Archivos Venezolanos de Farmacología y Terapéutica ISSN: 0798-0264 [email protected] Sociedad Venezolana de Farmacología Clínica y Terapéutica Venezuela

Vásquez de Ricciardi, Laura; Scorza, José Vicente; Vicuña-Fernández, Nelson; Petit de Peña, Yaneira; Bendezú, Herminia; Vasquez, Libia; Yanez, Carlos Influence of gentamicine on the pharmacokinetic of a pentavalent antimonial compound Glucantime® Influence of gentamicine on Glucantime kinetic Archivos Venezolanos de Farmacología y Terapéutica, vol. 25, núm. 2, 2006, pp. 60-63 Sociedad Venezolana de Farmacología Clínica y Terapéutica Caracas, Venezuela

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Laura Vásquez de Ricciardi 1, José Vicente Scorza 2, Nelson Vicuña-Fernández 3, Yaneira Petit de Peña 4, Herminia Bendezú 5, Libia Vasquez 6, Carlos Yanez 7 1 Doctora en Ciencias Médicas. Laboratorio de Farmacología., Facultad de Medicina Escuela de Medicina Valera. ULA. 2 Doctor en Parasitología. Centro de Investigaciones Parasitológicas ¨José W. Torrealba¨ NURR. ULA. 3 Médico Especialista en Farmacocinética. Laboratorio de Farmacología y Toxicología Facultad de Medicina ULA. Mérida, Venzuela. 4 Doctora en Química. Laboratorio de Espectroscopía Molecular. Facultad de Ciencias. La Hechicera. ULA. 5 Magister en Protozoología. Centro de Investigaciones Parasitológicas ¨José W. Torrealba¨ NURR, ULA. 6 Medico Microbiologo. Laboratorio de Microbiología. Facultad de Medicina Escuela de Medicina. ULA. Valera. Venezuela. . 7 Licenciado en Farmacia. Laboratorio de Toxicología Facultad de Farmacia. ULA. Corresponding autor: Laura Vásquez de Ricciardi Facultad de Medicina Escuela de Medicina Valera. Universidad de Los Andes, final calle 6 detrás del Hospital Central de Valera. Valera. Venezuela. Tele-Fax: 0271-2215382; 0271-2313317. e-mail: [email protected] Financial support: This work was supported in part by the CDCHT- ULA project NURR-C-271-00-B-7, CVI-NURR-0395 and FONACIT Project Frontera 98000576. Recibido: 01/09/2006 Aceptado: 20/10/2006

Resumen Abstract

Se estudiaron los parámetros farmacocinéticos del antimo- The pharmacokinetic parameters of Glucantime® was studied niato de meglumina Glucantime® después de su adminis- after alone administration and in combination with gentami- tración solo y en combinación con gentamicina, a objeto de cine, to determine the effect of the aminoglucoside on the determinar el efecto del aminoglucósido sobre las concen- plasmatic concentrations and the pharmacokinetic parame- traciones plasmáticas y los parámetros farmacocinéticos del ters the metal. Four injected dogs were used with unique daily metal. Se inyectaron cuatro perros con una dosis única/día de dose of alone Glucantime® (25.65 mg kg-1) and Glucantime® Glucantime® (25.65 mgkg-1) durante 5 días y Glucantime® + + gentamicine (25.65 mg kg-1 and 5 mg kg-1, respectively). gentamicine (25.65 mg kg-1 y 5 mg kg-1, respectivamente). Se The blood samples were collected 0.25, 0.75, 1.0, 2.0, 4.0, colectaron muestras de sangre 0.25, 0.75, 1.0, 2.0, 4.0, 8.0, 8.0, 12.0 and 24.0 hours post-treatment. Determination of an- 12.0 y 24.0 horas post-tratamiento. Las determinaciones de timony was carried out using atomic absorption spectrometer. 60 antimonio se realizaron usando espectroscopia de absorción The results demonstrated that the combination modifies the atómica. Los resultados demuestran que la combinación mo- depuration of the metal and their sanguine decline resulted dificó la depuración del metal y disminuyó sus concentracio- in plasmatic concentration minors. The pharmacokinetics pa-

