Absorption, disposition and preliminary metabolic pathway of 14 C-rifabutin in animals and man

This study was designed to describe the population pharmacokinetics of rifapentine (RFP) and 25-desacetyl RFP in a South African pulmonary tuberculosis patient population. Special reference was made to studying the influence of previous exposure to rifampin (RIF) and the variability in pharmacokinetic parameters between patients and between occasions and the influence of different covariates. Patients were included in the study if they had been receiving first-line antimycobacterial therapy (rifampin, isoniazid, pyrazinamide, and ethambutol) for not less than 4 weeks and not more than 6 weeks and were divided into three RFP dosage groups based on weight: 600 mg, <45 kg; 750 mg, 46 to 55 kg; and 900 mg, >55 kg. Participants received a single oral dose of RFP together with concomitant antimycobacterial agents, excluding RIF, on study days 1 and 5 after they ingested a soup-based meal. The RFP and 25-desacetyl RFP concentration-time data were analyzed by nonlinear mixed-effect modeling using NONMEM. The pharmacokinetics of the parent drug were modeled separately, and the individual pharmacokinetic parameters were used as inputs for the 25-desacetyl RFP pharmacokinetic model. A one-compartment disposition model was found to best describe the data for both the parent and the metabolite, and the metabolite was assumed to be formed only from the central compartment of the parent drug. Prior treatment with RIF did not alter the pharmacokinetics of RFP but appeared to increase the excretion of 25-desacetyl RFP in a nonlinear fashion. The RFP oral clearance and volume of distribution were found to increase by 0.049 liter/h and 0.691 liter, respectively, with a 1-kg increase from the median weight of 50 kg. The oral clearance of 25-desacetyl RFP was found to be 35% lower in female patients. The model developed here describes the population pharmacokinetics of RFP and its primary metabolite in tuberculosis patients and includes the effects of prior administration with RIF and covariate factors.Rifapentine (RFP) is a member of the rifamycin family and is currently registered in the United States for the treatment of tuberculosis in human immunodeficiency virus (HIV)-negative patients with noncavitary tuberculosis (TB) and with a sputum sample which is negative for acid-fast bacilli by smear at 2 months of therapy (2). Treatment guidelines recommend dosing RFP (600 mg orally) together with the companion firstline antimycobacterial drug isoniazid (INH) once weekly, following the first 8 weeks of treatment with rifampin (RIF), INH, pyrazinamide (PZA), and ethambutol (EMB), to complete 6 months of therapy.The primary metabolic pathways for RFP are deacetylation and nonenzymatic hydrolysis. This results in one primary enzymatic metabolite, 25-desacetyl RFP, and two secondary nonenzymatic metabolites, 3-formyl RFP and 3-formyldesacetyl RFP (18). The primary route of elimination for the rifamycins is via biliary excretion with enterohepatic recirculation, although gastrointestinal secretion and renal clearance also play a role (1,4...

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Population Pharmacokinetics of Rifapentine and Its Primary Desacetyl Metabolite in South African Tuberculosis Patients

Langdon

Wilkins

McFadyen

et al. 2005

“…The zones of inhibition produced by serial dilutions of homogenates of serum and tissue from treated animals were compared with the zones produced by measured concentrations of drug diluted in the corresponding tissue from untreated controls. Rifabutin concentrations were measured by a high-performance liquid chromatography assay modified from previously described methods (1 No bacteremia was detected in treated animals after 40 or 68 days of infection. Bacteremia was present in all control animals after 8, 40, and 68 days of infection.…”

mentioning

confidence: 99%

Azithromycin, rifabutin, and rifapentine for treatment and prophylaxis of Mycobacterium avium complex in rats treated with cyclosporine

Brown

Edwards

Bernard

et al. 1993

Azithromycin, rifabutin, and rifapentine were used to treat or prevent disseminated Mycobacterium avium complex (MAC) infections produced in rats immunosuppressed with cyclosporine. Animals with bacteremic infections were treated 1 week after intravenous inoculation with 107 CFU of MAC with azithromycin, 100 mg/kg of body weight administered subcutaneously for 5 days and then 75 mg/kg on Monday, Wednesday, and Friday, or with rifabutin or rifapentine, 20 mg/kg administered intraperitoneally on Monday through Friday. All three drugs showed efficacy after 1 and 2 months. Rifabutin cleared the organisms from tissues more rapidly than azithromycin or rifapentine. To approximate prophylaxis, treatment was started 2 weeks before intravenous inoculation with 104 organisms. MAC infections were undetectable in treated animals after 4 months, while control animals had disseminated infections. These findings support the rationale for clinical trials of treatment and prophylaxis with these agents. The cyclosporine-treated rat appears to be a useful model in which to evaluate compounds for the treatment and prophylaxis of disseminated MAC infections.Disseminated infection with the Mycobacterium avium complex (MAC) is the most common cause of bacteremia in patients with AIDS, occurring in up to 50% of these patients (14). Survival of MAC-and human immunodeficiency virusinfected patients is half that of those with similar stages of human immunodeficiency virus infection but who do not have disseminated MAC infections (13). Treatment regimens with significant activity against MAC have been described, but relapses have occurred and none of the regimens have reliably eradicated the infection (9,10,11,20,25). Thus, there is an urgent need for more effective agents and approaches to the treatment and prevention of MAC infections.Successful treatment of established infections probably requires combination therapy with two or more effective drugs having different mechanisms of action (17). Rifabutin and rifapentine are new rifamycin analogs which demonstrate significant in vitro activity against MAC isolates.Studies of treatment with these agents in animal models have produced contradictory results (4,5,15,16). Azithromycin is a new azilide antibiotic which, despite its low in vitro activity against MAC, has shown promise as a treatment in animal studies (12) and early human trials (26). This efficacy may stem from its unusual pharmacokinetic profile, which can result in high concentrations in tissues (6).A new model of disseminated MAC infection has recently been described in Sprague-Dawley rats immunosuppressed with cyclosporine (CsA) (2). We evaluated the response to treatment with azithromycin, rifabutin, or rifapentine in CsA-treated rats with bacteremic MAC infections. As a model of prophylaxis, we also tested whether these drugs prevent the progression of low-grade infection.(Results of the studies described here were presented in MATERIALS AND METHODSDrugs. Azithromycin was provided by Pfizer Central Research, Groton, Conn. ...

“…The considerable uptake of radioactivity in the lung may favor the greater efficacy of rifabutin in the treatment of tuberculosis. In a previous study conducted in rats after oral administration of rifabutin, in which plasma levels of both radioactivity and unchanged drug were measured, rifabutin accounted for 72% of plasma radioactivity at 2 h and for 41% at 24 h, whereas at 72 h, traces of unchanged drug were detected in only one rat (2). Therefore, it is reasonable to assume that tissue radioactivity at 2 h is mainly due to unchanged rifabutin, whereas metabolites might play a major role at later times.…”

Section: Discussionmentioning

confidence: 87%

“…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.)…”

Section: Rifabutin 4-deoxo-34-[2-spiro-(n-isobutyl-4-piperidyl)]-(1mentioning

confidence: 93%

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

Battaglia¹,

Salgarollo²,

Zini³

et al. 1991

'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,...