ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,
0066-4804/00/$04.00⫹0Ma . 2000, p. 756–759 Vol. 44, No. 3
Copy igh © 2000, Ame ican Socie y o Mic obiology. All Righ s Rese ed.
In a i eal, Re inal, and Cen al Ne ous Sys em Fosca ne
Concen a ions a e Rapid In a enous Adminis a ion o Rabbi s
LUIS F. LO
´PEZ-CORTE
´S,
1
* R. RUIZ-VALDERAS,
1
M. J. LUCERO-MUN
˜OZ,
2
E. CORDERO,
1
M. T. PASTOR-RAMOS,
3
AND J. MARQUEZ
4
In ec ious Diseases Se ice,
1
Depa men o Oph halmology,
3
and Depa men o Neu osu ge y,
4
Hospi al Uni e si a io
Vi gen del Rocı´o, and Pha macy and Pha maceu ical Technology, Facul y o Pha macy,
Uni e si y o Se ille,
2
Se ille, Spain
Recei ed 22 Ma ch 1999/Re u ned o modi ica ion 16 Oc obe 1999/Accep ed 29 No embe 1999
Re inal, i eous humo , b ain, and ce eb ospinal luid (CSF) osca ne le els we e measu ed by high-
pe o mance liquid ch oma og aphy a e adminis a ion o an in a enous dose o 120 mg/kg o body weigh
o 32 pigmen ed abbi s. A pha macokine ic analysis was done using a wo-compa men model. The pene a-
ion a ios, de ined as a ios o e inal, i eous humo , b ain, and CSF a eas unde he concen a ion- ime
cu e om 0 o 2 h we e 110% ⴞ1%, 12.3% ⴞ0.7%, 118% ⴞ1%, and 20.2% ⴞ2.2%, espec i ely. These esul s
sugges a good pene a ion o osca ne in o he e inal and b ain issues, eaching highe concen a ions han
hose es ima ed om i eous humo and CSF le els.
Fosca ne is a d ug used ex ensi ely in he ea men o
e ini is and neu ological condi ions caused by cy omegalo i-
us (CMV) in pa ien s wi h AIDS, and he e a e da a suppo -
ing he use o osca ne wi h aciclo i o ganciclo i in he
ea men o e ini is caused by o he he pes i uses (4, 15, 19).
I has been sugges ed ha in a enous ganciclo i o osca ne
main enance he apy o CMV e ini is may esul in sub he a-
peu ic in aocula concen a ions, a ac o implica ed in he
p og ession o his disease (1). Howe e , he e a e ew da a on
concen a ions o osca ne in issue, and he le els in e ina o
b ain ha e no been desc ibed o ei he humans o expe i-
men al models. The in aocula pene a ion o osca ne has
been assessed only in i eal samples om a ew pa ien s wi h
CMV e ini is (1). Likewise, he pene a ion o osca ne in o
he cen al ne ous sys em has been e alua ed only om single
de e mina ions in ce eb ospinal luid (CSF) and single a ios
o concen a ions in CSF o concen a ions in plasma in sam-
ples ob ained a a iable and a bi a y in e als om pa ien s
wi h nonuni o m dosages. Consequen ly, he esul s ha e been
e y a iable, 13 o 340% o he simul aneous concen a ion in
plasma (11, 21–23). Mo eo e , o assume ha e inal and b ain
osca ne le els a e simila o hose measu ed in i eous hu-
mo and CSF may be e oneous. Due o he di icul ies in
ob aining issue samples om humans, we used a abbi model
o e alua ing he e inal and b ain pene a ion o osca ne
a e i s in a enous adminis a ion. The a ios o he a eas
unde he concen a ion- ime cu e (AUCs) o issues and
CSF o he AUCs o se um we e used o ob ain mo e accu a e
esul s (16). We ha e also de e mined whe he he concen a-
ions de ec ed in e ina and b ain a e simila o hose in i e-
ous humo and CSF. In humans, no signi ican di e ences we e
obse ed in plasma concen a ions be ween single- and mul i-
ple-dose adminis a ion (25); he e o e, he s udy was designed
o ob ain samples a e a single dose o he d ug.
