Pharmacokinetics and tissue distribution of rifametane, a new 3-azinomethyl-rifamycin derivative, in several animal species.

Single and repeated dose experiments in mice, rats, dogs and monkeys are reported in this study to assess the pharmacokinetics and tissue distribution of rifametane, a new semi-synthetic rifamycin with the chemical formula 3-[(1-diethylaminoethylidene)azinomethyl]rifamycin SV (CAS 94168-98-6, SPA-S-565). All the kinetic tests were carried out in comparison with known rifamycin derivatives, as rifampicin (CAS 13292-46-1) or rifamycin SV (CAS 6998-60-3). Mice received single i.v. and oral administration of 10 mg/kg of rifametane or of rifampicin and serum samples were obtained up to 96 h after dosing. The two antibiotics showed similar peak of serum concentrations, but rifametane showed a longer half-life and higher AUC values. In an additional experiment, the tissue/serum ratio after the 10 mg/kg oral dose was lower than unity for lungs and kidneys, while the liver/serum ratio exceeded the unity at all sampling times. After 4 weeks of once weekly administration measurable serum and tissue concentrations were observed, and after twice weekly administration for the same time period some blood and tissue accumulation was seen. Rats were treated with a single intravenous injection of 20 mg/kg of rifametane or rifampicin and with single oral or i.m. administration of 60 mg/kg of rifametane or reference standards (rifampicin and rifamycin SV resp.), in two separate trials. The serum half-life of the test antibiotic after i.v. dose was 6 times longer than that of rifampicin and the serum concentrations of rifametane after oral and i.m. doses were higher and longer-lasting than those of the reference compounds. Repeated daily administrations of rifametane at three dose levels (3, 10, 30 mg/kg p.o.) for 4 weeks induced very high serum and liver concentrations. Dogs received a single oral dose of 1.25 mg/kg of rifametane or 2.5 mg/kg of rifampicin. The serum half-life of rifametane resulted 3 times longer than that of rifampicin. Remarkable serum and tissue concentrations were observed after 3-4 weeks of daily oral administration of rifametane at 3, 10, 30 mg/kg dose. Monkeys were given single oral or i.m. administration of 30 mg/kg of rifametane or reference standards (oral rifampicin and i.m. rifamycin SV). The serum concentrations after rifametane were higher and more sustained than those of reference compounds and the half-lives of the test antibiotic were about 2.5 (p.o.) to 6 times (i.m.) longer. The urine excretion of rifametane after a single intravenous dose in rats and a single oral dose in dogs was very low, while rifampicin had a little higher urine concentrations.

Overview of SPA-S-843 in vitro activity against filamentous fungi.

In this study, we investigated the in vitro antifungal activity of a new water-soluble partricin A derivative, N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide diascorbate, coded SPA-843, currently developed by Società Prodotti Antibiotici. The activity of SPA-S-843 was compared to that of amphotericin B against 13 strains of Aspergillus spp., 4 strains of Mucor sp., 4 strains of Rhizopus oryzae, 2 strains Paecilomyces variotii, 5 strains of Penicillium spp., 1 strain of Sporothrix schenkii, 7 strains of Trichophyton spp. and 2 strains of Microsporum spp.; the minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) were measured for all the organisms. The in vitro susceptibility testing method employed was an adaptation of the macrodilution reference method for yeasts as described in the National Committee for Clinical Laboratory Standards document M27-A. The in vitro inhibitory activities of SPA-S-843 and amphotericin B against the fungi were evaluated in RPMI-1640 supplemented with L-glutamine and buffered with morpholinepropanesulfonic acid, while the in vitro fungicidal activities were determined by subculturing 0.1 ml from all tubes with no visible growth onto drug-free Sabouraud dextrose agar plates. Comparison with amphotericin B showed that the in vitro inhibitory activity of SPA-S-843 against Aspergillus spp. was better than that of amphotericin B and similar against R. oryzae, P. variotii, Penicillium spp. and S. schenkii. Amphotericin B presented geometric means (GM) of the MICs lower than those of SPA-S-843 against Mucor sp., Microsporum spp. and Trichophyton spp. SPA-S-843 was most fungicidal against Mucor sp. and P. variotii; SPA-S-843 and amphotericin B showed the same fungicidal activity against Aspergillus spp. (GM of the MFCs 12.53 microg/ml), Penicillium spp. (about 12 microg/ml) and S. schenkii (MFC 19.2 microg/ml). Amphotericin B presented GM of the MFC values lower than those of SPA-S-843 against R. oryzae, Microsporum spp. and Trichophyton spp.

In vitro activity of a new polyene, SPA-S-843, against yeasts.

The in vitro activity of a new water-soluble polyene, SPA-S-843, was evaluated against 116 strains of Candida, Cryptococcus, and Saccharomyces spp. and compared with that of amphotericin B. SPA-S-843 demonstrated better inhibitory activity against all of the yeasts examined and better fungicidal activity against Candida albicans, Candida glabrata, Candida krusei, and Candida tropicalis than did amphotericin B.