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 Disponible en: http://www.redalyc.org/articulo.oa?id=55925204 Cómo citar el artículo Número completo Sistema de Información Científica Más información del artículo Red de Revistas Científicas de América Latina, el Caribe, España y Portugal Página de la revista en redalyc.org Proyecto académico sin fines de lucro, desarrollado bajo la iniciativa de acceso abierto Influence of gentamicine on the pharmacokinetic of a pentavalent antimonial compound Glucantime® Influence of gentamicine on Glucantime kinetic 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). The present study was designed to investigate the impact of Sample analyses of gentamicine were carried out using an gentamicine on antimony levels and its possible influence on analyzer TDx and immunofluorescent assay (Abbott Laborato- pharmacokinetic of metal. ries). The limit of detection was set at 0.01 μg/ml. Pharmacokinetic analysis. Standard methods of pharma- Materials and methods cokinetic analysis were use (Rowland & Tozer 1980, Wagner 1975). Concentration curves of plasma vs. time (Cp vs. t) Animal Four two-year old healthy female hybrid dogs were at logarithmic scale were plotted for the results obtained, used, averaging 15 kilograms of weight. The criteria of exclu- which included Cpmax, Tmax, Ka, half-life (t ), elimination sion were anemia, lengthering of abnormal prothrombine time, ½ constant (K ), distribution volume Vd, clearance Cl , and the and deterioration in renal, pancreatic or hepatic functioning. el B area under the curve (AUC) was calculated using the me- Three days prior to testing, blood and urine values were mea- thod of residuals. sured for platelet count and concentration levels of glycaemia, urea, creatinine, fractionate and total bilirrubine, amylases, Statistical analysis. Pharmacokinetic parameters were proteins and transaminases. analyzed through a paired t-test using the statistical program SPSS version 10.0. A statistical significant value of p<0.05 The Ethical Committee of the Center of Parasitological Re- was established. search “José Witremundo Torrealba” of Los Andes University, approved all procedures carried out in this study Results Drugs, doses, and routes of administration. A daily dose Systematic observations brought about between 0.25 and of Glucantime®, Specie Rhone-Poulnec Rorer in ampoules of 120 hours from the initial administration of NMG-Sb only and 5 ml with 1.5 of N-methylglucamine NMG-Sb (427.5 mg SbV) NMG-Sb plus gentamicine showed differences in the plasma Lote 456 Man 0698-Exp 0603, was administered for five days concentration of antimony between both groups. At 0.25 hours, via a subcutaneous injection (25.65 mg.Kg-1 of antimony). total average antimony concentration levels in the control group A daily dose of gentamicine, Servipharm in ampoules of 2 ml were higher than in the experimental group. At 24 hours, the ex- with 80 mg of gentamicine sulfate Lote 801 Exp 01.2001, was perimental group showed a concentration 0.57 μg/ml half equi- administered for five days via an intramuscular injection in the valent from the control group, the obtained differences were not right posterior leg, at a rate of 5 mg.Kg-1. statistically significant (Table 1). Table 1 Methods Total blood concentrations of antimony (SD) in dogs that recei- ved Glucantime® alone and Glucantime® plus gentamicine. Volumen 25, número 2, 2006 2, número 25, Volumen A controlled cross-experiment was carried out, the animals Glucantime alone 25.65 mgKg-1 s.c x 5 day were distributed into two groups (two dogs each), and the Dog Sb total Tiempo (hs) study was done in two steps. In a first step, a controlled expe- (µg/ml) 0.25 0.75 1.0 2.0 4.0 8.0 12.0 24.0 // riment was carried out. Two animals (Group 1) were injected 120.0 Terapéutica y de Farmacología Venezolanos Archivos with NMG-Sb to evaluate the pharmacokinetic parameters of 1 2.53 2.81 4.21 3.19 2.54 2.55 1.38 0.89 the pentavalent antimony; whereas the other two animals for 0.98 (Group 2) were injected with both NMG-Sb plus gentamicine, 2 1.82 1.61 1.76 2.36 2.47 1.67 1.30 0.88 0.69 to assay for changes in the pharmacokinetic parameters re- 3 4.41 6.76 10.88 17.99 4.42 1.76 1.85 1.24 61 sulting from the combined presence of the drugs. In a second 1.06 step carried out a month after, the two dogs from Group 1 4 2.53 7.41 12.62 13.37 9.84 3.30 2.42 1.00 2.79 were injected with the combination, whereas the two dogs Mean 2.82 4.65 7.37 9.23 4.82 2.32 1.73 1.00 from Group 2 were injected with NMG-Sb alone. 1.38 SD 1.11 2.86 5.20 7.69 3.47 0.76 0.51 0.22 Blood sampling. A blood sample was obtained previous to 0.95 drug administration, followed by time sampling 0.25 - 0.75 - 1 Glucantime combination 25.65 mgKg-1 s.c + gentamicina 5 mg.Kg-1 im x 5 day - 2 - 4 - 8 - 12 - 24 hours after the first day of drug administra- tion.