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MAJALAHFARMASI AIRLANGGA(Airlangga Journal of Pharmacy)

ISSN 0852-1050 VOL.6 No. 1-APR-2008

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PENERBITFAKULTAS FARMASI UNIVERSITAS AIRLANGGA

MAJALAH FARMASI AIRLANGGA

Prof. Dr. H. Achmad Syahrani, Apt., MSDekan Fakultas Farmasi Universitas Airlangga

Penanggung jawab:

Dewan RedaksiKetua: Prof. Dr.Tutuk Budiati, Apt., MS

Wakil Ketua: Prof Dr. rer.nat. H. Moh. Yuwono, Apt., MSProf Dr. H. Achmad Syahrani, Apt., MS.Prof Dr. Amirudin Prawita, Apt.Prof Dr. Purwanto, Apt.Prof Dr. Hj. Widji Soeratri, Apt. DEAProf Dr. Siswandono, Apt., MS.Prof Dr. Wahono Sumaryono, Apt., APUProf. Dr. Sukardiman, Apt., MS.Dr. rer.nat. Mulja Hadi Santosa, Apt.Dr. Hj. Umi Ahtujah, Apt. MS.Dr. Hj. Isnaeni, Apt., MSDr. Suhaijono, Apt., MS.Dr. Djoko Agus Purwanto, Apt., MS.Dr. Bambang Prayogo, Apt., MS.Dra. Esti Henradi, MS., Ph.D.Dra. Liza Pristianty, MSi., MMDr. Budi Suprapti, Apt., MS.

Anggota:

Redaksi Pelaksana:KetuaSekretaris:Anggota

Drs. Abdul Rahman, Apt., MSiDrs.Achmad Toto Poemomo, Apt., MSBambang Subakti Zulkamain, Apt., MSi.Azza Faturrohmah, S.Si, Apt, MSi.Muh. Agus Syamsur Rijal, S.Si., Apt, MSi.Rr. Retno Widyowati, S.Si., Apr., MSc.

Alamat Redaksi: Fakultas Farmasi Universitas AirlanggaJl. Dharmawangsa Dalam, Telp. (031)5033710 Fax. (031)5020514Surabaya-60286e-mail: achmad.toto.p@gmail.com. farmasi@unair.ac.id

Majalali Farmasi Airlangga, Vbl.6 Mo. I, April 2008 ii

DAFTAR ISI

halEditorial

Daftar Isi Majalah Farmasi Airlangga Vol.6 No.1 April 2008 ii

Efecl ofAl(OH)sandMg(OH),Suspesion Dosage Formon the Absorptionof OralCiprofloxacinAniek Setiya Budiatin, Nunlk Wahyuni, Suharyono, Toetik Aryani.... I

Mitogen-Activated Protein Kinase Menghambat Perkembangan ToleransiAnalgesik Morfina pada MencitToetik Aryani',Tri Kaloko, Junaidi Khotib .. 5

Hubungan Persepsi Terhadap Iklan Di Televisi Dengan Perilaku Swamedikasi PelajarSMU Negeri Di SurabayaOelva Dianawati, Fasich, Umi Athijah . . 9

Knowledgeand Attitudes of Doctors toward Adverse Drug Reaction Reporting and Monitoring in the Hospital :A Pilot StudyYunita Nita, Bamhnng Subakti Zulkarnain, Elida Zairina . 16

Penggunaan Dimetii Sulfoksida (DMSO)Sebagai Pclarut Untuk Analisis Uji Batas “Cemaran Organik MudahMenguap” Mcnggunakan Kromatografi GasAsri Darmawati,Ahmad Syafi'i Afandi, Achmad lnoni 21

TheComparisonof Densitometry andUPLC Method for Determination of Codein Phosphateand Paracetamol Simultaneously in Analgesic TabletJuniar Moechtar, Asri Darmawati 24

Kandungan Logam Berat Timbal (Pb), Kadmium (Cd)dan Tembaga (Cu)dalam airSungai Kali WonokromoAmirudin Prawita, Dewi Murnitasari, Asri Darmawati 27

Ganibarsampul:Skema amobilisasi molekul enzim didalam pendukung nanoporous. Credit: Eric Ackerman, PNNL. Gambardidownload dari : http://nanotechweb.org/

Effect of Al(OH),and Mg(OH), Majalah Farmasi Airlangga, Vol.6 No.I, April 2008 I

Efect ofAI(OH)3and Mg(OH)2 Suspesion Dosage Form on the Absorption of Oral Ciprofloxacin

Aniek Setiya Budiatin, Nunik Wahyuni, Suharyono, Toetik AryaniDepartement of Clinical Pharmacy, Faculty of Pharmacy, Airlangga University, Surabaya.

