Pharmacokinetic and safety evaluation of the use of ciprofloxacin on an isoniazid-rifampicin regimen...

BIOPHARMACEUTICS & DRUG DISPOSITIONBiopharm. Drug Dispos. 33: 501–509 (2012)Published online 25 October 2012 in Wiley Online Library(wileyonlinelibrary.com) DOI: 10.1002/bdd.1817

Pharmacokinetic and safety evaluation of the use ofciprofloxacin on an isoniazid-rifampicin regimen in rabbits

Elias Carvalho Padilhaa, Rodrigo Vieira Piresa, Marco Antonio Ferraz Nogueira Filhoa,Diego Vinicius de Pontes Machadoa, Helen Mariana Baldana, Marcelo Gomes Davançoa,Michel Leandro Camposa, Iguatemy Lourenço Brunettib, and Rosângela Gonçalves Peccininia,*aDepartment of Natural Active Principles and Toxicology, School of Pharmaceutical Sciences, São Paulo State University, Araraquara, SP, BrazilbDepartment of Clinical Analysis, School of Pharmaceutical Sciences, São Paulo State University, Araraquara, SP, Brazil

*CorrespMesquiRodoviAraraqE-mail: p

Copyrig

ABSTRACT: The combination of isoniazid (INH), rifampicin (RMP) and pyrazinamide (PYR) is usedin the treatment of tuberculosis. Although this treatment is effective in most clinical cases, the side-effectsand the development of mycobacterium resistance have hindered its success. There is evidence that thecombination of INH, RMP and ciprofloxacin (CIPRO) is useful in the treatment of tuberculosis. However,the influence of this drug combination on the hepatotoxicity of INH is unknown. In this study, the safetyof combined INH, RMP and CIPRO was evaluated. Male albino rabbits (n=20) were divided into fourgroups and subjected to multiple oral doses for 7days according to the following treatments: water(group 1); 50mg/kg INH (group 2); 50mg/kg INH+100mg/kg RMP (group 3) and 50mg/kg INH+100mg/kg RMP+50mg/kg CIPRO (group 4). Blood samples were taken before and after treatmentsfor the determination of ALT, AST, ALP and bilirubin to assess hepatotoxicity. For pharmacokineticanalysis, serial blood samples were collected over 24h on day 7 of treatment. Plasma concentrations ofINH and acetylisoniazid (AcINH) were determined by HPLC. Biochemical parameters did not showany statistically significant differences between the groups that received the drug combinations. Thepharmacokinetic profile of INH was also similar for both groups of combinations. These findings allowus to infer that the inclusion of CIPRO did not increase the risk of hepatotoxicity when compared withthe classic combination of INH and RMP. Copyright © 2012 John Wiley & Sons, Ltd.

Key words: ciprofloxacin; isoniazid; preclinical pharmacokinetics; hepatotoxicity; tuberculosis

Introduction

The treatment of tuberculosis is a very difficult pro-cess that requires drug combinations and long-termregimens. The classic treatment of tuberculosisinvolves first-line drugs, such as isoniazid (INH),rifampicin (RMP) and pyrazinamide (PYR), as wellas second-line drugs, such as streptomycin and

ondence to: São Paulo State University ‘Júlio deta Filho’, UNESP, School of Pharmaceutical Sciences,a Araraquara-Jaú Km, 01 s/n, University Campus,uara, São Paulo 14801-902, [email protected]

ht © 2012 John Wiley & Sons, Ltd.

ethambutol. Other broad-spectrum antibiotics areused in specific cases, such as hepatic failure causedby INH metabolites, resistance of the mycobacteriato a first-line drug and, in more serious cases, resis-tance to more than one of these drugs, so calledmultidrug resistant tuberculosis (MDR-TB).

Many other drug classes have been developedand applied to the treatment of tuberculosis, includ-ing the fluoroquinolones – antibacterials with abroad spectrum of activity –which were consideredby Di Prerry et al. [1] as the only class of drugs ofrelevance introduced in the treatment of tuberculosisin the past 20years. Of these drugs, first-generationciprofloxacin (CIPRO) and ofloxacin (OFX) are

