YAKUGAKU ZASSHI 125(2) 197\203 (2005) 2005 The Pharmaceutical Society of Japan

197

\Regular Articles\

tFm[LiSp\I@
c Fa
M`C
,a gxqCa RMqCa eNCb C

Simple Method for Precognition of Drug Interaction between Oral Iron and
Phenolic Hydroxyl Groupcontaining Drugs
Nobuyoshi SUNAGANE,,a Etsuko YOSHINOBU,a Nobuko MURAYAMA,a Yasufumi TERAWAKI,b
Naoki KAMIMURA,c and Tsutomu URUNOa
Faculty of Pharmaceutical Sciences, Tokyo University of Science (RIKADAI),a 2641 Yamazaki, Noda City 278_8510,
Japan, Kirishima Citizens' Pharmacy,b 3_22_17 Chuo, Kirishima City 899_
4332, Japan, and
Fujimidai Pharmacy,c 2_18_7 Fujimidai, Kunitachi City 186_0003, Japan
(Received September 10, 2004; Accepted November 10, 2004)
In the present study, we devised a simple method for detecting the drug interaction between oral iron preparations
and phenolic hydroxyl groupcontaining drugs, using the coloring reaction as indicator, due to the formation of com
plexes or chelates. In the method, oral iron preparations and test drugs in amounts as much as single dose for adults were
added to 10 ml of puried water to make sample suspensions for testing. Thirty minutes after mixing an oral iron sus
pension and a test drug suspension, the change of color in the mixture was observed macroscopically and graded as 0 to
3, with a marked color change judged as grade 3 and no color change as grade 0. Screening of 14 test drugs commonly
used orally was carried out. When using sodium ferrous citrate preparations as oral iron, 5 were classied as grade 3, 2 as
grade 2, 4 as grade 1, and 3 as grade 0, respectively. To verify usefulness of the method, the interactions suggested by
screening were pharmacokinetically assessed by measuring serum concentrations of the drug in mice. When a levodopa
or droxidopa preparation, judged as grade 3 in screening, was concomitantly administered with an iron preparation, a
signicant reduction in bioavailability of the test drug was observed, indicating possible drug interaction between the test
drug and oral iron. Combined administration of an acetaminophen preparation, judged as grade 1, and oral iron prepa
ration showed no inuence on the bioavailability of the test drug, implying no detectable interactions between them. In
conclusion, the simple method devised in the present study is useful for precognition of drug interactions between oral
iron preparations and phenolic hydroxyl groupcontaining drugs, and the drugs with a higher grade in screening may in
duce drug interactions with oral iron.
Key words\\drug interaction; oral iron; phenolic drug; levodopa; droxidopa

@p@

iJCmp
\CK@s
LplD

Dpp

SX`

C@QC

wIpDCegTCN

p@pdvv

nRj[LmnRS

DpCiYt

pCL[g`Cz

|{CYt

jQmD1,2) tFm[

p\CL

_LCSCI`

pDp\

mCtFm[_L

awwwCbsC
cxm
email: sunaganers.noda.tus.ac.jp

iCSp`C
pDC
D

198

Vol. 125 (2005)

tFm[_LS`
CFom

12.

@pi

DFCtFm[_L

@ 14 tFm[_L

ioS`wW

iyegTCNspD

\zDCFwW

AZgA~mtFiJi[CaHjC

tFm[_LiS

ALVViTVCjC_C\v

pL\l

iiC\j[CjC_G`t

iGz`[C{x[K[jC_x^

{CoStFm[_L

[igf[gCON\EX~XNC

ipp\o

jCT]Xt@sWiT]sCO

XN[jO@CtFm[_

Hj
ChLVhpihvXCZFjCqN

LS`F

iqR[CLbZCjCtvsIiRXp

wWXN[jO@CtF

mCG[UCj
CTWiy^TCjC

m[_Lior

`hpiAhbgCLjC_Tu^

Ipi 14 sp

[ixlgCOjC_eu^

@{DCXN[j

iuJj[CAXg[lJjC{hpi}h

O@oC}EX

p[FxZWhCOClVbgFJ

Zxp]

rhpCLjy_f`Neg

C@LpD

TCN
i_}CVC{CX_[jD

1.

CSNG_SigE
itF~ACG[UCjy_SitFE
OfbgC{jpC_S

P i`UC

FCFQl

CJvZeC

Ci_SU7 aj

`pD

11.

Q el 1 pCe 15 ml

2.

C10 ml CU

21.