Potential interaction of fluroquinolone with other drugs have been established in the several reports. Theabsorption of fluroquinolones were almost entirety inhibited by concomitant administration ofdi and trivalentcations such magnesium and aluminium in the antacids were significantly decreased the absorption ofciprofloxacin through formation of a complex. The effect ofantacid (Antasida DOEN) 1.4 ml/kg body weight doseswhich containing polyvalent cation Mg(OH). and Al(OH) ,on the absorption of ciprofloxacin, were examed inhealthy rabbit. Twelve subjects were given 23 mg/ml BW ciprofloxacin alone as control. On day 8 the six subjectswere given antacid and ciprofloxacin concomitant and the other were given antacid two hours after ciprofloxacin.The absorption parameters of ciprofloxacin were determined by spectrofluommetric method. Those parameterswere Cmax, tmax and AL/C, the administration of ciprofloxacin and antacids concomitantly result Cmax, tmax andAUC were I.27±0.45g/ml; 110ÿ.48.99 minutes and 248.63±94.77g.minutes/ml respectively in a significantdecrease in ciprofloxacin absorption (p<0.05) and the administration of antacids two hours after ciprofloxacinresult Cmax, tmax and AUC were l.37±0.65g/ml;75±36.74 minutes and 245.09±I00.46 g.minutes/ml respectivelyin a significant decrease in ciprofloxacin absorption (p<0.05). Percentages of relative bioavailability comparedwith control values were 27.06±16.70%> and 8.77±6.97% for concomitant and two hours after ciprofloxacinrespectively.

Keywords: Ciprofloxacin, Mg(OH),,Al(OH),.antacid, Spectrojluorometric

INTRODUCTIONCiprofloxacin (fig.l) is fluoroquinolone antibiotic a

broadspectrum which can against positive and negativemicroorganism as synthetic antibiotic and bactericidespecially negative microorganism P. aeruginosa (MeEvoy, 2002). Ciprofloxacin were used for treatmentdesease: GIT, respiratory tract up and down; urinary tract,skin infection, which inhibit enzim topoisomcrase II subunit A (ADN gyrase) and topoisomerasc IV in DNAsynthesis as a potential antibacterial (Ball, 2000). Plasmaconcentrations in healthy volunteers reach a mean peakdrug plasma concentrations (Cÿ,) of approximately 2.8and 5.2mg/L within 1 to 2 hours after oral administrationof ciprofloxacin 250 and 500mg tablets, respectively. Theoral absorption is very rapid and complete, thebioavailability of oral ciprofloxacin approaches 100%andit little affected by administration with food (Fish andChow, 1997).

aluminum and magnesium containing antacid withfluoroquinolones as ciprofloxacin, resulting insignificantly decrease absorption and bioavailabilitywhen administered concurrently (Stockley, 2001). Nix etal. (1989) were reseached that plasma concentrations inhealthy volunteers decreased 85% when ciprofloxacinewas gived 5 until 10 minute after antacid (Maalox*)because ciprofloxacine and antacid formed complexmetal (Stockley, 2001). A measure such as tÿ, does notadequately describe situations in which double peakingmay occur or which prolonged absorption are observed.Antacid (Mg (OH), and Al(OH) ,) is widely used for avariety of indications ( duodenal ulcer disease, dyspepsia,saur stomach), the mechanism of antacid are neutralizeacid and stimulate mucosal defenses (Me Evoy,2002).The probably that ciprofloxacin will be given to patientsreceiving long term therapy with antacid/H2 blocker ishigh. Since antacid affect oral absorption of variety ofagents, the effect of administration of antacid on theabsorption of ciprofloxacin was studied (Radanst et al.,1992), Therefore studies were perform to determined theeffect of antacid administration on the oral absorption ofciprofloxacin in healthy rabbits by spectrofluorometric(El-K.ommoseta!.,2003)

HN

N N.

