Download Pharmacokinetics of Hexamethylmelamine in

[CANCER RESEARCH 47, 5070-5073, October 1, 1987]
Pharmacokinetics of Hexamethylmelamine
Administration in Rabbits
in Intralipid following Hepatic Regional
Ian L. Gordon, Rita Kar, Richard W. Opfell,1 and Alan G. Wile2
Departments of Surgery [I. G., R. K., A. G. WJ and Medicine [R. W. O], University of California, Irvine, California 92668
ABSTRACT
Hexamethylmelamine
(HMM) is a cytotoxic agent demonstrated to
have broad antitumor activity. Poor solubility in aqueous media has
precluded significant evaluation of parenteral administration of this drug.
A formulation of HMM dissolved in Intralipid has demonstrated excel
lent tolerance following parenteral administration. The goal of this study
was to evaluate the pharmacology of HMM in Intralipid following hepatic
regional administration. The routes of administration were intraarterial
via the hepatic artery with and without arterial occlusion, i.v. via the
portal and jugular veins, and i.p. All animals received a total dose of 10
mg HMM/kg of body weight. Hepatic extraction of HMM was most
evident via the portal vein (PV) route |AUC(PV)/AUC(i.v.)
= 0.5; P <
0.05). Lower plasma levels and areas under the curve (AUCs) were
observed for the hepatic artery and hepatic artery-stop flow groups when
compared to i.v., but the difference was not significant. Administration
i.p. yielded low plasma levels but a very long half-life (88 min). Hepatic
tissue levels were highest in the group receiving HMM by the hepatic
artery-stop flow route. We conclude that the HMM-Intralipid
mixture
is well tolerated, that HMM is extracted to a significant degree by the
liver following PV administration, and that an i.p. installation of HMMIntralipid results in prolonged plasma drug levels. This preclinical study
supports further efforts at evaluation of parenteral administration of the
HMM-intralipid mixture.
INTRODUCTION
HMM3 is an S-triazine derivative which has been shown to
have clinical antitumor activity against ovarian cancer (1),
lymphoma (2), bladder cancer (3), and small cell lung cancer
(4) and as a component of multiple drug regimens (for review
see Refs. 5 and 6). Although the action of HMM is not
completely understood, it appears to entail W-demethylation
mediated by cytochrome P-4SO. Reactive intermediates are
formed, in particular /V-methylolpentamethylmelamine
(7)
which forms covalent adducts with cellular macromolecules (8,
9). Multiple metabolites of HMM, including PMM and triand tetramethylmelamine, are formed as a result of A^-demethylation and can be detected in plasma after HMM administra
tion (10, 11). A correlation between the degree of methylation
and antitumor activity has been drawn from in vitro and animal
studies, with the most methylated compounds, HMM and
PMM, having the greatest activity (12). It has also been sug
gested that the liberation of formaldehyde by reactive interme
diates is the basis of cytotoxicity of HMM (13).
HMM is poorly soluble in aqueous media except dilute
hydrochloric acid, limiting its use to p.o. preparations. PMM
is sufficiently water soluble for i.v. administration but has
unacceptable gastrointestinal and neurological toxicity (14,15).
It has recently been shown that HMM can be dissolved in 20%
Received 10/17/86; revised 4/13/87. 6/30/87; accepted 7/9/87.
The costs of publication of this article were defrayed in part by the payment
of page charges. This article must therefore be hereby marked advertisement in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1Present address: Penthouse Suite, 425 East 61 Street, New York, NY 10021.
1To whom requests for reprints should be addressed, at 1(1 Medical Center,
Division of Surgical Oncology, 101 City Drive South, Orange, CA 92668.
' I tu' abbreviations used are: HMM, hexamethylmelamine; PMM, pentamethylmelamine; HA, hepatic artery; HA-SF, hepatic artery stop flow; PV,
portal vein; AUC, area under the curve; HPLC, high performance liquid chromatography.
