Pharmacokinetics of pentavalent antimony (Pentostam) in hamsters.

Pentavalent antimony (Sb) is the classical treatment for visceral and cutaneous leishmaniasis. We investigated Sb levels in serum, liver, spleen, and skin of hamsters administered therapeutic dosages of Sb (600 and 300 mg Sb/kg). Single administration of Sb was more effective against hepatic parasites than dividing the same total dose into multiple administrations, which suggests that for elimination of hepatic parasites in vivo, peak Sb concentration is more important than total area-under-the-curve levels. Serum Sb declined with an initial half-life of 1 hr. Skin Sb levels (352 micrograms Sb/g 1 hr after 600 mg Sb/kg) were initially higher than liver levels (77 micrograms Sb/g) or splenic levels (156 micrograms Sb/g), but levels were comparable (7-24 micrograms Sb/g) in the three organs by 8 hr after dosing. The generally comparable levels of Sb in the skin and in the visceral organs support the present clinical practice of administering the same dosage of Sb for cutaneous and visceral leishmaniasis.

Effect of renal impairment on the pharmacokinetics of antimony in hamsters.

Renal failure was experimentally induced in 36 hamsters by intraperitoneal injection with uranyl nitrate (5 mg/kg). Twenty-four h later [during acute renal failure (ARF), as indicated by the serum concentrations of creatinine and urea nitrogen] or 72 h later [during chronic renal failure (CRF)] these hamsters plus 18, uninjected, control hamsters were each given a single, intramuscular dose of sodium stibogluconate (120 mg pentavalent antimony/kg). The pharmacokinetic parameters for the antimonial drug were calculated using a non-compartmental model. Urine was collected for 72 h after similar treatment with the antimonial drug, from another 30 hamsters (10 controls, 10 with ARF, and 10 with CRF), so that the fraction of the antimony administered that was subsequently excreted in the urine could be estimated. Compared with the controls, both the hamsters with ARF and those with CRF had significantly higher maximum concentrations of antimony (C(max)), significantly larger 'areas under the curve' for the plots of blood concentration v. time, and significantly longer plasma half-lives (P < 0.001 for each). The mean (S.D.) values of C(max), for example, were more than three-fold higher in the hamsters with ARF [467.5 (59.04) microg/ml] or CRF [461.1 (68.9) microg/ml] than in the controls [154.01 (17.3) microg/ml]. The systemic clearance of antimony was also significantly lower in the hamsters with CRF than in the control animals [0.051 (0.002) v. 0.296 (0.047) litres/h/kg; P < 0.01]. In addition, the fraction of the antimony administered that was excreted in urine was significantly lower in the animals with ARF (0.25) or CRF (0.08) than in the controls (0.37), indicating significant dysfunction of the kidneys in the hamsters injected with uranyl nitrate. It seems clear that, if severe toxicity is to be avoided, patients with renal dysfunction requiring treatment (for leishmaniasis) with sodium stibogluconate should be given lower doses than similar cases with normal kidney function.

Renal clearance of pentavalent antimony (sodium stibogluconate).

Kenyan kala-azar is sometimes unresponsive to a standard course of sodium stibogluconate. The renal excretion of sodium stibogluconate was therefore studied in patients with kala azar and in volunteers; both urine and serum levels of sodium stibogluconate were measured. After intravenous injection sodium stibogluconate seemed to be distributed throughout the extracellular fluid and to have a renal clearance similar to that of inulin. At 6 h blood levels had fallen to less than 1% of peak values. After intramuscular injection, peak blood levels were lower and more sustained. However, more than 80% was excreted in the first 6 h, and blood levels fell to around 1% of peak values in 16 h. The dangers of cumulative toxicity may be exaggerated, and restriction of courses of sodium stibogluconate to 30 days or even to 10 days (in the U.S.A.) may not be necessary. If shorter courses are ineffective prolonged and continued courses may be given provided that renal function is assessed and the dosage is adjusted when indicated.