The Distribution of Free and Non-Ionic Vesicular Sodium Stibogluconate in the Dog

Abstract

The pharmacokinetics and tissue distribution of antimony after the administration of sodium stibogluconate in a free form or entrapped in vesicles prepared from non-ionic surfactant were studied in the dog. Animals were given either one or two intravenous bolus injection(s) equivalent to 45 mg Sb kg-1 as free drug or 0.625 or 0.685 mg Sb kg-1 as vesicular drug. Blood samples were taken at various times after dosing and antimony levels in various tissues were determined at 3 h, 48 h and 6 days after dosing. After free stibogluconate antimony clearance from the blood occurred in a rapid elimination phase with a blood half-life of 0.58 +/- 0.08 h. This rapid elimination phase did not occur after vesicular drug. Both drug preparations gave similar antimony levels in the spleen, liver and femur and humerus bone marrow at all time points assessed even though the vesicular dose was one-seventieth of the free drug dose. After the free drug there was marked urinary excretion of antimony and, as a result, increased kidney loading at the expense of other tissue. Vesicle-mediated drug delivery suppressed renal excretion and a much greater proportion of the antimony dose was recovered from tissue than was obtained after free drug. A hypothesis is presented to account for the differences in tissue antimony concentrations produced by the two formulations.

Pharmacokinetic and parasitological evaluation of the bone marrow of dogs with visceral leishmaniasis submitted to multiple dose treatment with liposome-encapsulated meglumine antimoniate

“…Even though sodium stibogluconate and meglumine antimoniate are different pentavalent antimony complexes, the fact that both drugs showed identical pharmacokinetics in humans (10) justifies the present comparison. In the bone marrow, antimony levels in the range of 2 µg/g were found 3 and 48 h after administration (8). Strikingly, these levels are in the same range as those found in the present study.…”

“…Our results can also be compared to those obtained following a single iv injection in healthy dogs of another vesicular system given at 0.65 mg Sb/kg body weight (8). In the latter study, antimony levels of 5-30 µg Sb/g and 1-8 µg Sb/g were found in the bone marrow 3 and 48 h after administration, respectively.…”

“…Although 10-fold higher and multiple doses were given in the present study, antimony levels in the bone marrow still remained relatively low. These low antimony levels may be attributed to the large size (1.2 µm) of the liposomes used in the present study when compared to that of the liposomes previously used (0.12 µm) (8), and to the fact that bone marrow is expected to be more accessible to smaller liposomes (9).…”

“…The antimony levels in the bone marrow of dogs following treatment with free and liposome-encapsulated antimonials have been reported in two previous studies (5,8). However, these studies used healthy animals and did not evaluate the effect of multiple dose treatment.…”

Efficacies of Vesicular and Free Sodium Stibogluconate Formulations against Clinical Isolates of Leishmania donovani

“…The greater efficacy of SSG-NIV in vivo presumably reflects its ability to modify its in vivo distribution and thus direct a great proportion of the drug dose to tissues (7,8). For example, tissue antimony levels (spleen, liver, femur, and humerus) at 6 days posttreatment were similar in free-SSG-and SSG-NIV-treated animals, despite a 70-fold difference in the drug dose administered (8). There was interstrain variability in susceptibility to SSG-NIV.…”