Intralipid, a soybean oil emulsion widely used for parenteral
nutrition, and safely infused i.v. (16). As a consequence phase
I clinical trials with the use of HMM dissolved in Intralipid are
currently under way.4
Our interest in HMM stems from studies in animals showing
a significant first pass hepatic extraction of HMM when ad
ministered via the gastrointestinal tract or portal vein (17). This
study raised the issue of the value of HMM in Intralipid in the
therapy of primary and secondary hepatic cancer by means of
regional administration. If sufficient hepatic extraction of
HMM in the lipid medium could be demonstrated, then this
mixture might have application analogous to the intraarterial
infusion of fluorodeoxyuridine.
Fluorodeoxyuridine
is effi
ciently extracted by the liver (18), providing for the administra
tion of increased amounts of drug and increased activity against
colorectal carcinoma metastatic to the liver compared to sys
temic administration of S-fluorouracil (19, 20).
The goal of this study was to characterize the pharmacokinetics of HMM dissolved in Intralipid and the extent of hepatic
extraction in various modes of regional administration in rab
bits. The routes of administration studied were intraarterial
administration via the hepatic artery with and without arterial
occlusion proximal to the point of infusion, i.v. administration
via the portal and jugular veins, and i.p. instillation.
MATERIALS AND METHODS
HMM was obtained from the Drug Synthesis and Chemistry Branch,
Division of Cancer Treatment, National Cancer Institute, Bethesda,
MD. The HMM was dissolved at a concentration of 3 mg/ml in 20%
Intralipid (Kabivitrum, Alameda, CA) at room temperature and stored
at 4*C. Prior to use this mixture was filtered through Whatman No. 1
filter paper. Quantitative HPLC analysis showed that nearly 100%
dissolved HMM remained in solution.
Female New Zealand White rabbits (3.5 to 4.5 kg) were housed
under standard vivarium conditions. Food and water were withheld for
12 h prior to drug administration. General anesthesia was induced by
the i.v. injection of acepromazine (1 mg/kg; Ayerst Laboratories, New
York, NY), Rompun (5 mg/kg; Cutter Labs, Shawnee, KS), and ketamine hydrochloride (50 mg/kg; Bristol Laboratories, Syracuse, NY). The
right jugular vein was cannulated for the infusion of maintenance fluids.
All animals received a total dose of 10 mg HMM/kg body weight.
Animals undergoing i.v. administration (\ = 5) received drug through
the jugular vein catheter. To accomplish portal vein administration (N
= 5) the proximal superior mesenteric vein was exposed via an abdom
inal incision and cannulated by puncture with a sharply beveled small
caliber polyethylene tube. HA infusion ( v - 4) was achieved by exposing
the celiac artery near its origin from the aorta. Direct puncture with a
beveled polyethylene tube was used to cannulate the common hepatic
artery. During all hepatic arterial infusions a clamp was placed across
the left gastric artery to prevent egress of drug from the hepatic arterial
tree. HA-SF (N = 4) was achieved by occluding blood inflow into the
common hepatic artery with a second clamp proximal to the site of
arterial puncture by the catheter used for drug infusion. Administration
¡.p.(N = 5) was achieved by instilling the drug directly into the
peritoneal cavity through a small midline incision. A syringe pump was
used to deliver the HMM-Intralipid preparation at a constant rate of
4 M. M. Ames, Mayo Clinic, personal communication.
5070
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1987 American Association for Cancer Research.
PHARMACOKINETICS
0.66 ini/min with the average infusion time being 20 min. At the end
of drug infusion for all PV, HA, and HA-SF infusions catheters and
clamps were removed, hemostasis at the puncture sites was achieved
with temporary pressure, and blood was sampled.
Blood samples were obtained via a No. 5 French catheter in the right
carotid artery. Blood was collected in heparinized syringes with volu
metric replacement using isotonic saline. For i.p. experiments, blood
was collected at intervals up to 10 h. For other routes, sampling was
performed at 5 min intervals during infusion and then at intervals up
to 2 h. At the end of each experiment the rabbit was euthanized with
pentobarbital i.v. and the liver was removed for liver tissue drug level
determinations.