Zx

4 T ddY nY}EX

CtDCn

pDJn 2 OH}EX

lCsn

iP^QiS

pDSlD

^Q 2 QCeQ

R 2 tiySj 5 ml

5 CpD

CCUD

22.

o^

iC

cet 5 ml

CJvZeCC

tD

C 3CMC tC}

S t 30 nCt

EXd 10 g 0.1 ml o^D

tF@CF 4

i^Cqgl 1

iKO[hiO[h 0\3j]

pWdikgjld

^ZC^

O[h 0FF

HPLC oEl}E

O[h 1FFx

X^ZoD{hpChLVhpCA

O[h 2FXisF

ZgA~mtFC

O[h 3FF

50 mg/kgC30 mg/kgC50 mg/kg Dp

S^CSp

No. 2

199

l 1 ^v

uxviFP_920C{jpC

^D

Ng 282 nmCug 322 nm sD

^e

AZgA~mtFZxCBrunner

G[e}EXJC

@4) C_ pH 2.2

D{hpi}hp[GxZW

0.05 mmol/l _igEFAZgjg

hj^Q^ 10C15C20C60 C

i95F5jntpC1.0 ml/min x

hLVhpihvXj^QC10C20C40C

oDAZgA~mtFoCO

60C90 CAZgA~mtFiJi[j

xviSPD_10CjpCg

^QC5C10C15C30C40

254 nm xsD

23.

Tv@

Dt

25.

f[^Cl}W

2\3 { 0.5 mol/l f_CS

iS.E.jDP^Q^Qe

^pNCu

{hpCyAZgA~mt

tB^[ HPLC pTvD

FZxl Student ttest

CAZgA~mtFp

pCp0.05 LD

WeItB 10 mg/ml

CZxiAUCjC

`@pD

24.

HPLC

HPLC C HPLC

u i LC _10AT C jC ODS J
1.

iSenshu PakjpD
{hpChLVhpZxC

XN[jO

{@

ICiYtS

OSAi2~

pL[g`p

mol/lj

\LegTCNi_}

C|_ pH 3 0.025 mol/l |_ig

CVjy{@p

EF^m[i92F8jntpC0.9

XN[jOsDNG_SigE

ml/min xoDoC

itF~Aj

Betto
10|4

@3) C

mol/ljCEDTAE2Nai3~10|4

Table 1.

Grades of Coloring Reaction after Mixing Oral Iron Suspension with Test Drug Suspension

NG_SigEp

_Sp

_C\viiF)
hLVhpiF)
TWiZF)
`hpiF)
{hpiF)

_C\viiF)
_x^[iF)
hLVhpiDF)
TWiF)
`hpiF)
{hpiF)

Grade 2

_x^[iF)
tvsIiZF)

tvsIiF)

Grade 1

AZgA~mtFiF)
_G`tiqo)
T]Xt@sWiF)
qNiF)

_G`tiWF)
T]Xt@sWiF)
qNiF)

ALVV
_Tu^[
_eu^

AZgA~mtF
ALVV
_Tu^[
_eu^

Grade 3

Grade 0

JbRFD

200

Vol. 125 (2005)

Fig. 1. Coloring Reaction after Mixing Oral Iron (Sodium

Ferrous Citrate) Preparation with Tetracycline (Demethyl
chlortetracycline Hydrochloride) Preparation (A) or Tea
(B)

Left: oral iron suspension, middle: mixed suspension, right: tetracycline

suspension (A) or tea (B).

Fig. 1 CegTCNnty
SntF
C{XN[jOO[h 3
D
qtFm[_Li
oppCp
l 14 iX
N[jOsDSNG_S
igEitF~Ajp
Table 1 vDiA
LVVC_Tu^[C_eu^
3 OCxF

Fig. 2. Coloring Reaction after Mixing Oral Iron (Sodium

Ferrous Citrate) Preparation with Levodopa Preparation
(A), Droxidopa Preparation (B) or Acetaminophen Prepa
ration (C)

Left: oral iron suspension, middle: mixed suspension, right: test drug
suspension.

No. 2

201

{@zCC{hp
ixZWhCJrhpjC`h

Table 2. Pharmacokinetic Parameters of Levodopa in Mice

after Ingestion of Levodopa Preparation with or without
Oral Iron (Sodium Ferrous Citrate) Preparation

pChLVhpCTWCC\vi
5 CFO[h 3 C

P^Q

NG_S
igEpQ

15

15

_x^[CtvsI 2 O[

Tmax (min)

h 2 Cc 4 iAZgA~mtFC_G`

C 20 min (mg/ml)

14.9}0.7(n5)

10.1}1.1(n5)

tCT]Xt@sWCqN

AUC060
(mg ml|1/min)

732.1

569.9

jO[h 1 DFigure 2
CO[h 3 {hpixZWh
jChLVhpyO[h 1 AZg
A~mtFDS
_SpypC

: p0.05

Table 3. Pharmacokinetic Parameters of Droxidopa in Mice

after Ingestion of Droxidopa Preparation with or without
Oral Iron (Sodium Ferrous Citrate) Preparation

pFfnotF

P^Q

NG_S
igEpQ

40

20

C 40 min (mg/ml)

4.9}0.5(n5)

2.3}0.3(n5)

_SNG_SigEp

C 60 min (mg/ml)

4.4}0.3(n5)

1.7}0.1
(n5)

CiFF

AUC090
(mg ml|1/min)

342.2

198.9

FDpXN[jO
\CFm
p\iTable 1jD

CO[hF
CXN[jO
vD
2.