nes plasmáticas. Solo ClB mostró una diferencia significativa rameters evaluated only ClB showed a statistically significant (0.353 ± 0.110 a 0.733 ± 0.33 mLh-1kg-1), sugiriendo menor difference (0.353 ± 0.110 to 0.733 ± 0.33 mL h-1kg-1) sug- persistencia tisular con la administración conjunta. En el futu- gesting minor tisular persistence of antimony when adminis- ro debe aclararse si la gentamicina interfiere en el análisis de tered together with gentamicine. It is important to recognize las concentraciones de antimonio o viceversa. in future if the gentamicine interferes with the analysis of the antimony concentration o viceversa. Palabras claves: farmacocinética antimonio, antimoniato de meglumina, Glucantime®, gentamicina. Key words: Pharmacokinetic antimony, N-methylglucamine antimoniate, Glucantime, gentamicine.

Introduction

Chemotherapeutic treatment of cutaneous and visceral leish- lly and experimentally was monomycine (Neal 1968). More maniasis has not seen progress since the time antimony was recently, the use of aminosidine against different species of first used some fifty years ago. Its cost and levels of toxicity, Leishmania has been experimentally evaluated Scorza et al. the prolonged duration of the therapy, and individual variations 1988. Different researchers have shown positive results when in response to the therapy have created the need of evaluating pentavalent antimony was used in combination with aminosi- the use of other pharmacological options such as: aminoglu- dine (Chunge et al. 1990, Scott et al. 1992, Belloli et al. 1994, coside antibiotics. The first antibiotic evaluated both clinica- Tecklemariam et al. 1994, Belloli et al. 1999). search “José Witremundo Torrealba”Re of Los Andes ParasitologicalUniversity, of Center the of Committee Ethical The proteins and transaminases. amylases, bilirrubine, total and fractionate creatinine, urea, sured for platelet count and concentration levels of glycaemia, Three days prior to testing, blood and urine values were mea functioning.hepatic or pancreatic renal, in deterioration and sion were anemia, lengthering of abnormal prothrombine time, averagingused, kilogramsweight.15of exclu of criteria The Animal Materials andmethods ofmetal.pharmacokinetic antimonylevels on possibleon influence its gentamicine and of impact investigatethe to designed was study present The de Peña et al. 2001). (Petitspecies both of concentrations the of sum the as lated ng-L for antimony V (SbV). Total antimony content was calcu 3.2 and (SbIII) III forantimony ng-L 2.8 werevalue) target of deviation standard times 3 at (set detection of limits sulting (Varianspectrophotometer TechronAA-1475).model re The absorption an using processed were samples blood philized Quantification of antimony andgentamicine content. frozen invialsandtestedfor gentamicinecontent. then was which serum, its separate to g 1500 at centrifuged total determine antimony content. Another 2 ml of blood were to used were blood of ml 2 sample,state. Fromeach steady at concentration drug determine to order in drugs the tering tion. A last sample was taken on the fifth day prior to adminis - 2 - 4 - 8 - 12 - 24 hours after the first day of drug administra administration,drug followed by time sampling 0.25 - 0.75 - 1 sampling. Blood dogs from Group2were injectedwith NMG-Sbalone. two the whereas combination, the with 1 injected Group were from dogs two the after, month a out carried step sulting from the combined presence of the drugs. In a second re parameters pharmacokinetic the in changes for assay to (Group 2) were injected with both NMG-Sb plus gentamicine, foranimals two other pentavalentantimony;the the whereas evaluateparametersof to NMG-Sb with pharmacokinetic the out.injected carried were wasTwo 1) riment (Group animals the and study was done in each), two steps. In dogs a first step, a controlled (two expe groups two into distributed were animals the out, carried was cross-experiment controlled A Methods leg,atarate of5mg.Kg posterior right administered for five days via an intramuscular injection in the with 80 mg of gentamicine sulfate Lote 801 Exp 01.2001, was in A ampoules daily of dose 2 of ml gentamicine, Servipharm via asubcutaneousinjection(25.65mg.Kg Lote 456 Man 0698-Exp 0603, was administered for five days 5 ml with 1.5 of N-methylglucamine NMG-Sb (427.5 mg SbV) of Glucantime administration. of routes and doses,Drugs, approved outinthisstudy allprocedurescarried or w-er l haty eae yrd os were dogs hybrid female healthy old two-year Four