Plasma was separated from blood samples in a tabletop centrifuge
and stored at —20°C.
Minced liver specimens were similarly stored.
Drug concentrations were determined by reverse phase HPLC analysis
(21). After thawing, 0.5 ml of the plasma samples was extracted twice
with 1.5 ml of ethyl acetate. The organic layers were combined and
evaporated to dryness under nitrogen, and the residue was dissolved in
0.25 ml methanol. The concentration of HMM in the methanol solution
was analyzed by injection into a HPLC apparatus.
Weighed samples of minced liver were homogenized in 0.15 M
hydrochloric acid (1:6, w/v) in a Polytron tissue homogenizer (Tekmar
Corporation, Cincinnati, OH). After centrifugation for 10 min at 1500
rpm, the supernatant was withdrawn. Three ml of supernatant were
neutralized with 4 M NaOH and then extracted twice with 4 ml of ethyl
acetate. The organic layers were pooled and processed as above. Greater
than 85% recovery of HMM was demonstrated in control experiments
using this technique, in accord with previous reports (22).
A 0.45- x 25-cm dg Econosphere Chromatographie column (Alltech,
Los Altos, CA) was used for HPLC analysis with a Beckman pump
and UV detector system read at 254 nm (Models I IDA and 164;
Beckman Instruments, Fullerton, CA). The solvent used was mei ha
nohphosphate buffer (0.01 M, pH 7.4, with 0.01 M EDTA), 60:40 (v/v)
(8), at a flow rate of 1.1 mi/min. HMM had a retention time of 18 min
and could readily be distinguished from other metabolites. HMM
i)uam nai ion was performed using planimetrie analysis of the area under
the HMM peak with reference to a standard curve. Under these
conditions a lower limit of 0.05 /tg HMM/ml in plasma was detectable.
The terminal half-life and elimination constants were determined from
semilogarithmic plots. Statistical analysis was conducted using Stu
dents' / test.
OF HMM
o IQ
IO
0.1
Eoi
20
40
60
TIME (min)
80
100
120
Fig. 1. Concentration of HMM in plasma for those rabbits undergoing sys
temic (i.v.) infusion of HMM in Intralipid. A slow infusion of the mixture was
administered to avoid acute toxicity. Samples were obtained periodically from the
end of infusion (Eoi). The i.v. group demonstrated the highest peak plasma level
(24.0 Mg/ml) and the largest AUC (423 MgHMM/ml x min). Bars, SD.
10
6
Ì
S
S
; ..o
RESULTS
In general, administration of HMM in Intralipid was well
tolerated. Preliminary experiments using rapid drug infusions
encountered a high incidence of cardiopulmonary arrest similar
to the experience of other investigators (23). Slower infusion
rates were adopted for the remainder of the study.
Figs. 1 to 4 show the plasma concentration versus time plots
for i.v., PV, HA, and HA-SF groups. In general, plasma levels
were near the limit of sensitivity of the HPLC assay or undetectable by 2 h after the end of the drug infusion. Fig. 5 shows
the results of i.p. administration which revealed prolonged but
low plasma levels in comparison to the intravascular routes.
The pharmacokinetic parameters and liver tissue levels for each
treatment group are displayed in Table 1.
Administration i.v. resulted in the highest peak plasma levels
and the largest AUC of any route. In contrast, PV administra
tion yielded the lowest peak plasma level and smallest AUC of
any intravascular route. PV administration resulted in a peak
plasma level 39% and an AUC 50% of the values obtained
following i.v. administration. The 50% decrease in the AUC
represents a 50% hepatic extraction with the PV route when
compared to systemic HMM administration.
