A study on the pharmacokinetics of rifapentine, a new long-lasting rifamycin, has been carried out in the rat, the mouse and the rabbit. The investigation was made using either radioactive or unlabelled rifapentine and both the total -=C and the unchanged compound were assayed.In the rat, the overall evidence obtained was: (a) the oral absorption of rifapentine into central compartment, due to its poor water solubility, appears to be dose-dependent with a satisfactory oral absorption (84°0) after a dose of 3 mg/kg, lower (65%) after 10 mg/kg; (b) the antibiotic undergoes rapid liver uptake while it diffuses into the tissue compartment more slowly, with particular affinity for the adrenals, pancreas and kidneys; concentrations higher than in plasma were also measured in the lungs; (c) elimination of rifapentine from the blood and tissue compartments suggests a non linear capacity-limited kinetics where the terminal elimination phase has monoexponential course. Terminal plasma half-life ranged between 14 and 18 hours: (d) the compound is eliminated mainly via the bile with the feces (92% of dose).In mice rifapentine shows a kinetic profile resembling that obtained in rats, whereas in rabbits is metabolized and or eliminated much more rapidly with a half-life of only 1.8 hours.Rifapentine (INN), Fig.

No abstract

In 24 hr urine of rats orally given 150 mg/kg of 3-hydrazino-6-[bis-(2-hydroxyethyl)amino]pyridazine dihydrochloride (DL 150), no unchanged compound was detected. Three metabolites, less polar than DL 150, were isolated, their structures assigned by UV, MS, IR and 1H NMR spectroscopies, and confirmed by synthesis. They are: 3-[bis-(2-hydroxyethyl)amino]-6-isopropoxypyridazine (1); 3-[bis-(2-hydroxyethyl)amino]pyridazine (2); 3-methyl-6-[bis-(2-hydroxyethyl)amino]-s-triazolo[4,3-b]pyridazine (3). The metabolism of DL 150 in the rat follows some of the metabolic pathways reported for hydralazine.

The disposition of four C3-substituted piperazinyl rifamycins was studied in the rat following the intravenous administration of 5 mg/kg of the 14C-labelled antibiotics. Considerable quantitative differences in the pharmacokinetics of these antibiotics were shown in blood levels, tissue distributions and body clearances. Feces were largely the major route of elimination for the parent drug and metabolites. The results suggest that the liver compartimentalization, regulating the biliary excretion, is to be the kinetic parameter affecting the pharmacokinetic behaviour of this class of antibiotics. rifamycin SV) specific activity 10.21 mCi/mmole and 38-14C-AF/ABDP (3-[(4-cis-aminobenzyl-2,6-dimethyl-piperazinyl)imino]methyl rifamycin SV) specific activity 12.15 mCi/mmole, were kindly supplied by G. SAR-TORI from our research laboratories.9) Animal treatment and sample collection Male Wistar rats weighing 200260 g were fasted for 18 hours before they were used. Rifamycins, dissolved in 0.3 ml of 0.1 M NaHCO3, containing 10-3 M ascorbic acid and 2.5 % N,N'-dimethylformamide, were administered intravenously via the femoral vein at a dosage of 5 mg/kg. Animals were kept in appropriate glass metabolic cages for collection of urines and feces. Bile was collected from urethane-anesthetized animals cannulated in the bile duct. Blood was sampled by puncture of the orbital sinus. Tissues were taken after exsanguination from the abdominal aorta; livers were excised, washed once with ice-cold 0.05 M Tris-HCl buffer, pH 7.4, weighed and homogenized with 4 volumes of buffer, containing 0.25 M sucrose, using a glass Teflon homogenizer. The homogenate was centrifuged