® , Specie Rhone-Poulnec Rorer in ampoules of A blood sample was obtained previous to previous obtained was sample blood A -1 . -1 ofantimony). A daily dose daily A Lyo ------perimental group showed a concentration 0.57 NMG-Sb plus gentamicine showed differences in the plasmagentamicinetheshoweddifferences plusNMG-Sb in andinitialadministration theandfromhours NMG-Sbonly 120 of 0.25 between about brought observations Systematic Results was established. p<0.05 of value significant statistical A 10.0. version SPSS programstatistical the using t-test paired a analyzedthrough analysis. Statistical me residuals. of the thod using calculated was (AUC) curve the under area (K constant (t half-life Ka, obtained, Tmax, Cpmax, results included the which for plotted were scale logarithmic t) vs. at (Cp time vs. plasma of curves Concentration 1975). & were use (Rowland analysis Tozercokinetic 1980, Wagner analysis. Pharmacokinetic ries). The limit of detection was set at 0.01 μg/ml. analyzerimmunofluorescentandTDx an usingassay (Abbott Laborato out carried were gentamicine of analysesSample statistically significant (Table 1). valent from the control group, the obtained differences were not were higher than in the experimental group. At 24 hours,total averagethe ex antimony concentration levels in the control groupconcentration of antimony between both groups. At 0.25 hours, 1.06 SD 0.104.334.14 2.391.700.440.350.25 1.33 Mean 1.307.175.39 6.572.371.080.940.57 1.07 4 1.270.972.44 8.161.221.371.030.74 1.30 3 1.2110.413.534.622.621.491.410.85 0.16 2 1.289.8711.529.084.700.950.670.35 1.79 1 1.477.434.084.440.990.520.660.36 Glucantime combination 25.65 mgKg 0.95 SD 1.112.865.207.693.470.760.510.22 1.38 Mean 2.824.657.379.234.822.321.731.00 2.79 4 2.537.4112.6213.379.843.302.421.00 1.06 3 4.416.7610.8817.994.421.761.851.24 0.69 2 1.821.611.762.362.471.671.300.88 0.98 1 2.532.814.213.192.542.551.380.89 120.0 (µg/ml)0.250.751.02.04.08.012.024.0// Dog Sbtotal Tiempo (hs) Glucantime alone25.65mgKg-1s.cx5day ved Glucantime Total blood concentrationsofantimony (SD)indogsthatrecei Table 1 el ), distribution volume Vd, clearance Cl volume clearance Vd, ), distribution ® aloneandGlucantime hraoiei prmtr were parameters Pharmacokinetic -1 s.c + gentamicina 5 mg.Kg Standard methods of pharma of methods Standard ® plusgentamicine. µ ½ g/ml half equi ), elimination elimination ), -1 im x 5 day B , and , the and ------