S udy design, d ug adminis a ion, and sampling. Thi y-
wo heal hy, pigmen ed abbi s wi h a mean weigh o 3 kg
we e used. The s udy was conduc ed acco ding o he Minis-
e io de Ag icul u a guidelines. A e animals we e anes he-
ized wi h an in amuscula injec ion o xylazine (12 mg/kg o
body weigh ) and ke amine (60 mg/kg), a jugula ein was
ca he e ized by a su gical p ocedu e and main ained as pe -
meable by a 0.9% saline solu ion-lock echnique. The en i e
expe imen s we e conduc ed unde su gical anes hesia. Each
abbi ecei ed 120 mg o osca ne (As a Pha maceu ical,
So¨de a¨lje, Sweden) pe kg, as an in a enous dose o e a
3-min pe iod, since his is a usual dose in humans du ing he
main enance ea men o CMV e ini is in pa ien s wi h
AIDS. Blood (2 ml) was aken be o e and a 5, 15, 30, 45, 60,
75, 90, and 120 min a e he end o in usion. Re ina, i eous
humo , b ain, and CSF samples we e ob ained a 30 and 90
min and 60 and 120 min, so ha each animal yielded issue
da a o wo di e en ime poin s, be o e being eu hana ized
wi h in a enous pen oba bi al. Vi eous humo was ob ained
by cu ing he eyes jus behind he lens (mean olume ob-
ained, 638 ⫾184 ␮l); a e wa ds, he e ina was ca e ully
dissec ed (mean weigh ob ained, 49.3 ⫾13.5 mg). B ain issue
was ob ained h ough a small c aniec omy (mean weigh ob-
ained, 596 ⫾169 mg), and CSF was ob ained by punc u e o
he cis e na magna (mean olume ob ained, 528 ⫾193 ␮l).
A e cen i uga ion, plasma and CSF samples we e s o ed a
⫺80°C un il es ing. Be o e being ozen, i eous humo and
e inal and b ain issues we e sonica ed a 0.5 cps o 40 s
(50-W sonica o ; Sonics & Ma e ials Inc., Danbu y, Conn.).
Fo p ocessing, each sample was ans e ed o a mic opa i-
ion ube (Cen icon 30; Amicon Inc., Be e ly, Mass.) and
cen i uged a 1,500 ⫻g o 20 min.
Assay p ocedu e. Concen a ions o osca ne we e de e -
mined acco ding o he modi ied me hod o Pe e sson and
No dg en (20), using a high-pe o mance liquid ch oma o-
g aph wi h an elec ochemical de ec o (Gilson Medical Elec-
onics, Inc., Middle on, Wis.). The analy ical column (125 by
4 mm [inside diame e ]) was a Lichosphe 100 RP-18 wi h
5-␮m pa icles (Me ck, Da ms ad , Ge many). The olume
injec ed was 20 ␮l, and he low a e was 0.7 ml/min. Quan i-
ica ion was based on measu ing s anda d solu ions o osca -
ne (As a Pha maceu ical) in 0.9% (w / ol) NaCl solu ion and
hyd ochlo o hiazide as he in e nal s anda d. The de ec ion
limi was 10 ␮g/ml. Calib a ion lines we e linea (
xy
⬎0.9000)
o e a ange o 10 o 1,200 ␮g/ml. An analysis o a iance was
* Co esponding au ho . Mailing add ess: Se icio de En e -
medades In ecciosas, Hospi al Uni e si a io Vi gen del Rocı´o, A da.
Manuel Siu o , s/n. 41013, Se ille, Spain. Phone: 34-5-4248265. Fax:
34-5-4248184. E-mail: [email p o ec ed].
756
on July 31, 2017 by USE/BCTA.GEN UNIVERSITARIAh p://aac.asm.o g/Downloaded om
ca ied ou o de e mine in e assay [F(1–27) ⫽0.84; P⫽
0.5343] and in a-assay [F(1–37) ⫽0.72; P⫽0.6692] a iabil-
i y; no s a is ically signi ican di e ences we e obse ed be-
ween hem. The in a- and in e assay coe icien s o a ia ion
we e 1 and 1.7%, espec i ely. Reco e y o osca ne om
plasma, e ina, i eous humo , b ain, and CSF, a e adding
known concen a ions o osca ne o hem, was 86, 82.7, 79.8,
84, and 94.8%, espec i ely.