Received 22 March 2012Revised 29 August 2012

Accepted 18 September 2012

502 E. C. PADILHA ET AL.

recognized by the World Health Organization assecond-line drugs against MDR-TB.According to Soudani et al. [2], the fluoroquino-

lones are useful in the treatment of MDR-TB, andthese drugs have presented good activity againstMycobacterium tuberculosis. Bhusal et al. [3] evaluatedthe in vitro antimicrobial activity of the combinationof INH, RMP and CIPRO, and found synergisticeffects, which could be useful in the treatment oftuberculosis. Souza and Vasconcelos [4] suggestedthat CIPRO may serve as a first-line agent againstthemycobacteria, thus benefiting the treatmentwithits synergistic potential in an effort to reduce theduration of the therapy with INH and RMP.Boogaard et al. [5] evaluated fluoroquinolone

resistance inM. tuberculosis samples from Tanzanianpatients – with and without previous fluoro-quinolone exposure. Their findings indicated alow occurrence of fluoroquinolone resistance,not related to previous exposure. These authorsconcluded that fluoroquinolones could be incor-porated in first-line TB treatment regimens.Clinical application of this new combination of

drugs requires careful evaluation to prevent the riskof an increase of hepatotoxicity. This toxic effectis one of themain limiting factors of the classic treat-ment of tuberculosis. Yet the influence of CIPRO onthe hepatotoxicity of INH remains unknown.This study evaluated the effects of the simulta-

neous administration of multiple doses of CIPROand RMP on the pharmacokinetic profile of INHand its metabolite acetylisoniazid (AcINH) inrabbits – an animalmodel susceptible to the hepato-toxic effects of INH [6]. Biochemical parameters –AST, ALT, ALP and bilirubin –were also evaluatedas biomarkers of hepatotoxicity [7,8].This information will allow us to determine the

risks of CIPRO inclusion in the proposed drugcombination for tuberculosis treatment.

Material and Methods

Chemicals

The INH and RMP were kindly donated by theFundação do Remédio Popular (FURP), and theCIPRO was donated by the Fundação OswaldoCruz (FIOCRUZ). Monopotassium phosphate andtrichloroacetic acid were purchased from Labsynth

Copyright © 2012 John Wiley & Sons, Ltd.

(São Paulo, Brazil) and trans-cinnamaldehyde wasobtained from Merck (Germany). Acetonitrileand isopropanol were purchased from J. T. Baker(USA) HPLC grade. Heparin (LiquemineW) waspurchased from Roche Pharmaceuticals (SãoPaulo, Brazil).

Monopotassium phosphate buffer was preparedat 0.05M and used as a component of the mobilephase; the trichloroacetic acid (TCA) was used at10% in water for sample deproteinization; trans-cinnamaldehyde was used at 1% in methanolfor derivatization of isoniazid before sampleinjection into the chromatographic system. INHwas prepared in water at 50mg/ml, CIPRO wasalso diluted in water at 25mg/ml and RMP wasprepared in water acidified at pH 3 with HCl0.1 N at 50mg/ml as described by Tayal et al. [8].

Animals

Male New Zealand albino rabbits (n=20) weighing3.0–3.5 kgweremaintained in controlled conditionsof temperature (23� 1 �C), humidity (55� 5% ) andlight (12 h cycle beginning at 7 a.m.). The animalswere deprived of food for 8 h before drug adminis-tration. This animal model is most susceptible toINH toxicity when compared with Wistar rats dueto sensitivity to the induction of cytochrome P450caused by RMP [6].

Experimental design

The animals were divided in four groups (n=5) thatreceived their substances orally once a day viagavage for 7days. Group 1 (control) received water;group 2 (INH) received isoniazid (50mg/kg); group3 (INH+RMP) received isoniazid (50mg/kg) andrifampicin (100mg/kg) 1h after the administrationof INH; group 4 (INH+RMP+CIPRO) receivedisoniazid (50mg/kg), rifampicin (100mg/kg) andciprofloxacin (50mg/kg) [6,9]. The drugs wereadministered at intervals of 1 h in order to avoidphysicochemical interactions between drugs, espe-cially between RMP and INH, as reported byImmanuel et al. [10]. For the first 6 days theadministration of the drugs followed the sequenceINH–CIPRO–RMP. On day 7, the order was alteredto RMP–CIPRO–INH, since RMP undergoes enter-ohepatic circulation and may still be present in theintestine of the animal during the administrationof INH. On day 7, however, the series blood

Biopharm. Drug Dispos. 33: 501–509 (2012)DOI: 10.1002/bdd

reviou

sdatarelatesto

samples

before

thefirst

Group

4

rBefore

After

a 3.69)

98.37

(72.43

–124.31)

55.84a

(44.53–6

7.15)

a 08.12)

56.00

(43.68–68.32)

84.17a

(54.26–114.07)

50 9.26)

38.63

(23.18–54.07)

69.81

(36.56–103.06)

+rifampicin(100

mg/

kg)+

ciprofl

oxacin

(50mg/

kg).