61 Archivos Venezolanos de Farmacología y Terapéutica Volumen 25, número 2, 2006 Figure 1 compares the lowering medium values of antimony Table 2 content in blood across time. Both showed decay in two pha- Mean pharmacokinetic parameters of antimony (SD) administe- ses. In the line corresponding to the NMG-Sb injected animals red alone or in combination with gentamicine to four dogs. the first 4 hours the plasma concentration fell from 9.23 ± 4.82 Parameter Units Glucantime alone Glucantime® μg mL-1 to 4.82 ± 3.47 μg mL-1, indicating a rapid distribution. combination In the second phase, the concentration fell more slowly and Cpmax µg/ml 9.51 (7.40) 8.63 (3.12) -1 the drug was still detectable at 24 hrs (1.00μg mL ± 0.22), Tmax hs 2.25 (1.25) 1.41 whereas the line corresponding to the NMG-Sb plus gentami- (0.64) cine showed two peak concentrations between 0 and 4 hours, Ka h-1 2.76 (2.25) 2.54 (2.05) similarly, the second phase concentration fell more slowly and t½ß hs 10.02 (3.5) 17.60 the drug was systematically minor with combination. It should (4.87) be stated that calculations of the pharmacokinetic parame- Kel h-1 0.075 (0.02) 0.041 (0.013) ters related to the apparent phase of elimination were carried Vd ß L/Kg 5.54 (3.6) 18.60 out beginning the eighth hour (Tassi 1994), as it was thought (10.62) best considering that drug administration was done subcuta- ClB L/ Kg xh 0.353 (0.11) 0.733 neously. The complete curve was taken for AUC values. (0.33) * AUC(o-∞ ) µg/ml x h 81.02 (28.1) 52.06 (10.11) Table 2 shows the results of the statistical analysis for the di- * Significative difference (p<0.05) fferent pharmacokinetic parameters used. Peak concentratio- ns of antimony for all four animals when injected with NMG-Sb only oscillated between 2.47 and 19.99 μg/ml with an average value of 9.51 (7.40) μg/ml. Peak concentrations of antimony Discussion for all four animals when injected with NMG-Sb plus gentami- cine oscillated between 7.43 and 11.52 μg/ml. The obtained Lack of research in the pharmaceutical industry to promote differences were not statistically significant. The time needed the synthesis of new drugs aimed to the treatment of leishma- to reach peak concentrations of antimony was 2.25 hours niasis has brought about the need to evaluate combinations (range of 1 to 4 hours) for NMG-Sb animals and 1.41 hours well-known pharmaceuticals, in an effort at increasing their (range of 0.8 to 2 hours) for NMG-Sb + gentamicine animals, potency and effectiveness. which was not statistically significant. From the pharmacoki- netic parameters assayed, only the clearance showed signifi- The present work was carried-out based on the results ob- cant differences between both groups (p<0.048). The half-life tained by Belloli et al. (1994), who studied the disposition of of animals with NMG-Sb only was 10.02 ± 3.5 hours, and for antimony and aminosidine in dogs following separated and animals NMG-Sb plus gentamicine was 17.60 ± 4.87 hours. combined administrations. The researchers reported a syner- gistic effect of both compounds, interpreted as a consequen- It should be noted that the constant of elimination values (Kel) diminished to 0.075 h-1 for the first group and to 0.041 h-1 for ce of the similarities in the pharmacokinetic patterns of both. the second group (differences between both groups were not Furthermore, they reported that aminosidine slowed down statistically significant). the elimination of antimony, due to the significant increase in the half-life of antimony and the reduction in its clearan- It should be stated that of the paraclinic criteria evaluated be- ce when both compound when administered together. This does not seem to be applicable to the case of gentamicine, 62 fore and after drug injection, serum creatinine levels increased temporarily in one of the experimental animals. as there were significant differences in the rate of body clea-

rance (ClB). A possible explanation for a gentamicine-induced increase in the rate of elimination of antimony might be that the antibiotic somehow modifies the binding of the metal to tisular proteins allowing the changes in presence of the metal in tissues. Plasma levels of antimony were found lower, which might be explained by the well-known effect that metal-bin- ding to serum proteins has over its elimination via glomerular filtration (Camner et al. 1986).

The antimony half-life obtained in our results when admi- nistered only is more prolonged than the ones previously reported for intravenous and subcutaneous administration (Chulay et al. 1988; Tassi 1992; Belloli et al. 1999). The diffe- rence might be explained by differences in diffusion mecha- nisms related to subcutaneous drug injection.