Significantly
lower peak plasma levels, approximately 50% that of i.v. admin
istration, were also seen with HA and HA-SF routes. The AUC
measurements for HA and HA-SF were approximately 75% of
01
Eoi
20
40
60
TIME (min)
80
100
120
Fig. 2. Plasma concentration of HMM over time for those animals undergoing
PV intusion. When compared to the i.v. group this group had a lower peak
plasma level (9.8 pg HMM/ml) and the smallest AUC (211 MgHMM/ml x min)
(/' < O.OS)representing significant hepatic extraction. Eoi, end of infusion. Bars,
SD.
the i.v. AUC, representing 25% hepatic extraction, but these
differences were not significant at the 0.05 level.
The distributions of HMM via the i.V., PV, and HA routes
were very similar with peak plasma levels achieved at the end
of infusion and a rapid clearance of drug from circulation with
a terminal half-life of approximately 20 min for all three routes.
This is consistent with a pharmacokinetic model in which the
elimination of HMM is not altered, despite tirsi pass hepatic
extraction once the drug reaches systemic circulation. With
HA-SF administration the peak plasma level is achieved 2 min
after the end of infusion suggesting an accumulation of drug in
the liver with a washout into systemic circulation after the
restoration of arterial inflow. Of interest is the observed de
crease in plasma clearance of HMM with an approximate
doubling of the drug half-life seen with the HA-SF route. This
may represent sequestration of the Intralipid in the hepatic
5071
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1987 American Association for Cancer Research.
PHARMACOKINETICS
OF HMM
•K01
001
0!
Fig. 3. Plasma concentration of HMM over time for those animals undergoing
HA infusion. Although peak plasma HMM concentration was less than that in
the i.v. group (12.8 pg HMM ml: /' < O.OS)the AUC was intermediate (298 *tg
HMM/ml x min) and not significantly different from the i.v. group. Eoi, end of
infusion. Bars, SD.
200
300
400
TIME (min)
500
600
Fig. 5. Plasma concentration of HMM over time for those animals receiving
i.p. infusion. Although plasma concentrations were substantially lower than in
those animals receiving HMM through vascular routes, drug persisted over time
yielding an AUC (216 ^g HMM/ml x min) similar to that observed in groups
receiving intravascular HMM. Bars, SD.
120
40
60
TIME (mm)
100
was seen with the HA-SF and was 2.5 times higher than i.v.
administration results.
DISCUSSION
10
io
§
01
Eoi
20
40
60
TIME (min)
100
120
Fig. 4. Plasma concentration of HMM over time for those animals undergoing
HA-SF infusion. Again peak plasma concentration was less than the i.v. group
(12.9 /ig HMM/ml; r < O.OS)with an intermediate AUC (325 pg HMM/ml x
min). It can be observed that the peak plasma level was reached shortly after end
of infusion (Eoi) following release of the clamp from the hepatic artery. Bars,
SD.
vascular tree with washout of the mixture occurring only after
restoration of blood flow.
Administration of HMM i.p. yielded the lowest peak plasma
level and the longest half-life. The total systemic exposure to
the drug, as measured by the AUC, was reduced approximately
50% when compared to the i.v. AUC. The prolonged half-life
is consistent with the Intralipid acting as a depot within the
peritoneal cavity and prolonged absorption into systemic cir
culation as previously reported with i.p. delivery of HMM in
Intralipid in a murine model (22).
When liver tissue levels were examined, HMM was not
detectable in liver 10 h after i.p. administration, consistent with
the short half-life of the drug in tissue (11). HA-SF, HA, and
PV administration all resulted in higher tissue levels than
systemic i.v. administration, although not significant at the
0.05 level. The highest tissue level, 2.17 /ugHMM/g liver tissue,
The relative insolubility of HMM in aqueous solution has
precluded significant clinical experience with parenteral admin
istration of this drug. Administration p.o. of HMM to rats
resulted in extensive drug metabolism with urinary, biliary, and
fecal excretion accounting for only 0.1 % of the administered
dose (24). This finding suggested that regional administration
of HMM might generate substantial pharmacological advan
tage due to decreased systemic drug exposure. When this po
tential was investigated during portal vein and intraduodenal
administration in rats, HMM was found to be extracted exten
sively by the liver and bowel wall [73 and 71%, respectively
(18)]. The conclusion of this study was that administration p.o.
resulted in very little drug being available to come in contact
with cancer cells residing beyond the liver.
