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

Single and repealed dose experiments in mice, rats, dogs and monkeys are re ported in this study to assess the pharmacokinetics and tissue districution of rifametane, a new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 rifam ycin 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 rifame tane showed a longer half-life and higher AUC values. In an additional expe riment, 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 measura ble serum and tissue concentrations were observed, and after twice weekly a dministration for the same time period some blood and tissue accumulation w as seen. Rats were treated with a single intravenous injection of 20 mg/kg of rifame tane or rifampicin and with single oral or i.m. administration of 60 mg/kg of rifametane or reference standards (rifampicin and rifamycin SV resp.), i n 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 concentrati ons of rifametane after oral and i.m. doses were higher and longer-lasting than those of the reference compounds. Repeated daily administrations of ri fametane at three dose levels (3, 10, 30 mg/kg p.o.) for 4 weeks induced ve ry high serum and liver concentrations. Dogs received a single oral dose of 1.25 mg/kg of rifametane or 2.5 mg/kg o f rifampicin. The serum half-life of rifametane resulted 3 times longer tha n that of rifampicin. Remarkable serum and tissue concentrations were obser ved 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 rifame tane or reference standards (oral rifampicin and i.m. rifamycin SV). The se rum concentrations after rifametane were higher and more sustained than tho se of reference compounds and the half-lives of the test antibiotic were ab out 2.5 (p.o.) to 6 times (i.m.) longer. The urine excretion of rifametane after a single intravenous dose in rats a nd a single oral dose in dogs was very low while rifampicin had a little hi gher urine concentrations.