It seems likely that a competition between gentamicine and N-methylglucamine antimoniate (NMG-Sb) takes place during renal excretion. Our results suggest that an interaction between the antimony-containing drug and gentamicine exists, as the Fig. 1. Blood reduction mean in antimony levels as a function of time, for Glucantime® half-life of elimination for both was prolonged. Finally, it is impor- alone and for Glucantime® plus gentamicine 3 2 1 Referencias cios Prü and Mireya Parilli for critical review of the manuscript. Acknowledgment: with the analysis of the antimony concentration o vice versa. tant to recognize in future research if the gentamicine interferes References 12 11 10 9 8 7 6 5b 5a 4 ...... Scorza J, Hernández A, Villegas E, Marcucci M, Araujo P. Comprobación Neal R. The effect of antibiotics of the group on experimental Wagner J.G. Fundamentals of Clinical Pharmacokinetics Drugs ScottJ, Davidson R,Moody A,Grant H,Fremingham D, Scott ChungeC, Owate J, Pamba H,DonnoL.Treatment ofvisceral Rowland M, Tozer T. ClinicalPharmacokinetics. Conceptsand Tecklemariam S, GebreA,Frommel D, Miko T, A. Ganlov G,Bryceson, Petit de Peña Y, Vielma O, Burguesa J, Burguesa M, Rondón C, Carrero stibogluconate. Trans. Roy. Soc. Tro. Med. Hyg1990; 84: 221-225. Kenyain sodium bywith combined or alone aminosidine Malar & Saneam. Amb 1988; 28: 23-5. leishmaniasis mientoladetegumentaria enTrujillo, Venezuela. DirBol trata elGabbromicina enla Glucantimesinergismo yentre delclínica . Am. Trop. MedParasitol 1968; 12:54-68. mic absortion spectrometry.mic absortion Talanta 2001; 55: 743-754. liver tissue and whole blood by flow - injection hydride generation - ato P,antimonyof antimony and (III) three five determination line in On (V) Trop. Med. Hyg1992; 86: 617-619. Kingdom.United the Trans. into imported leishmaniasis of Roy. Soc. P,treatment Olliaro the M, in ()A. Aminosidine Bryceson . . . . . Intelligence Publications ING. Hamilton. 1975. Applications. LeaandFebiger Philadelphia. 1980. Tassi P. Pharmacokinetic of N-methylglucamin antimoniate after Camner P, Clarkson T, NordbergG.Routesofexposure, doseand Belloli C, S, CeciL,Carlis Tassi P, Montesissa C, DeNataleG, aethiopica. Tran. Roy.Leishmania by Soc. Trop.caused the leishmaniasis Med.cutaneous Hyg1994; in 88:334-339. diffuse of stibogluconate treatment sodium with combination its ant Aminosidine 157(3): 315-321. dogs.in injection subcutaneous multiple ter 1999; VeterinaryJournal P. S,Ormas antimonyDisposition of combination af aminosidine and therapy ofleishmaniasis. Res. Vet. Sci. 1994; 58(2): 123-127. the for implications together: and separately administration after dog P,Marcotrigiano P.Ormas Disposition of antimony and aminosidine in Belloli C, CrescenzoS, G,Carli ZaghiniA,MengozziG,Bertini 82:69-72. and . Trans. Roy. Soc. Trop. Med. & Hyg 1988; treatment of during with Ed Friberg and V.B Vouk . Amsterdam.metabolism Elsevierofmetals. InHandbook Science. onthe Toxicology 1986. pp.ofMetals 2nd Ed.85-127 dog. the Res. in Veter. in Sci1994; 56:144-150. administration subcutaneous and intramuscular intravenous, Chulay L,Fleckenstein L,SmithD. ofantimony Pharmacokinetics We thank Drs. Nestor Añez, Ernesto Pala - - - -

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