Zx

{hpi50 mg/kgjP

^C{hpZxC^ 15

Tmax (min)

: p0.05

Table 4. Pharmacokinetic Parameters of Acetaminophen in

Mice after Ingestion of Acetaminophen Preparation with or
without Oral Iron (Sodium Ferrous Citrate) Preparation
P^Q

NG_S
igEpQ

12.8}0.5(n5)

16.1}3.3(n5)

290.9

314.5

BC60 xZx
D{hpNG_Sig
E^C{hp\
ZxCP^
C20 {hpZxSp

Tmax (min)
C 5 min (mg/ml)
AUC040
(mg ml|1/min)

LD{hp}EX
p[^[ Table 2 C
{hpP^Q AUC NG_S

CAZgA~mtFZxC^ 5

igE^Q AUC 22D

ZxBC 40

hLVhpi30

mg/kgjP^C

oDAZgA~mtF

hLVhpZxC^ 40

NG_SigE^QC^

BC90 xhLVhpZ

5 AZgA~mtFZxP

xDhLVhpNG_

^QlXC

SigE^ChLVhp

AZgA~mtF\ZxP

\ZxCC40

^QvDAZgA~mtF

C60 hLVhpZxSp

AUC lP^Q^QF

LDhLVhp

iTable 4j
D

Table 3 CAUC lCP^Q

S^Q 42D
AZgA~mtFi50

mg/kgjP^

StFm[`

202

Vol. 125 (2005)

FCopD{

VbgpCxZWh

@CFS

JrhpCq

i`op

tFm[isK[yJeR[

DSYtL[g`

jLC@C

pegTCNy

DC

C{@KpCO[h

L hpPp

3 ziFig. 1jD

CO[h 3 C

C{@`o\

@{hp

mFD

{@pXN[jO

npSS

i 14 11 zD

pD{NG_Sig

CziCSp

E_SpXN[jOs

`Dz

CSvD

11 CNG_SigES

C{@CSW

p 5 C_Sp 6

@lD

O[h 3 C

{C@z

C_C\viChLVhpC`h

i}EXZx

pC{hpqJeR[L

{@wI]D

CuLi

@O[h 3 {hp

DJeR[LSCIL

i}hp[jhLVhpCNG_

[g`mC{@

SigE^CP^

L 4 iFL[g`

{hpyhLVhpZx

\zD

y AUC lCoCIAxCr

`Czey

eB@CCw

\zC{C{XN[jO

ISpmFD

ziSp

C{@XN[jOz

`p\

iC

DO[h 3

O[hiSp

iCSpp

pwIo

\\zDC{XN

C{@CSp

[jOO[h 3 {hp

oXN[jOLp

`hpCSpL[g`

DC@O[h 1 A

zjQCZx

ZgA~mtFCNG_SigE

CO[h 3

poCIAxCreB

zegTCNS

oCSpp

pCzjQ

mFDC{@

1,2)
pD

O[hiSp

{hpC`hpOXN[jOz

p\\zC{

iCSp

@O[hp\

\C{XN[j

wWlD

D5,6)

OCp\dv
|^lD
{{hpC}hp[l

{ h p S p C
Campbell _Spp[L\
a{hpZxC

No. 2

203

REFERENCES

D7) CCampbell C`hp

SppC~
8) C{
D

hLVhpC
Spp
D
ipYtL
C{hpSpC{
hpixZWhCJ
rhpji2003 Nj
Yt9,10)CC`hpO
i1999 NjLD11) C
{hLVhpC
SpYtLD
ChLVhpSp
\{CI
lD
_CtFm[S`
Fp{@CtF
m[_LiSp\
LpCp
ilD

hLVhpWiZF

\D

1)

Stockley I. H., ``Drug Interaction,'' 2nd ed.

Blackwell Sci. Publ., Oxford, 1991.
2) Hansten P. D., ``Drug Interaction,'' 5th ed.,
supervised for translation by Sekiguchi K.,
Katagiri S., Shimada H., Suzuki E., Suguro
N., Hayashida A., Ishiyaku Publishers, Inc.,
Tokyo, 1987.
3) Betto P., Ricciarello G., Giambenedetti M.,
Lucarelli C., J. Chromatogr., 459, 341_
349
(1988).
4) Brunner L. J., Bai S., J. Chromatogr., 732,
323_329 (1999).
5) Campbell N. R. C., Hasino B., Clin. Phar
macol. Ther., 45, 220_
225 (1989).
6) Campbell N. R. C., Campbell R. R. A.,
Hasino B. B., Clin. Invest. Med., 13, 329_
332 (1990).
7) Campbell N. R. C., Rankine D., Goodridge
A. E., Hasino B. B., Kara M., Br. J. Clin.
Pharmacol., 30, 599_605 (1990).
8) Campbell N. R. C., Paddock V., Sundaram
R., Clin. Pharmacol. Ther., 37, 308_
315
(1988).
9) Attached document Madopar vqhttp://
www.info.pmda.go.jpr.
10) Attached document Menesit Tab.v
qhttp://
www.info.pmda.go.jpr.
qhttp://
11) Attached document Aldomet Tab.v
www.info.pmda.go.jpr.