Skin uptake, distribution, and elimination of antimony following administration of sodium stibogluconate to patients with cutaneous leishmaniasis

Abstract

We examined in this study the pharmacokinetics of Sb in the affected skin and normal skin of patients treated with sodium stibogluconate for cutaneous leishmaniasis and compared the results with those for the blood. The procedure was fully explained, and a written consent was obtained from each of nine patients. After a dose of sodium stibogluconate equivalent to 600 mg of Sb was administered intramuscularly, small skin biopsies were collected under local anesthesia at different time intervals from the circumferences of the lesions and simultaneously from normal skin. Antimony was measured in these biopsies after suitable ashing and processing by flameless atomic absorption spectrophotometry. The means (with standard errors of the means in parentheses) of the peak concentration, time to peak concentration, area under the curve, half-life, and mean residence time in lesions were 5.02 (1.43) g/g, 2.1 (0.4) h, 32.8 (6.1) g ⅐ h/g, 6.88 (0.54) h, and 10.4 (1.2) h, respectively, and those in normal skin were 6.56 (2.01) g/g, 2.6 (0.8) h, 44.0 (15.8) g ⅐ h/g, 5.44 (0.83) h, and 8.08 (1.34) h, respectively. There was no significant difference in any of these parameters between lesions and normal skin, whereas the differences in peak concentration, half-life, and mean residence time between lesions and whole blood were significant (P Յ 0.05). The penetration of Sb into skin, either affected or normal, as measured by the skin/blood area under the curve ratio appears to be complete, but the disposition is slow compared with that from the blood.The best treatment for leishmaniasis is currently achieved with pentavalent antimonials in the form of sodium stibogluconate (SSG) or meglumine antimonate. However, because of the rapid blood clearance of these drugs (5,13,14,17), an increase in dose and dosing frequency has been recommended by the World Health Organization (18). The amount of exposure of the infectious parasite to pentavalent antimony is believed to be an important factor in eradicating the cutaneous leishmania disease. Thus, delivering the dose by intralesion injections of SSG has recently been advocated (8,10,15). When the drug is administered intramuscularly, the contact with the parasite is undoubtedly controlled by the rate and extent at which this metal reaches and leaves the lesions following the administration of SSG. Therefore, knowledge of the kinetics of the uptake and disposition of this metal in affected skin is vital for optimization of the dosage regimens of these drugs in the treatment of cutaneous leishmaniasis. Although these drugs have been in use for more than four decades (11,16), no such study has yet been reported for SSG. Plasma kinetic data are clinically relevant to the extent that they reflect those of the site of action.We undertook to examine in this study the kinetics of Sb in the affected skin and normal skin of patients treated intramuscularly with sodium stibogluconate for cutaneous leishmaniasis and to compare the results with those for the blood samples of these patients. The impac...

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

“…Pharmacokinetic parameters of Sb V in humans have been described previously [11,12] and are similar to those measured in hamsters in this study. A consistent finding was the appearance of a second peak in the plasma concentration at ca.…”

“…However, no reports were found to indicate whether active tubular secretion has a role in Sb V elimination. ALJaser et al [12] reported Sb V renal clearance in patients infected with CL to be 211.7 ± 19.3 mL/min, which shows possible involvement of active tubular secretion in addition to glomerular filtration. Accordingly, the significant increase in AUC and decrease in CL/F of Sb V following multiple dosing could be due to FLZ competition with Sb V renal excretion in hamsters infected with CL.…”

“…More than 80% of Sb V is cleared by urinary excretion [11][12][13]. However, no reports were found to indicate whether active tubular secretion has a role in Sb V elimination.…”

Disseminated Cutaneous Leishmaniasis Resembling Post-Kala-Azar Dermal Leishmaniasis Caused by Leishmania donovani in Three Patients Co-Infected with Visceral Leishmaniasis and Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome in Ethiopia

“…30 In the Mediterranean basin, biochemical differences were observed between dermatotropic and viscerotropic isolates of L. infantum . 31 However, other studies in different Mediterranean countries 32,33 showed that this association was not absolute.…”

Inhibition of Hepatitis C Virus Replication by Antimonial Compounds

“…SSG consists of Sb conjugated with glucose. After administration to humans, the peak concentration of Sb in plasma is approximately 10 g/ml (ϳ82 M) (1,7,11). Though such a peak Sb concentration seems relatively low compared to the SSG EC 50 for HCV inhibition found in this study (0.2 to 0.3 mg/ml of SSG or 345 to 517 M of Sb), several factors should to be taken into consideration.…”