close

Вход

Забыли?

вход по аккаунту

?

Influence of [6S]-N5 -Formyltetrahydrofolic Acid on the Bioavailability of 5-Fluorouracil Combined with Interferon-╨Ю┬▒-2b.

код для вставкиСкачать
373
Formyl-THF, 5-Fluorouraci1, and Interferon-a-2b
Influence of [6S]-N5-FormyltetrahydrofolicAcid on the Bioavailability
of 5-Fluorouracil Combined with Interferon-a-2b
EinfluB von [6S]-N5-FormyltetrahydrofoMureauf die Bioverfiigbarkeitvon 5-Fluoruracil in Kombination mit
Interferon-a-2b
Martin J. Czejkaa'*,Johann SchiilleP),and Ulrike Foglb)
a)
b)
Institute for PharmaceuticalChemistry, University of Vienna, W&ngersuasse 10, A-1090 Vienna, Austria
1'' Medical Department, KrankenanstaltRudolfstiftung,Juchgasse 23, A-1030 Vienna. Austria
Received January 20,1992
The coadministration of interferon-a-2b (2) to 5-fluorouracil (l),a well established antineoplastic agent'), has been
found to improve the tumor response-rate of 1 combined
with a statistically significant change of the pharmacokineThe triple combination of 1and 2 with the biomodulating agent folinic acid ([6RS]-N5-formyltetrahydrofolic
acid), however, neutralizes the effect of 2 on the pharmacokinetics of 14! As folinic acid is administered in its racemic
form whereby the [6S]-enantiomer is the active species of
the drug, we performed a second clinical trial with [6S]folinic acid (3) to check whether this effect is based on the
[6S]- or on the [6RS]-form.
40
-I
30
-
20
-
10
-
-
1
0: .OH
0
ij
I
I
I
I
I
T
20
40
60
80
100
120
time Iminl
Mean plasma concentration-timecurve of 1without (0).under the influence
of 2 (0)and in combination with 2 + 3 (m)
1
As can be seen from the figure, the mean plasma concentration-time curve of 1 is elevated distinctly under the influence of 2, whereby the initial plasma concentration of 1
rises from 34.5 k 7.6 pdml to 52.6 +- 12.7 pglml when 2 is
preadministered (p < 0.008). The additional coadministration of 3, however, almost abrogates the effect of 2 on the
pharmacokinetics of 1 (cg = 39.9 & 8.6 pdrnl).
The bioavailability (expressed as AUC-values) is increased by 2 at about 65 % (p < 0.003). The change of the
pharmacokinetic parameters caused by 2 (table) can be ob
served for the volume of distribution (- 34 %) and the total
body clearance (- 60 %). Anova analysis of variance revealed that these changes of the parameters of 1are statistically significant. The half life of the terminal elimination
from the blood is not influenced at all neither by 2 nor by 3.
The triple combination 1 + 2 + 3 causes no significant difference of the pharmacokinetics of 1 in comparison to the
control group.
The present results indicate that the effect of folinic acid
might be caused by its [6S]-enantiomer, as the percentual
Arch. Pharm. (Weinheim) 325.373-374 (1992)
change in the pharmacokinetic parameters is in the same
order of magnitude as with the racemat4).Furthermore, the
mechanism of action of 2 and 3 might be different: no
multiplication of efficacy but an opposite effect was observed.
Experimental Part
Patients
The study was carried out on eight patients, suffering from gastrointestinal cancer with liver metastases (2 hepatoma, 6 colorectal). The patients
were informed about the purpose of the trial and had given their permission. Their mean age was 61.5 years (range 51-69) and their mean body
mass was 65.3 kg (range 57 to 103).
Drugs and administration
[6S]-N~-f01myltetrahydrofolic
acid (3): Ebewe Pharmaceuticals (Unterach, Austria).- 5-Fluorouracil-Roche (1)and Roferon-Roche (2): Hoffmann
La-Roche AG (Vienna, Austria). In a course of repeating cycles of chemotherapy 1 was given as a rapid intravenous bolus (750 mp/m2) in the
first cycle, after a rest of two weeks 1 with preceeding subcutaneous doses
of 9 million units 2 (three times weekly), and in the third cycle 1 was given
after 2 as in the second cycle, but in combination with a 30 min infusion of
3 (200 mg/m2 in isotonic sodium chloride solution).
OVCH VerlagsgesellschaftmbH, D-6940 Weinheim. 1992
0365-67-33192/0606-0373$3.50 + .25/0
34.5 k 7.6
661 k 159
13.3 k 5.8
52.6 k 12.7
1108 -+ 156
14.7 -I 6.2
39.9 -+ 8.6
877 k 308
15.5 k 4.7
Ckot
37.3 5 19.4
1.95 t 0.83
24.6 f 6.1
1.16 f 0.27
32.7 2 13.5
1.47 5 0.57
cd
0.86 k 0.53
0.46 k 0.26
0.77 5 0.48
CO
AUCtot
t1/2e1
Vd
<> 1+2
1 <> 1+2+3
1+2 <> 1+2+3
=0
0.0008+)
0.05
NS
AUCO- 120
Anova analysis
_1.
tl/24
0.0003
NS
Vd
0.02
Cltot
0.04
Cd
NS
NS
NS
NS
NS
NS
0.002
NS
NS
NS
NS
.........................................................
-_----___-__________-----------------------------------*) . .. . . p-values (level of probability)
NS . . . . not significant
Co . . . . initial plasma concentration of 1 [bg/ml]
AUC . area under the concentration-timecurve for the first 120 min [pg/ml. min]
Vd . . . . volume of distribution [l]
Clot . . total body clearance [Vmin]
cd . . . . coefficient of distribution [lkg]
.
Samples
Blood samples of 5 ml were collected from the cubital vein at 0, 5, 10,
15,30,45,60,90, and 120 min after administration of 1 in sodium-citrate
impregnated tubes, centrifuged for 5 min at 6000 RpM (Biofuge B,
Haereus Christ, Vienna, Austria) and frozen at -3OOC until analysis.
Assay of 1
1was quantified in the plasma samples by HPLC as described5).
Calculations
Pharmacokineticcalculations were performed on a AT386 (program PCNonlin 3.1), statistics (Anova variance analysis) were calculated on a Atari
MegaST (program Wistat).
References
1
2
3
4
5
M.I. Antilla, E.A. Sotaniemi, M.I. Kairaluoma, R.E. MokJca, and H.T.
Sundquist, Cancer Chemother. Pharmacol. 10, 150 (1983).
H. Hanaue, T. Kurosawa, S. Miyakawa, F. Hone, A. Nemoto, S. Nishimura, H. Yamoto, H. Vasuda, T. Asagoe, T. Miura, T. Ta-Keda, and
J. Shikat, Jpn. J. Cancer Res. 76,1230 (1985).
M. Czejka, J. Schiiller, U. Fogl, and C. Weiss, Pharmazie 46, 817
( 1991).
M. Czejka, W. Jager, J. Schiiller, U. Fogl, and G. Schemthaner, Arzneim. Forsch.41,860(1991).
W. Jager, M. Czejka, J. Schiiller, U. Fogl, H. Lackner, and E. Czejka,
J. Chromatogr. Biomed. Appl. 532.41 1 (1990).
[KPh578]
Arrh. Pharm. (Weinheim) 325.373-374 11992)
Документ
Категория
Без категории
Просмотров
3
Размер файла
146 Кб
Теги
acid, combined, fluorouracil, formyltetrahydrofolic, bioavailability, influence, interferon
1/--страниц
Пожаловаться на содержимое документа