Effects of fluconazole on the pharmacokinetics and pharmacodynamics of antimony in cutaneous leishmaniasis-infected hamsters

• Published in: International journal of antimicrobial agents 2007-06, Vol.29 (6), p.728-732
• Main Authors: Alnaim, Lamya, Abou Alsoud, Nermeen, Zaghloul, Iman, AL-Jaser, May
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal Agents - administration & dosage; Antifungal Agents - pharmacology; Antimony; Antimony - administration & dosage; Antimony - blood; Antimony - pharmacokinetics; Antimony - urine; Antiprotozoal Agents - administration & dosage; Antiprotozoal Agents - blood; Antiprotozoal Agents - pharmacokinetics; Antiprotozoal Agents - urine; Area Under Curve; Biological and medical sciences; Cricetinae; Drug Therapy, Combination; Fluconazole; Fluconazole - administration & dosage; Fluconazole - pharmacology; Half-Life; Human protozoal diseases; Infectious Disease; Infectious diseases; Injections, Intravenous; Leishmaniasis; Leishmaniasis, Cutaneous - metabolism; Leshmaniasis; Medical sciences; Mesocricetus; Parasitic diseases; Pharmacokinetics; Pharmacology. Drug treatments; Protozoal diseases; Random Allocation; Sodium stibogluconate
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2007.01.013

Abstract Pentavalent antimony (SbV ) compounds are the drugs of choice for the treatment of all forms of leishmaniasis. For 20 years there has been an interest in antifungal azoles for treating leishmaniasis, with variable success. In the current study, we examined the effects of co-administration of fluconazole (FLZ) on the pharmacokinetics and pharmacodynamics of SbV in cutaneous leishmaniasis-infected hamsters. Hamsters were divided into four groups. All hamsters were injected with 0.1 mL of 1 × 108 promastigotes/mL into the right foot on Day 1. Treatment was started 5 days after the infection. The antimony group received 80 mg/kg/day of Pentostam® intramuscularly whilst the FLZ group received FLZ 20 mg/kg/day orally for 14 days. The combination group received both Pentostam® and FLZ at the above mentioned doses for 14 days. Animals in the control group received no treatment. The infected footpads were measured on Days 1 and 14. A pharmacokinetic study was conducted on Days 1 and 14 of treatment, representing single- and multiple-dose pharmacokinetics, respectively. Blood samples were collected at different time intervals up to 24 h. SbV was determined using flameless atomic absorption spectrophotometry. Pharmacokinetic parameters were calculated using a non-compartmental analysis. In the single-dose study, there was no statistically significant difference in any of the pharmacokinetic parameters of SbV when given alone or with FLZ. However, on Day 14 a significant increase in peak plasma concentration ( Cmax ) (three-fold) and area under the concentration–time curve (AUC) (four-fold) of antimony was observed when SbV was co-administered with FLZ. A statistically significant prolongation of the terminal half-life from 1.63 to 8.67 h ( P < 0.05) was also observed. A significant reduction in clearance was detected. However, FLZ had no effect on the pharmacodynamics of SbV as measured by footpad sizes. In conclusion, FLZ did not improve the therapeutic effect of SbV when given concomitantly despite the significant increase in blood concentration and prolongation of the elimination half-life of SbV.