Absorption, disposition, and urinary metabolism of 14C-rifabutin in rats

Abstract

'4C-rifabutin was given orally (25 mg/kg) and intravenously (i.v.) (10 mg/kg) to female Sprague-Dawley rats.Radioactivity was eliminated by both the renal and fecal routes, amounting to 44.49 and 43.39% of the dose, respectively, in urine and feces at 96 h after the oral dose and to 47.81 and 40.76% of the dose, respectively, in urine and feces after the i.v. dose. Differences between the two routes of administration were negligible. Tissue distribution of radioactivity after the oral dose was investigated by the combustion technique. At 2 h, the highest concentration of radioactivity was observed in the liver, followed by the lung, abdominal adipose tissue, and spleen, whereas at 72 h, the sequence was abdominal adipose tissue, liver, spleen, bone marrow, and lung. Brain levels of radioactivity were very low. The results of whole-body autoradiography after i.v. administration confirmed the above. Whole-body autoradiography of pregnant rats showed higher concentrations of radioactivity in the uterus than in the placenta and trace levels in the fetuses up to 8 h. Radioactivity was absent in the amniotic fluid. The urinary metabolism was studied by radio-high-pressure liquid chromatography. Rifabutin accounted for 7.4 and 7.2% of the dose in 0-to 48-h urine after oral and i.v. administration, respectively. Metabolites 31-OH rifabutin and 25-O-deacetyl rifabutin amounted to 4.3 and 1.6% of the dose, respectively, after oral administration and to 2.6 and 0.7% of the dose, respectively, after i.v. administration. The remaining urinary radioactivity was mainly due to polar compounds. Fig. 1), is a new spiropiperidylrifamycin with a broad spectrum of activity against typical and atypical gram-positive and gram-negative bacteria in vitro (6). The drug is also active against many rifampin-resistant Mycobacterium tuberculosis strains both in vitro and in vivo (6, 11).A comparative study of the absorption, elimination, and metabolic pattern in some animals and humans after oral administration of the labeled drug has been previously reported (2). The aim of the present study was to further investigate the absorption, disposition, and urinary metabolism of 14C-rifabutin in rats following oral and intravenous (i.v.) administration.As the chemical structure of rifabutin is similar to that of rifampin, a drug currently used in the treatment of tuberculosis, but its lipophilicity is much higher (3), it was considered interesting to compare data obtained in this study with those reported in the literature for labeled rifampin. MATERIALS AND METHODSChemicals. 14C-rifabutin (Fig. 1), with a specific activity of 1.50 MBq/mg and a radiochemical purity higher than 97% by thin-layer chromatography, was synthesized in the Radioiso- 160 and 215 g) and three pregnant (on day 16 of gestation) female Sprague-Dawley rats were used in this study. The animals were fasted overnight and up to 4 h after dosing. Water was available ad libitum. Animals were housed individually in cages suitable for separate collection of urine and feces.Absorption,...

A Pharmacology Perspective on Simultaneous Tuberculosis and Hepatitis C Treatment

“…Rifabutin undergoes extensive intestinal and hepatic metabolism, resulting in more than 20 metabolites (22,29). The primary metabolites are 25-O-desacetyl-rifabutin and 31-hydroxyl-rifabutin (22,23,29,30). Rifabutin elimination t 1/2 is in the range of 25 to 67 h, depending on whether the data are obtained using a single dose (longer) or at steady state (shorter) (22,23,31).…”

“…CYP3A is the major isozyme that transforms rifabutin to its oxidative metabolites in human enterocytes and liver microsomes, and it also catalyzes oxidation of 25-O-desacetyl-rifabutin (22,29). Rifabutin excretion occurs through the biliary tract and, to a small degree, renally (30). After a 150-mg dose, biliary concentrations reach up to 3 to 5 times the plasma concentration (34).…”

Comparison of Compartmental and Non-Compartmental Analysis to Detect Biopharmaceutical Similarity of Intravenous Nanomaterial-Based Rifabutin Formulations

“…Additionally, the lungs represent an important organ that is known to accumulate nanoparticles due to the fine capillaries that filter colloidal carriers from blood circulation. An accumulation in the spleen and liver is also an important characteristic of rifabutin [18], and it is further enhanced by the cellular uptake of the nanoparticles by the macrophages which may indicate differences in particle elimination from the blood plasma.…”

Rifabutin loaded floating gellan gum beads: In vitro and in vivo evaluation

“…Rifabutin levels in blood were determined by HPLC after an extraction procedure according to Battaglia et al (1991) and Benedetti et al (1995) with adaptations. Briefly, 500 µl of blood were mixed with 250 µl of mobile phase and extracted twice with 1 ml of a dichloromethane: isooctane mixture (2:3 v/v) under stirring (15 min), followed by a centrifugation step at 1200 x g for 10 min.…”