F COOH MATERIALAND METHODSMaterials and reagents. Ciprofloxacin was a kind

gift of PT Kimia Farma. Methanol (HPLC gradient) waspurchased from JT Baker, antacid DOEN was a kind giftof First Medipharma. dipotassium hydrogenphosphateand phosphoric acid 85% were purchased from Merck(Darmstadt, Germany), double distilled water wasobtained from PT. Ikapharmindo Putramas (Indonesia).

oFigure 1. Ciprofloxacin

In separate study, the effect of antacid, sucralfat; food,H2 receptor antagonis on fluoroquinolon interaction wasexamined (Radanst et al., 1992). The interactions with

Effect ofAWOH),and Mg(OH)}2 Majalah Farmasi Airlangga, Vol.6 No. I. April 2008

One milliliter of clear supernatant was spiked with 1 ml ofdrugstock solution.The mixture was then extracted with 2portions; each of 5ml chloroform. The chloroform extractwas collected, evaporated on a boiling water bath, thenappropriate dilutions were made to obtain drug solutionscontaining 100, 300 and 500ng/ml, then generalprocedure was followed.

The effect of antacid. The twelve rabbits were thesame treatment as ciprofloxacin alone, and the day 8, sixrabbits were administered antacid and ciprofloxacinconcomitant and the other one were administered antacid2 hoursafterciprofloxacin.

The pharmacokinetic analysis of plasmaconcentration of ciprofloxacin were determined usingspectrofluoro metric method . The assay had a dynamicrange of 10 to 60 ng/ml (El-Kommos et al.. 2003). Themaximum plasma concentration of ciprofloxacin (Cÿ)and earliest time at which occurred (t„„) wereestimated directly from the experimental data. Theintensity under the plasma concentration-time curve fromtime zero to the last time (t) plasma ciprofloxacin wasmeasurable (AUQ.,,,,) was estimated by the liniertrapezoidal approximation (Shargel, 2005).

Student's t tests with 95% confidence limits were usedto examine pair-wise differences between the groups.Value of p<0.05 were considered to be statisticallysignificant (Santosa et al., 2005).

Previous studies have demonstrated that theabsorption of orally administered ciprofloxacin isimpaired by concomitant administration of magnesiumand aluminum-containing antacids. This interaction mayresult from the formation of ciprofloxacin - metalcomplexes that poorly absorbed (Nix et al., 1989). Themean plasma ciprofloxacin concentration-time curves forthe administered antacid and ciprofloxacin concomitantgroups were significant different (p<0.05). Cmax, tmaxand AUC were 1.27±0.45pg/ml; 1 10±48.99 minutes and248.63±94.77jjg. minutes/ml respectively (figure 2, andTable I as Tl) and the administered antacid two hoursafter ciprofloxacin result Cmax, tmax and AUC were 1.37±0.65pg/ml; 75±36.74 minutes and 245.09±100.46pg.minutes/ml respectively in a significant decreased inciprofloxacin absorption (p<0.05). Percentagesof relativebioavailability compared with control values were 27.06±16.70% and 8.77±6.97% for concomitant and antacid twohoursafterciprofloxacin respectively.(Figure 3,andTable

Heparin 500unit/ml, ammonium molybdat werepurchased from Fluka AG, citric acid was purchased fromRiedel-de Haen, xylol was obtained from BratacoChemika, Acetonitril was purchased from Riedel-deHaen,

Apparatus. Hitachi F-4000 Spectrofluorometer(Japan) was used for fluorometric measurements, DirectReading Micro Balance LM-20 Libror, UltrasonicCleaner Sakura US-10E, Centrifuge Hettich, Protofix 32,Thermolyne Bamstead type 37600, glassware andinjection syringe.

Standard preparations. Stock solutions containinglg/ml of each ciprofloxacin was prepared in methanol.Workingstandard solutionscontaining 100-600ng/ml wasprepared by suitable dilution of the stock solutions withmethanol.