503CIPROFLOXACIN AND THE ISONIAZID’S PHARMACOKINETICS AND HEPATOTOXICITY

sampling demanded the INH to be the last drugadministered.Right after the last administration of INH, the

rabbits were submitted to a series of blood sam-pling at 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 18and 24 h for the pharmacokinetics evaluation.One ml of blood was collected from the animalsinto heparinized microtubes. The plasma sampleswere maintained at �20 �C until analysis.For the biochemical assays, blood was collected

from the marginal vein of the left ear of the animalsbefore the first and after day 7 of administration.Serum was stored at �80 �C until analysis.

regive

nviaga

vage

for7day

s.P

r7day

sof

administration

Group

3

Before

Afte

86.88

(53.10–120.65)

56.58

(29.48–8

64.67

(49.21–80.13)

82.75

(57.38–1

50.67

(41.89–59.44)

49.

(39.74–5

/kg

);grou

p4,ison

iazid(50mg/

kg)

easu

re.

Biochemical parameters assay

The AST, ALT and bilirubin kits were purchasedfrom LabTestWDiagnostica SA (Lagoa Santa, MinasGerais, Brasil), and ALP analysis was performedby the catalysis of p-nitrophenyl phosphate intop-nitrophenol in a kinetic reaction, measured byspectrophotometer at 405 nm.

asmean(C

I 95)in

U/lfor

n=5su

bjects.D

oses

we

steriordataarereferred

tothesamples

take

nafte

Group

2

ter

Before

After

.38

256.83)

93.69

(76.89

–110.48)

55.38a

(32.75

–78.00)

.20

48.59)

55.60

(46.29–64.91)

63.17

(43.33

–83.01)

.00

75.77)

64.64

(51.23–78.03)

60.88

(41.89

–79.89)

/kg

);grou

p3,ison

iazid(50mg/

kg)+

rifampicin(100

mg

nn’stest

withp<0.05,com

paredwithgrou

p1After

m

Isoniazid and metabolites analysis

The HPLC analysis was conducted according toDe Rosa et al. [11], a method to determine INHand metabolites in plasma.The chromatographic system was constituted

by a Waters AllianceW HPLC with UV-VS 2487detector operating at 340 nm; SymmetryW C18

(5mm, 90 Å, 3.9mm� 150mm) column and pre-columnwith the same stationary phase. Themobilephase was composed by isopropanol: acetonitrile:phosphate buffer (8:32:60), in gradient mode(Table 1) at 1ml/min flux in a 20min run time.

Table 1. Chromatographic system gradient mode

Time(min)

Solvent - mobile phase

Isopropanol(A%)

Acetonitrile(B%)

Phosphatebuffer (C%)

0 8 32 601 8 32 6010 14 56 3015 14 56 3016 8 32 6018 8 32 6022 8 32 60

Table2.

ALP,ALT

andAST

values

expressed

day

ofad

ministrationof

thecompo

unds.Po

Group

1

Before

Af

ALP(U

/l)

107.17

(89.45–1

24.89)

191

(125.94–

ALT

(U/l)

30.80

(20.32–4

1.28)

46(43.81–

AST

(U/l)

49.00

(40.05–5

7.95)

59(42.23–

Group

1,control(water);grou

p2,ison

iazid(50mg

a Statistical

differenc

esby

ANOVA

follo

wed

byDu

Copyright © 2012 John Wiley & Sons, Ltd. Biopharm. Drug Dispos. 33: 501–509 (2012)DOI: 10.1002/bdd


Sample treatment

The concentrations of INH in the rabbit plasmawere measured by liquid chromatography afterderivatization with trans-cinnamaldehyde. The300 ml plasma sample was mixed with 300 ml at10% trichloroaceticacid, vortexed and centrifugedat 2500 rpm for 10min. To the deproteinizedsupernatant were added 30 ml H2O and 60 ml of a1% solution of trans-cinnamaldehyde in methanol.After being vortexed and incubated for 10minat room temperature, the samples (50 ml) wereinjected into the HPLC system.To determine the acetylatedmetabolite, the super-

natant samples were first hydrolysed by addition of30ml 6mol/l HCl and incubated at 80 �C for 1 h.The samples were then derivatized as before andquantified as INH.