The realization that HMM can be administered in Intralipid
in relatively high drug concentrations per volume of Intralipid
has rekindled enthusiasm for regional administration of HMM.
This would obviate the mucosal degradation of HMM by the
gastrointestinal tract. If sufficient extraction of HMM could be
demonstrated by the liver, then the combination of HMM and
Intralipid when administered in regional manner may be effi
cacious in the treatment of cancer involving the liver. Evalua
tion of the pharmacokinetics in this preclinical model of re
gional chemotherapy was the goal of this project.
It was demonstrated that the greatest extraction of HMM in
Intralipid was only 50% by the PV route when compared to the
i.v. route. Although this difference was statistically significant
it was not the 1- to 3-log difference in extraction as seen with
some drugs when administered regionally to the liver. It is
concluded that hepatic regional administration of HMM would
be only slightly more efficacious than systemic administration
but might not warrant the extra morbidity associated with
regional chemotherapy.
The observation that HMM in Intralipid is stable, is well
tolerated in i.v. infusion, and provides a means of parenteral
administration deserves further attention. In light of the low
bioavailability following administration of HMM p.o. the use
of the lipid vehicle combined with HMM should provide re-
5072
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1987 American Association for Cancer Research.
PHARMACOKINETICS OF HMM
Table 1 Pharmacokineticparametersand livertissuelevelsfor experimentaltreatmentgroups
plasma level
(jig
I24.0
HMM ml
Routei.v.
±4.1°
(N = 5)
1.6 ±1.3*
i.p.(7V=5)
9.8 ±7.1*
PV(JV=5)
12.8 ±8.6*
HA(/V=4)
12.9 ±6.3*AUC
HA-SF (N = 4)Peak
•
Mean ±SD.
* P < 0.05 compared to i.v. route.
tissue level
(MgHMM/g
tissue)0.84
(tigmin)423
HMM/ml x
±92
2 16 ±305
211 ±95*
298 ±205
325 ±144Hepatic
newed enthusiasm for this drug. This enthusiasm should be
further supported by its activity in a variety of malignant
diseases.
The modes of regional chemotherapy utilized in this study
were intended to mimic those approaches in clinical medicine
requiring a direct surgical approach or placement of a catheter
by an interventional radiologist. The HA-SF mode is intended
to provide access to the hepatic arterial tree by a percutaneously
placed balloon-tipped catheter. Inflation of the balloon proxi
mal to drug infusion is intended to retard drug washout. Pre
vious experimental studies with this technique had demon
strated high tissue levels of 5-fluorouracil in a dog hind limb
model (25) and high tissue levels of cisplatin in a rabbit hind
limb model (26). The present study is the initial evaluation of
this mode of therapy in the potential treatment of hepatic
disease. Although the trends toward longer drug half-life and
higher tissue levels were in favor of HA-SF they did not reach
statistical significance. This failure might have been overcome
by enlarging the treatment groups. It is also known that the
liver has a dual blood supply via the portal vein and hepatic
artery. Occlusion of the hepatic artery in the normal liver should
allow for continued perfusion of hepatic parenchyma by portal
venous blood by means of collaterals. This portal venous blood
would remove drug from the hepatic vascular tree. However,
the major blood supply to hepatic tumors is by means of the
hepatic artery with poorly established collaterals from the portal
vein (27). It is possible that HA-SF directed at hepatic cancer
would demonstrate significantly higher tumor levels of drug
than those observed in normal hepatic parenchyma.
Administration of HMM i.p. in Intralipid was included in
this study because it might be used as a means of treating
intraabdominal disease such as ovarian cancer or as a means of
treating hepatic disease. Uptake of the HMM-Intralipid com
bination by the peritoneal surface of the bowel would subse
quently deliver drug to the liver via the portal vein. While
prolonged absorption into the systemic circulation can be dem
onstrated in this model it is unclear whether or not HMM can
be cytotoxic without metabolic conversion. At the present time
this issue remains to be resolved.