Sampling. The method animal was used AustralianRabbit from Batu Malang, weight 2,5kg. Treatmentantacid 14mg/kg BW of rabbit, 70mg/ml oral solutionform and ciprofloxacin 23mg/ml kg BW of rabbits (Paget,1964). The twelve rabbits were fast overnight before drugadministration and 2 hours after the dose wasadministered. Water was allowed ad libitum 10 ml. Bloodsample (2ml) were collected with injection syringe 2.5cccontaining anticoagulant via ear of marginal venous.Samples were collecting in a vacuum test tube. Bloodsamples were obtained immediately before and 5, 10, 20,30 ,45, 60, 75, 90, 120, 300 minutes after ingestion of theorally administered formulation.. Plasma was harvestedand samples were stored at -20°C until assayed. Plasmaconcentration of ciprofloxacin were determined byspectrofluorometric. The assay was liniar over thecalibration range 100 to 600ng/ml (El-Kommos et all,2003)

General procedure.One milliliter aliquot volumes ofstandard or sample solutions were transferred into 10-mlcalibrated flask. One milliliter of the ammoniummolybdenum solution (7.5g/ml) was added and pH wasadjusted to 3.5 using 1 ml ofTeorell and Stenhagen buffersolution. The volume was completed with methanol. Therelative fluorescence intensity of resulting solutions weremeasured against reagent blanks treated similarly at theexcitation and emission maxima specified forciprofloxacin. (El-Kommosetui,2003).

Plasma treatment (El-Kommos et.al., 2003). Fivemilliliter of plasma were deproteinized by the addition of10 ml acetonitrile, centrifuged at 4000 rpm for 5 minutes. 2)

Table 1. Summary of pharmacokinetic parameter of the administrated antacid and ciprofloxacin concomitant (Tl )andantacid 2 hoursafterciprofloxacin (T2)

Treatment I and Treatment 2Control Tl and T2VariabelAUC 0-300minutts

(jig.minute/L)t max (minute)

C max (pg/L)

188.23±99.83 224.35±93.92248.63±94.77 245.09±100.46

65.00±12.251.41±0.55

1 10±48.991.27±0.45

75.00±36.741.37±0.65

170.00±72.661.05±0.40

Eject ofAI(OH) 3 and Mg(OH)2 Majalah Farmasi Airiangga, Vol.6 No. I, April 2008 3

1,20Oo 1,00 -

0,80 -3 0,60 - Control

TreatmentB5

0,40 -3

0,20 -in

3 0,00100 200 3000 400

time (minute)

Figure 2. Concentration (pg/ml) versus time (minutes) curve trom antacid and ciprofloxacin concomitant

Table 2. Summary of t account; t table and probability of absorption parameter

Absorption parameter t table probabilityt accountCmax Ti 1.468 2.571 0.202

0.788T2 -0.283 2.571AUC0-300

5.140 2.571 0.004Tl3.313 2.571 0.021T2

T max-1.581 2.571 0.175Tl

T2 0.598 2.571 0.576

n U60 -§ 1.40 -° 1,20 -9$ l'00

0,80 -0,60 -0,40 -

* 0,20 -3 0,00 ■

ControlTreatment

too 300 400200time (minute)

0

Figure 2. Concentration (pg/ml) versus time (minutes) curve administered antacid 2 hours after ciprofloxacin

4RESULTSAND DISCUSSION

To determine the effect of timing on absorption ofantacid and ciprofloxacin administered of single 23mg/kgBW dose of ciprofloxacin to 12 healthy rabbits in two-waycrossover study, ciprofloxacin was given alone orcombined with otheran magnesium/aluminum containingantacid 14ml/kg BW; the timing of antacid andciprofloxacin administration was varied (concominantand antacid 2 hours after ciprofloxacin). The literaturedescribing reduced absorption of fluoroquinolones due toantacid administration to patients and volunteers is most

extensive for ciprofloxacin (Figure 4) where in the gastrointestinal region the complex chelat form of antacid(metal = Mg and Al) and ciprofloxacin couldn't absorbed(Nix et al.. 1989; Brighty et al.,2000) Those parameterswere Cmax, tmax and AUC, the administration ofciprofloxacin and antacids concomitantly result Cmax,tmax and AUCminutes and 248.63 ±94.77 g.minutes/ml respectively55.29%, 53.91% significant different (p<0.05) (Santosa,et al., 2005) respectively and t„s increased 180% but notsignificant different (p>0.05) (Table 1 and figure 2).

were 1.27±0.45 g/ml; I10±48.990-300

Ihfi r»i —i i t.ungga, Vot.6 No. I. April 2008 Effect of Al(OH)} and Mg(OH)2*

..IMtaaMBaccc of the antacid 2 hours after ciprofloxacin4bck INK *j* significant different in C