Pharmacokinetic analysis

The parameters of maximum plasma concentration(Cmax) and time to reach Cmax (tmax) were obtaineddirectly from experimental data. Pharmacokineticparameters of INH administered in each treatmentwere calculated using non-compartmental analysis(NCA) and then compared to determine if thedifferences were statistically significant. Data were

Figure 1. Comparison of ALP values between groups. Columns asubjects. Data were compared by ANOVA for multiple comparisobefore the first day of administration of the compounds. The aftergrey area is the ALP range for normal rabbits as reported from Emby Dunn’s test with p< 0.05, compared with the group 1 After me


analysed usingWinNonlin W 6.2.1; Pharsight Corp.,Mountain View, CA, USA. The calculated para-meters included the rate elimination constant (lz),elimination half-life (t1/2), area under concentration–time curve (AUC), apparent clearance (Cl/F)and apparent volume of distribution (Vd/F).

Statistical analysis

The pharmacokinetic parameters of INH are pre-sented as means and confidence interval (CI95).The data were analysed by ANOVA for multiplecomparisons followed by Dunn’s test to evaluatethe differences between groups (p< 0.05), as wellas the results of biochemical parameters. Analyseswere made by Graphpad Prism 5.01 (GraphPadSoftware Inc. San Diego, CA).

Results and Discussion

Biochemical parameters

ALP. The ALP reference values in rabbits are60–120 U/l, according to Emanuelli et al. [12].Table 2 reports ALP experimental values obtainedin the treatments. There was no statistical differencebetween the values of ALP before and after the

re presented as means with 95% confidence interval for n= 5ns followed by Dunn’s test. The before data relate to samplesdata refer to samples taken after 7 days of administration. Theanuelli et al. [12]. *Statistical differences by ANOVA followed

asure


Table3.

Bilirubinva

lues

expressedas

mean(C

I 95)in

mg/

dlfor

n=5su

bjects.D

oses

weregive

nviaga

vage

for7day

s.Prev

ious

datarelate

tosamples

before

thefirstd

ayof

administrationof

thecompo

unds.Po

steriordataarereferred

tothesamples

take

nafter7day

sof

administration

Bilirubin

Group

1Group

2Group

3Group

4

Before

After

Before

After

Before

After

Before

After

Direct

0.198

(0.045–0

.350)

0.126

(0.022-0.135)

0.108

(0.052–0

.165)

0.186

(0.004–0.224)

0.198

(0.079–0

.317)

0.262

(0.018–0.507)

0.280

(0.139–0.392)

0.130

(0.059

–0.201)

Indirect

0.636

(0.335–0

.936)

0.552

(0.251–0.835)

0.498

(0.291–0

.705)

0.480

(0.365–0.595)

0.900

(0.185–1

.615)

1.009

(0.198–1.812)

0.740

(0.521–0.996)

0.570

(0.336

–0.774)

Total

0.834

(0.459–1

.209)

0.678

(0.360

–0.9958)

0.606

(0.414–0

.789)

0.666

(0.379–0.953)

1.025

(0.416–1

.634)

1.420

(0.453–2.082)

1.020

(0.527–1.512)

0.700

(0.526–0.874)

Group

1,control(water);grou

p2,

ison

iazid(50mg/

kg);grou

p3,

ison

iazid(50mg/

kg)+

rifampicin(100

mg/

kg;g

roup

4,ison

iazid(50mg/

kg)+

rifampicin(100

mg/

kg)+

ciprofl

oxacin

(50mg/

kg).


administration of drugs, or water, in the samegroup. The values of ALP after administration ingroups 2, 3 and 4 showed statistical differences inrelation to the group 1 After value (Figure 1).The animals that received the drugs presented

lower values of ALP when compared with controlgroup (drug versus control). During the experimentsit was observed that every animal under any INHregimen showed a decrease in food intake, beingmore intense in group 2. Consequently, a significantweight loss in the animals occurred. This phenome-non probably relates to the anorectic effect of INH.Banerjee et al. [13] found that the decrease in ALPmay occur as a result of a chronic decrease in food in-take, as observed in the experimental subjects. On theother hand, the high value of ALP observed in thecontrol group may have occurred due to the stresssuffered by the animals during the week of adminis-tration, or even to irritation of mucous membranescaused during the insertion of the gavage tube.

