the transport of a wide variety of extracellular
organic anions into the cytosol. The molecular nature of the renal
probenecid-sensitive transporter(s) has not yet been clarified.
Recently, a hepatic organic anion-transporting polypeptide has been
cloned and characterized (17, 21, 36). Transport of organic
anions by this protein is inhibited by probenecid (21), and
it may therefore be implicated in the uptake of (S)-HPMPA by
parenchymal liver cells. However, the involvement of other transport
systems in the hepatic uptake of (S)-HPMPA cannot be excluded.
(S)-HPMPA displays broad-spectrum antiviral activity against
several viruses, including hepadnaviruses that cause hepatitis (10). In mice (S)-HPMPA is also active against
the liver stage of the rodent parasite P. berghei
(32), an established murine model for the development of
human malaria. Because both the hepatitis viruses and the
Plasmodium parasites replicate in parenchymal liver cells,
this cell type is a highly relevant target cell for (S)-HPMPA. Unfortunately, we found that only a limited
amount of the (S)-HPMPA administered is taken up by the
liver. The level of uptake by the kidneys was more than 25 times higher
than that by the liver, and the resulting nephrotoxicity precludes the
administration of a therapeutically effective dose to the liver.
Probenecid has been proposed as a drug that can be used to reduce the
nephrotoxicity of acyclic nucleosides (28). Indeed, we found
that probenecid decreases the level of uptake of (S)-HPMPA
by the kidneys (and consequently nephrotoxicity) by >75%. However,
uptake by the liver is reduced to the same extent by probenecid, so
there is no benefit for the treatment of hepatic disease. A much more
effective therapy of diseases associated with parenchymal liver cells
can be achieved if the uptake of (S)-HPMPA by these cells is
increased, with a concomitant reduction of uptake by the kidneys. This
therapeutic goal may be accomplished by associating
(S)-HPMPA with carriers that are specifically taken up by
the parenchymal liver cell. Carriers that can be used for this approach
include several galacose-terminated targeting devices that are taken up
via the asialoglycoprotein receptor (2, 3, 5, 18) and the
recently developed artificial chylomicrons, which are taken up via the
remnant receptor (30).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Division of
Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, P.O. Box
9503, 2300 RA Leiden, The Netherlands. Phone: 31-71-5276038. Fax:
31-71-5276032. E-mail: BIJSTERB{at}CHEM.LEIDENUNIV.NL.
| |
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Antimicrobial Agents and Chemotherapy, May 1998, p. 1146-1150, Vol. 42, No. 5
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
