Amide derivatives of partricin A with potent antifungal activity

Pharmacokinetics of a new semisynthetic polyene antibiotic (N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide) in the form of its diaspartate salt (code SPA-S-753) was studied in rats and mice following intravenous injection and in rats following oral administration at different dose levels. In rats the urinary and biliary recovery after intravenous administration was also determined. Rats and mice received a single intravenous injection of 1.25 and 2.5 mg/kg of SPA-S-753 (about 1–2 mg/kg of free base) or 1 mg/kg of amphotericin B as reference drug. Blood samples were obtained at 5 min to 96 h after injection. The half-lives at the elimination phase in serum were 21.3, 26.5, 10.8 h in rats and 11.7, 13.7, 19.8 h in mice, respectively, for 1.25 and 2.5 mg/kg of SPA-S-753 and 1 mg/kg of amphotericin B. The values of AUC_0–∞ for SPA-S-753 were about 5 times higher in rats and twice higher in mice than those for amphotericin B. Rats received also a single oral dose of 200 or 500 mg/kg of SPA-S-753. Serum samples were obtained at 0.5–96 h after dosing. The compound is poorly absorbed by the oral route. The mean cumulative urinary recovery of SPA-S-753 at 48 h after intravenous injection of 1.25 mg/kg in rats accounts only for 0.5% of the dose, while the cumulative recovery from the bile at 10 h after 2.5 mg/kg i.v. administration in rats accounts for 5.5% of the dose.

Section: Discussionmentioning

confidence: 49%

“…In a recent paper, we have reported the synthesis and some biological properties of new amide or diamide derivatives of partricin A endowed with potent antifungal activity [1].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of a New Derivative of Partricin A (SPA-S-753) in Rodents

Galmozzi¹,

Bruzzese²,

Buffa³

et al. 2000

“…The effort to improve the biological properties of partricin A has led to the preparation of N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide (SPA-S-752), which possesses higher potency and lower toxicity [3] than the parent compound, and more recently two hydrosoluble salts of SPA-S-752: the diaspartate (SPA-S-753) [4,5] and the diascorbate (SPA-S-843), also coded as SPK-843 [6,7].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics in Rats of N-Dimethylaminoacetyl-Partricin A 2-Dimethylaminoethylamide Diascorbate (SPK-843)

Bruzzese¹,

Galmozzi²,

Buffa³

et al. 2001

Single- and multiple-administration trials in rats were performed in this study to assess the serum and tissue concentrations of SPK-843 (N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide diascorbate), a new polyene antibiotic with a heptaene structure. A dose of 1.25 mg/kg (roughly 1 mg/kg of free base) by intravenous route was used both for the single- and multiple-administration trials. The single-administration trial was carried out in comparison with amphotericin B (AmB) at intravenous doses of 1 mg/kg. Plasma samples were drawn at intervals from 15 min to 96 h after injection. The elimination half-lives were 22.15 and 18.15 h, and the area under the curve to infinity (AUC_0–∞) values were 35.52 and 10.33 µg·h·ml^–1, respectively, for SPK-843 and AmB. Both drugs showed an extensive tissue distribution, with higher uptake by the kidneys, followed by the liver, spleen and lungs for SPK-843, and higher uptake by the spleen, followed by the lungs, liver and kidneys for AmB. The multiple-administration trial (1.25 mg/kg/day for 7 days) led to sustained serum and tissue concentrations. On the seventh day, the rats were bled at intervals from 5 min to 96 h after dosing. The serum elimination half-life and AUC_0–∞ values were roughly twice those of the single-dose study (41.4 h and 72.1 µg·h·ml^–1, respectively). Also, the half-lifes and AUCs from 0 to ∞ of tissues were greater than those in the single-dose trial.

“…The chemical development of partricin led to the synthesis of its methylester, which showed in vitro antifungal activity superior to that of amphotericin B and nystatin and less toxicity than the parent compound [2][3][4]. Further research led to the isolation of partricin A and to some water-soluble amide derivatives with limited toxicity, among which SPK-843 was chosen for pharmacological development [5].…”

Section: Introductionmentioning

confidence: 99%

Comparative Pharmacokinetics of Three Preparations of the New Antifungal SPK-843

Bruzzese¹,

Galmozzi²,

Ferrari³

et al. 2001

The pharmacokinetics and tissue distribution of three preparations of SPK-843 (N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide diascorbate), a new polyene antibiotic with a heptaene structure, were compared in rats after a single 1.25 mg/kg intravenous administration. Blood and tissue samples were obtained at 0.25–96 h after injection. The serum pharmacokinetics of the three dosage forms of the antibiotic, A (5% glucose solution), B (10% lipid emulsion at pH 5.3) and C (10% lipid emulsion at pH 7.5), did not show large differences, the half-lives being 22.2, 26.5 and 23.2 h and the AUC_0–∞ 35.5, 40 and 44.8 µg·h·ml^–1 for preparations A, B and C, respectively. The tissue uptake of the two lipid-based preparations, particularly the spleen uptake, was greater than that of the glucose preparation, suggesting an active role of the lipid vehicle in tissue distribution.