ALT and AST. The AST parameter was not alteredby any treatment. The ALT showed significantincreases in groups 3 and 4 (Table 2). However, nostatistical difference was observed among groups3 and 4, demonstrating that the combination ofciprofloxacin with rifampicin and isoniazid doesnot differ from the rifampicin and isoniazid. Bothgroups showed a slight raise in ALT, as predictedfor this kind of combination as reported from Kalraet al. and Tayal et al. [7,8]. Since ALT is a morereliable biochemical assay to assess hepatic integ-rity, the obtained results allow us to infer that cipro-floxacin does not increase the risk when comparedwith the current treatment (INH+RMP).

Bilirubin. Table 3 presents values for bilirubin.Evenwhen the INH and RMPwere associatedwithCIPRO, no significant difference was observed inbilirubin levels either in its direct or indirect forms.These results allow the inference that the use ofciprofloxacin in the combination does not modifythe risk of hepatotoxicity, which was expressed bythis biochemical parameter.

Pharmacokinetics

Isoniazid. Figure 2 demonstrates the pharmacoki-netic profiles of INH in the three groups studiedand Table 4 demonstrates the pharmacokinetic

Copyright © 2012 John Wiley & Sons, Ltd. Biopharm. Drug Dispos. 33: 501–509 (2012)DOI: 10.1002/bdd

Table 4. Isoniazid pharmacokinetics parameters. Values expressed as mean (CI95) for n= 5 subjects per group. Samples were takenon day 7 of administration to determine pharmacokinetic parameters

Pharmacokinetics of isoniazid

Parameter Group 2 Group 3 Group 4

l (h-1) 0.149 (0.111–0.187) 0.145 (0.114–0.173) 0.161 (0.088–0.234)t1/2 (h) 5.03 (3.82–6.24) 5.12 (4.14–6.10) 5.46 (2.91–8.00)AUC 0-t (mg/ml.h) 218.20 (133.10–303.30) 144.90 (113.20–176.50) 110.10a (84.53–135.60)Cl/F (ml/h.kg) 285.57 (156.54-414.59) 365.81 (285.04–446.58) 468.11a (382.86–553.36)Vd/F (ml/kg) 2194.5 (1452.2–2936.9) 2658.0 (1951.5–3364.5) 3669.9 (1816.3–5523.4)Cmax (mg/ml) 54.98 (20.61–89.35) 31.68 (26.51–36.86) 21.89 (6.20–37.59)tmax (h) 1.083 (0.567–1.599) 0.792 (0.140–1.443) 2.050 (0.071–3.595)

Group 2: isoniazid (50mg/kg); Group 3: isoniazid (50mg/kg)+rifampicin (100mg/kg); Group 4: isoniazid (50mg/kg)+rifampicin (100mg/kg)+ciprofloxacin (50mg/kg). l- elimination rate constant; t1/2– elimination half-life; AUC0-t – Area under curve; Cl/F– apparent clearance; Vd/F– apparent volume of Distribution; Cmax – maximum concentration; tmax – time to reach Cmax.aStatistical differences compared with Group 2, by ANOVA followed by Dunn’s test with p< 0.05.

Figure 2. Pharmacokinetic profile of INH. Doses were given via gavage for 7days. On day 7, blood samples were taken at 0, 0.25,0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 18, 24 h, allowing the plot of a plasma concentration vs time curve (n=5 per group). Data are presentedas means with 95% confidence interval


parameters. Significant differences inAUC andCl/Fcan be observed between groups 2 and 4. However,no statistical difference was observed betweengroups 3 and 4. Although it is an expected eventfor the combination of INH and RMP, the inclusionof ciprofloxacin in the regimen did not significantlyalter the prognostic, showing a similar increase inclearance. Usually a decreased AUC requires anadjustment of the dose regimen, but since the resultsfound are already expected in the clinic for INHwith RMP, there is no need for adjustment whenciprofloxacin is associated. Ofoefule et al. [9], studiedthe influence of CIPRO on the pharmacokinetics of


INH. They concluded that there was no need tomake any posological adjustments when both areadministered in humans.

It is well established that continuous exposureto rifampicin causes an induction of a series ofCYP450 isoforms [14]. The CYP450 have animportant role in the metabolism of isoniazid,mainly the 2E1 isoform. RMP had a significantinfluence on isoniazid clearance in both combina-tion groups, in the same proportion, despite thepresence of ciprofloxacin in the last group.

There was no meaningful difference in Vd/Fbetween the studied groups.