REFERENCES
1. Wharton, J. T., Rutledge, F., Smith, J. P., Herson, J., and Hodge, M. P.
Hexamethylmelamine: an evaluation of its role in the treatment of ovarian
cancer. Am. J. Obstet. Gynecol., ¡ÌÌ:
833-844, 1979.
2. Bennett, J. M., Lenhard, R. E., Ezdinli, E., Johnson, G. J., Carbone, P. P.,
and Popcock, S. J. Chemotherapy of non-Hodgkin's lymphomas: Eastern
Cooperative Oncology Group experience. Cancer Treat. Rep., 61: 10791083, 1977.
3. Gad, E. L., Mawla, N., Fergler, J. L., Hamza, R., Elserafi, M., and Khaled,
H. Randomized phase II trial of hexamethylmelamine versus pentamethylmelamine in carcinoma of the bilharzial bladder. Cancer Treat. Rep., 68:
793-794, 1984.
4. Greco, F. A., Richardson, R. L., Snell, J. D., Shoop, S. L., and Olkham, R.
K. Small cell lung cancer—complete remission and improved survival. Am.
J. Med., 66:625-630, 1979.
5. Legna, S. S., Slav ik. M., and Carter, S. K. Hexamethylmelamine: an evalu
±0.22
Not detectable
1.37+ 1.45
1.54 ±1.64
2.17 ±1.87*«•*,
(rain"1)0.0315
0.0079
0.0385
0.0385
0.0182Drug
half-life
(min)22
88
18
18
38
ation of its role in the therapy of cancer. Cancer, 38:27-35, 1976.
6. Hahn, D. A. Hexamethylmelamine and pentamethylmelamine: an update.
Drug Intel!. Clin. Pharm., 17:418-424, 1983.
7. Gescher, A., D'Incaici, M., Fanelli, R., and Farina, P. /V-Hydroxymethylpentamethylmelamine, a major in vitro metabolite of hexamethylmelamine. Life
Sci., 26:147-154,1980.
8. Bonn, P. J. A., Mingels, M. J., Frankhuijzen-Sierevogel, A. C, Von Graft,
M., Hulshoff, A., and Noordhoek, J. Cellular and subcellular studies of the
biotransformation of hexamethylmelamine in rat isolated hepatocytes and
intestinal epithelial cells. Cancer Res., 44: 2820-2826, 1984.
9. ( ¡aratimi.E., Donelli, M. G., Colomiso, T., Paesani, R., and Pantarotto, C.
In vivo and in vitro irreversible binding of hexamethylmelamine to liver and
ovarian tumor macromolecules of mice. Biochem. Pharmacol., 30: 11511154,1981.
10. Leyland-Jones, B. R., Deesen, P. E., Casper, E. S., and Young, C. W. Specific
determination of pentamethylmelamine and its demethylated metabolites in
human plasma by high pressure liquid chromatography. Ther. Drug Monit.,
4:185-190, 1982.
11. Broggini, M., Rossi, C., Colombo, T., and D'Incaici, M. Hexamethylmelam
ine and pentamethylmelamine tissue distribution in M 5076/73A ovarian
cancer bearing mice. Cancer Treat. Rep., 66:127-133, 1982.
12. Ross, D., Langdon, S. P., Gescher, A., and Stevens, M. F. G. Studies on the
mode of action of anti-tumor triazenes and triazines—V. The correlation of
the in vitro cytotoxicity and in vivo antitumor activity of hexamethylmelamine
analogues with their metabolism. Biochem. Pharmacol., 33: 1131-1136,
1984.
13. Rutty, C. J., and Connors, T. A. In vitro studies with hexamethylmelamine.
Biochem. Pharmacol., 26: 2385-2391, 1977.
14. Muindi, J. R. E., Newell, D. R., Smith, I. E., and Harrap, R. R. Pentame
thylmelamine: phase I clinical and pharmacokinetic studies. Br. J. Cancer,
¿7:27-33,1983.