Pha macokine ic analysis. Compa men al pha macokine ic
pa ame e s we e calcula ed om he concen a ion- ime cu e
da a (12). The co esponding mac ocons an s we e calcula ed
om he biexponen ial equa ion Cs
⫽A
0
e
⫺␣
⫹B
0
e
⫺␤
, whe e
Cs
is he concen a ion o he d ug in se um a ime .A
0
and
B
0
, and ␣and ␤, a e he in e cep s and exponen s, espec i ely,
o he wo exponen ial phases. Twen y da a pe ime poin
we e used o de e mine he se um pha macokine ic pa ame-
e s, which we e calcula ed manually, and 8 o 10 da a o each
issue pe ime poin we e used. The AUC om0h oin ini y
(AUC
0–⬁
) was calcula ed up o he ime o he las quan i iable
se um concen a ion using he apezoidal ule and hen o
in ini y using he quo ien o he las measu able concen a ion
o he e minal-phase a e cons an , which was calcula ed by
he abo e-men ioned cu e i ing. Resul s we e exp essed pe
millili e , assuming issue densi ies as 1. The pene a ion a io
was de ined as he a io o he AUC
0–2
o issues and CSF o
he AUC
0–2
o se um.
Resul s. Figu e 1 shows he mean se um and issue concen-
a ion- ime cu es a e he in a enous adminis a ion o os-
ca ne (120 mg/kg). The da a i ed o a wo-compa men
model, he equa ion being Cs
⫽0.49e
⫺10.02
⫹0.382e
⫺0.636
.
The p o ile clea ly shows he wo dis inc phases associa ed
wi h a wo-compa men model. The ␣phase is basically he
apid dis ibu ion o he d ug (A/␣⬍B/␤), while he ␤phase
is basically i s elimina ion, a e eaching he s a iona y equi-
lib ium s a e. Fosca ne has a apid disappea ance om se um
wi h a mean ␣-phase hal -li e o 0.065 ⫾0.001 h and a ␤-phase
hal -li e o 1.09 ⫾0.26 h. Table 1 summa izes he alues o he
pha macokine ic pa ame e s o osca ne ob ained wi h his
model.
High le els o osca ne we e ound in e ina and b ain, wi h
AUC
0–2
o 532 ⫾183 and 574 ⫾202 ␮g䡠h/ml, espec i ely.
Pene a ion in o bo h he e ina and he b ain was ema kably
high, wi h es ima ed pene a ion a ios o 110% ⫾1% and
118% ⫾1%, espec i ely. Lowe le els o osca ne we e ound
in i eous humo and CSF, wi h AUC
0–2
o 59.7 ⫾23.0 and
93 ⫾1.8 ␮g䡠h/ml and pene a ion a ios o 12.3% ⫾0.7% and
20.2% ⫾2.2%, espec i ely.
Discussion. In his model, he es ima ed dis ibu ion ol-
umes sugges ha osca ne is a d ug widely dis ibu ed in
di e en o gans, as deduced om he equa ion V
ss
/V
c
⫺1⫽
0.96 (12), whe e V
ss
is olume o dis ibu ion a s eady s a e
and V
c
is olume o dis ibu ion in cen al compa men , in
spi e o a sho biological hal -li e in bo h ␣and ␤phases. Ou
da a show ha osca ne has a good pene a ion in bo h e inal
and b ain issues, eaching le els a abo e he 50% inhibi o y
concen a ion (120 ␮g/ml; ange, 7.5 o 240) o mos s ains o
FIG. 1. Mean (⫾s anda d de ia ion; mic og ams pe millili e ) se um and issue concen a ion- ime cu es a e an in a enous dose o osca ne (120 mg/kg).
VOL. 44, 2000 NOTES 757
on July 31, 2017 by USE/BCTA.GEN UNIVERSITARIAh p://aac.asm.o g/Downloaded om
human CMV (7). Fosca ne is a e y small and highly nega-
i ely cha ged molecule, wi h a p o ein binding le el o 15%
and wi h an o ganic/wa e pa i ion coe icien o 0.426 (3).
These physicochemical p ope ies would acili a e i s di usion
h ough he blood-b ain and blood- e inal ba ie s (17). These
high a ios may also be due o a slowe elimina ion om e ina
and b ain han om se um, so ha he a io o d ug concen-
a ions in hese issues and se um inc eases wi h ime a e
in usion, as equen ly occu s wi h o he d ugs (13, 16). How-
e e , he concen a ions and AUC
0–2
obse ed in he i eous
humo a e much lowe han hose in he e ina. Thus, he
e inal concen a ions eached a e he in a enous adminis-
a ion o osca ne canno be es ima ed om hose obse ed
in he i eous humo .