_5.74% and

I 07% ip>0.05) respectively and tm> increased1 % 56« not significant different (p>0.05). The

of absorption can be significant and potentiallyat so the failure of the treatment, even whenaprofioxacin dose are separated from antacid dose by-rsoce than 2 hours ( Radanst et al. 1992) in a significantdecrease in ciprofloxacin absorption (p<0.05) and the

administration of antacids two hours after ciprofloxacinresult Cmax, tmax and AUC were 1,37±0.65g/ml;75±36.74 minutes and 245.09±100.46 g.minutes/mlrespectively in a significant decrease in ciprofloxacinabsorption (p<0.05). Percentages of relativebioavailability compared with control values were27.06±16.70%and 8.77±6.97% forconcomitant and twohours afterciprofloxacin respectively.

l ,Y h::x .:-b

Metal. ■r•V.1.. I,

fTGugus katboksilat

Gugus okso ;*Ni,

1Bentuk kornpleks tidak larut1evofloksasin-logam

Figure 4. Ciprofloxacin/ levofloxacin and metal complex form the reaction (Nix et al.. 1989; Brighty et al ,2000)

Conclusions. Complex form of ciprofloxacin withMg(OH), and AI(OH), re-precipitated in small intestinewould play an important role in the reducedbioavailability (C max and AUC) if ciprofloxacin co¬administration with Mg and Al-containing antacidsconcomitant.Acknowledgements. Many thanks to the organizingcommittee for the opportunity to present this poster.Furthermore, we thank to Dean of Faculty of PharmacyAirlangga University for the supportive fund.

McEvoy, G. K., (2002). AHFS Drug InformationAmerican Society of Health SystemBiopharmacuetics & Pharmacokinetics 5“ Ed.,USA : American Society of Health SystemPharmacist, Inc., pp. 764-781,2772-2776.

Nix, D. E., Watson, W.A., Lencr, M. E„Frost, R. W„Korl,G., Goldstein, H., Lettieri, J.,Schentag, J. J., (1989).Effects of Aluminium ang Magnesium Antacids andRanitidine on The Absorption of Ciprofloxacin.Clin. Pharmacol.Ther., Vol. 46, pp. 700-705.

Paget, G.E., Bames, J.E., Toxicity Test. In: Laurence, D.R„Bacharach., A. L., (1964). Evaluation of DrugsActivities: Pharm Acometrics, Vol. I, Lndon:Academic Press, pp.161

Radandt, J. M„Marchbants, C. R„Dudley, M. N„(1992).Interaction of Fluoroquinolones With Other Drug :Mechanism. Variability, Clinical Significance, andManagement, 1991. din. Infect. Dis., Vol. 14, pp.272-284

Santosa, P. B„Ashari, (2005). Analisis Statistika dengattMicrosoft Exel dun SPSS,Yogyakarta : Andi Offset,hal.60-65.

Shargel, L., Wu-Pong, S., Yu, A. B. C., (2005). AppliedBiopharmaceutics and Pharmacokinetics 5“ Ed,Boston: The McGraw-Hill Companies, Inc., pp.371-395,460-461.

Stockley, I. H., (2001). Drug Interaction A Source Book ofAdverse Interaction, Their Mechanisms, ClinicalImportance and Management 5“ Ed., United

Kingdom: Pharmaceutical Press, pp. 3-12,174-176.

REFERENCEBall, P., (2000). The Quinolones History and Overview.

In: Vincent T. Andriole (Eds). The Quinolones,London:Academic Press, p. 19-20.

Brighty, Katherine E. dan Gootz, Thomas D., (2000).Chemistry and Mechanism of action of theQuinolone antibacterials. In: Vincent T. Andriole(Eds). The Quinolones,London: Academic Press, p.43-44.

El-Kommos, M. E., Saleh, G. A., El-Gizawi, S. M., Abou-Elwafa, M. A., (2003). SpectrofluorometricDetermination of Certain Quinolone AntibacterialUsing Metal Chelation. Talanta.Vol. 60, pp.1033-1050.

Fish, D.N. and A.T. Chow, (1997). The ClinicalPharmacokinetics of Levofloxacin. Clin

Pharmacoki net., Vol. 2 No. 32, p. 101-19. i