15. Foster, B. J., Claqqett-Carr, K., Hoth, D., and Leyland-Jones, B. Pentame
thylmelamine: review of an aqueous analog of hexamethylmelamine. Cancer
Treat. Rep., 70: 513-516, 1986.
16. Ames, M. M., and Kovach, J. S. Parenteral formulation of hexamethyl
melamine potentially suitable for use in man. Cancer Treat. Rep., 66: 15791581, 1982.
17. Klippen. P. J. M., Hulshoff, A., Mingels, M. J., Hofman, G., and Noordhoek,
J. Low oral bioavailability of hexamethylmelamine in the rat due to simul
taneous hepatic and intestinal metabolism. Cancer Res., 43: 3160-3164,
1983.
18. Ensminger, W. D., Rosowsky, A., Raso, V., Levin, D. C., Glode, M., Come,
S., Steele, G., and Frei, E. A clinical-pharmacological evaluation of hepatic
arterial infusions of 5-fluoro-2'-deoxyuridine and 5-fluorouracil. Cancer Res.,
38: 3784-3792, 1978.
19. Niederhuber, J. E., Ensminger, W., Gyves, J., Thrali, J., Walker, S., and
Lozzi, E. Regional chemotherapy of colorectal cancer metastatic to the liver.
Cancer (Phila.), 55: 1336-1343, 1984.
20. Baldi, C M., I risi. M. M., Soong, S., and McGregor, M. A prospective
phase II clinical trial of continuous I I I)R regional chemotherapy for colo
rectal métastasesto the liver using a totally implantable drug infusion pump.
Ann. Surg., 198: 567-573, 1983.
21. Benvenuto, J. A., Stewart, D. J., Benjamin, R. S., Smith, R. G., and Loo, T.
L. High-performance liquid Chromatographie analysis of pentamethylmela
mine and its metabolites in biological fluids. J. Chromatogr., 222: 518-522,
1981.
22. Wickes, A. D., and Howell, S. B. Pharmacokinetics of hexamethylmelamine
administration via the IP route in an oil emulsion vehicle. Cancer Treat.
Rep., 69:657-662,1985.
23. Legna, S. S., Slav ik. M.. Livingston, R. B., and Carter, S. K. Clinical brochure
on hexamethylmelamine. Investigational Drug Branch, Clinical Therapeutics
and Experimental Pharmacology, National Cancer Institute, 1974.
24. Colombo, T., Broggini, M., Grescher, A., and D'Inalci, M. Routes of elimi
nation of hexamethylmelamine and pentamethylmelamine in the rat. Xeno
biotica, 315-321, 1982.
25. Anderson, J. H., Gianturco, C., and Wallace, S. Experimental transcatheter
mi mark-rial ¡illusion<uvliisii >nchemotherapy. Invest. Radio!., 16:496-500,
1981.
26. Wile, A. G., Kar, R., Cohen, R. A., Jakowatz, J. G., and Opfell, R. W. The
Pharmacokinetics of cisplatin in experimental regional chemotherapy. Cancer
(Phila.), 59:695-700, 1987.
27. Breedis, C., and Young, G. The blood supply of neoplasms in the liver. Am.
J. Pathol., 50:969-975, 1954.
5073
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1987 American Association for Cancer Research.
Pharmacokinetics of Hexamethylmelamine in Intralipid following
Hepatic Regional Administration in Rabbits
Ian L. Gordon, Rita Kar, Richard W. Opfell, et al.
Cancer Res 1987;47:5070-5073.
Updated version
E-mail alerts
Reprints and
Subscriptions
Permissions
Access the most recent version of this article at:
http://cancerres.aacrjournals.org/content/47/19/5070
Sign up to receive free email-alerts related to this article or journal.
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Department at [email protected].
To request permission to re-use all or part of this article, contact the AACR Publications
Department at [email protected].
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1987 American Association for Cancer Research.