In he same way, le els o osca ne in CSF a e lowe han
hose obse ed in b ain. CSF d ug concen a ions a e e-
quen ly lowe han hose o he ce eb al ex acellula luid and
he b ain issue, o e all when CSF is ob ained om en icles
o he cis e na magna (6, 18, 26). Howe e , he p esence o an
AUC in he b ain six old highe han ha in he CSF sugges s
ha , a leas in his animal, he e may be a high e lux clea ance
o osca ne om CSF. This could be p oduced ia he a ach-
noid illi and nona achnoidal CSF d ainage pa hways (c ibi-
o m a ea, o bi al a ea, and inne ea ) p esen in he abbi and
o he lowe mammals (8, 15). In addi ion, as osca ne is a
weak acid (9), he e could be an ac i e e lux om he CSF, as
occu s wi h o he weak o ganic acid d ugs (5).
Al hough he in a i eal le els o osca ne obse ed in he
pa ien s s udied by A e alo e al. (1) we e simila o hose we
ha e ound in abbi s, i is di icul o know whe he ou da a
a e en i ely applicable o humans since he ew epo ed pha -
macokine ic s udies o osca ne in humans ha e been ca ied
ou wi h he e ogeneous doses, a es o pe usions, and pha -
macokine ic analyses. I would be expec ed ha he concen-
a ions o osca ne in hese issues would be simila o o
highe han hose obse ed in abbi s, since in humans he V
ss
o osca ne is highe and he hal -li e is longe han hose in
abbi s (2, 24, 26).
F om ou s udy, i canno be uled ou ha he cu en
dosages o osca ne du ing he main enance phase o CMV
e ini is (90 o 120 mg/day, in a single dose) gi e ise o sub-
he apeu ic concen a ions in he e ina du ing pa o he day
and ha his may be a ac o in he p og ession o he disease.
Ne e heless, ou esul s show ha osca ne pene a es well
in o he e ina and b ain issue, eaching highe concen a ions
han hose es ima ed om i eous humo and CSF.
This wo k was suppo ed by g an SAF97-0012 om he Comisio´n
In e minis e ial de Ciencia y Tecnologı´a, by g an 64/96 om he
Conseje ı´a de Salud, Jun a de Andalucı´a, and by As a S.A., Spain.
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TABLE 1. Pha macokine ic pa ame e s o osca ne a e
in a enous adminis a ion o 120 mg/kg o abbi s
Pa ame e (uni e)
a
Value
(mean ⫾SD)
Concn (␮g/ml)
0 h...................................................................................... 872 ⫾120
Maximum in pe iphe al compa men .......................... 343 ⫾92
A
0
....................................................................................... 490 ⫾45
B
0
........................................................................................ 382 ⫾75
Phase (h
⫺1
)
␣.........................................................................................10.02 ⫾0.24
␤.........................................................................................0.636 ⫾0.12
1/2
(h)
␣.........................................................................................0.065 ⫾0.001
␤......................................................................................... 1.09 ⫾0.26
ss
(h)...................................................................................... 0.37 ⫾0.078
V(ml/kg)
V
c
........................................................................................137.6 ⫾22
V
p
.......................................................................................132.4 ⫾14.2
V
ss
....................................................................................... 270 ⫾37
CL (ml/kg/min)..................................................................... 2.86 ⫾0.91
k(h
⫺1
)
k
1–2
..................................................................................... 4.57 ⫾0.01
k
2–1
..................................................................................... 4.47 ⫾0.12
k
el
....................................................................................... 1.34 ⫾0.2
AUC (␮g䡠h/ml)
AUC
0–2
.............................................................................. 484 ⫾166
AUC
0–⬁
............................................................................. 649 ⫾38
a
1/2
, hal -li e;
ss
, ime in s eady s a e; V
c
,V
p
, and V
ss
, olume o dis ibu ion
in he cen al o pe iphe al compa men o a s eady s a e, espec i ely; CL,
clea ance; k, a e cons an ; k
el
, elimina ion a e cons an .
758 NOTES ANTIMICROB.AGENTS CHEMOTHER.
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