AcINH. According to Preziosi [15], since 1952,several isoniazid metabolites have been identified,such as hydrazine (HZ), isonicotinic acid (INA),ammonia, acetylisoniazid (AcINH), hydrazoneconjugated to pyruvic or ketoglutaric acid, mono-acetylhydrazine, diacetylhydrazine and free radi-cals. However, in quantitative terms, the AcINHseems to be the most important metabolite, whichis produced by the action of N-acetyltransferase(NAT).The plasma profile of AcINH in the groups

treated with INH and combinations is demon-strated in Figure 3. This figure shows that the tmax

of AcINH occurred earlier. The values of AUC,Cmax and tmax for AcINH are shown in Table 5for the treated groups.

Figure 3. Pharmacokinetic profile of AcINH. Doses were given via g0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 18, 24 h allowing the plot of a plasma coas means with 95% confidence interval

Table 5. Acetyl-isoniazid pharmacokinetics parameters. Values exptaken on day 7 of administration to determine pharmacokinetic pa

AcIN

Parameter Group 2

Cmax (mg/ml) 48.5 (6.97–90.03)tmax (h) 2.00 (2.00–2.00)AUC0-t (mg/ml.h) 297.70 (68.33–527.00)

Group 2, isoniazid (50mg/kg); group 3, isoniazid (50mg/kg) + rifampicinciprofloxacin (50mg/kg).ap< 0.05 in comparison with group 2.bp< 0.05 in comparison with group 3.


For a drug, the tmax reflects the rate of drugabsorption, and decreases as the absorption rateincreases. However, AcINH is a metabolite, thus,the early tmax might indicate that the productionof AcINH was either favoured or had its sequen-tial metabolism partially blocked.

According to Hersh et al. [16], ciprofloxacin is aninhibitor of CYP1A2 isoform, the main formresponsible for the biotransformation of AcINHto produce hydrazine and acetylhydrazine. Theearlier occurrence of tmax might be related to animpairment of the sequential metabolism of AcINHcaused by CIPRO. However, this was not sufficientto increase the AUC significantly.

Nevertheless, according to Timbrell et al. [17], thehepatotoxicity is related to AcINH hydrolysis and

avage for 7days. On day 7, blood samples were taken at 0, 0.25,ncentration vs time curve (n=5 per group). Data are presented

ressed as mean (CI95) for n=5 subjects per group. Samples wererameters

H

Group 3 Group 4

26.87 (4.03–49.72) 59.93 (37.98–81.89)1.90 (0.25–3.55) 0.46ab (0.26–0.66)

227.00 (36.64–417.30) 403.70 (178.22–629.30)

(100mg/kg); group 4, isoniazid (50mg/kg) + rifampicin (100mg/kg) +



the relationship of this toxic effect with AcINHitself is not yet evidenced [17]. The hepatotoxicityof INH has been mainly related to hydrazine andacetylhydrazine [16].These results allow us to conclude that the use

of ciprofloxacin in combination with INH andRMP neither increases the hepatotoxicity of INHnor causes any difficulty in treatment with theadvantage of synergistic effect on mycobacteria.

Conclusion

The use of drug combinations in the treatment oftuberculosis is a useful tool to improve therapeuticefficacy and to reduce the treatment time. However,multi-drug regimens must be chosen carefully toavoid increasing potential risks to the patient.Hepatotoxicity is the major problem found in

the classical tuberculosis treatment, and Mycobac-terium resistance can be an additional problemto solve.The use of fluoroquinolones has been proposed

for MDR-TB treatment. The present study hasanalysed the use of a second-line drug (CIPRO)in combination with two common, but problem-atic, first-line drugs (RMP and INH) in orderto evaluate the safety of this combination in thetreatment of tuberculosis.Biochemical analysis showed that there are no

differences between the group that receivedINH+RMP and the group in which CIPRO wasadministered. In other words, CIPRO did notincrease the risk of hepatotoxicity known fromthe previous combination. Also, the pharmacoki-netic profile of INHwas similar for both combina-tion groups. These results support the safetyof the combination of CIPRO associated withINH+RMP.

Acknowledgements

The authors would like to thank Fundação deAmparo à Pesquisa do Estado de São Paulo(FAPESP – Process no 2008/57029-2) and InstitutoNacional de Ciência e Tecnologia – InovaçãoFarmacêutica (INCT-if) for providing financialsupport during the course of this study.


Conflict of Interest

There is no conflict of interest.

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