25-deacetylrifampicin and Tuberculosis--Pulmonary

We investigated the pharmacokinetics of rifampicin and its major metabolites, 25-desacetylrifampicin and 3-formylrifampicin, in two groups of six patients with active pulmonary tuberculosis, who received either multiple oral or intravenous rifampicin therapy in combination with intravenous isoniazid and ethambutol. Serum concentrations of rifampicin were each determined after a single oral and intravenous test dose of 600 mg rifampicin at the beginning and after 1 and 3 weeks of tuberculostatic treatment. Analysis of rifampicin and its metabolites was performed by high-pressure liquid chromatography. It was found that, due to autoinduction of its metabolizing hepatic enzymes, the systemic clearance of rifampicin increased from 5.69 to 9.03 l/h after 3 weeks of multiple dosing. The volume of distribution of the drug was constant over the period of this study. The bioavailability of the active, orally administered rifampicin decreased from 93% after the first single oral dose to 68% after 3 weeks of oral and intravenous rifampicin therapy. Relating to the increase in systemic (hepatic) clearance, a bioavailability no lower than 90% can be predicted. The reduction to 68% indicates that, in addition to an increase of hepatic metabolism, an induction of a prehepatic "first-pass" effect resulted from multiple rifampicin doses. Our study of rifampicin metabolites confirm that prehepatic metabolism was induced, since a higher metabolic ratio resulted after the oral doses than after the intravenous rifampicin test doses. A preabsorptive process can therefore be excluded as a cause of reduced bioavailability.

Topics: Administration, Oral; Adolescent; Adult; Aged; Biological Availability; Drug Therapy, Combination; Ethambutol; Female; Humans; Infusions, Parenteral; Isoniazid; Male; Metabolic Clearance Rate; Middle Aged; Rifampin; Rifamycins; Tuberculosis, Pulmonary

Measurement of rifampin levels is not part of routine practice. However, low levels are associated with failure of tuberculosis treatment. The clinical relevance of serum levels in daily practice is unclear. The objective was to evaluate rifampin serum concentrations and factors associated with insufficient concentrations.. Patients with at least one rifampin concentration drawn 3 hours after intake (C3) between 2005 and 2014 were included. Data on demographic and clinical characteristics were collected, including side effects and dose adjustments. Two different criteria were used to define adequate concentrations (criterion 1: C3 a nd C 6 ≥ 3 mg/l; criterion 2: C3 or C6 ≥ 5 mg/l).. Of 63 patients, 66% and 76% had a sufficient level according to criterion 1 or 2, respectively. C3 exceeded C6 in most patients, while a late maximum was significantly associated with diabetes mellitus (p = 0.003). A dose adjustment was made in 19% of cases, more frequently in patients with insufficient levels (p = 0.02) or with ≥ 2 side effects (p = 0.03).. Rifampin levels varied but were mostly adequate and a single measurement at 3 hours after intake provided the required information in most cases, indicating that full AUC0-24 measurements could be limited to specific situations.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Child; Child, Preschool; Drug Monitoring; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Retrospective Studies; Rifampin; Time Factors; Tuberculosis, Pulmonary; Young Adult

Topics: Aged; Antibiotics, Antitubercular; Antitubercular Agents; Chromogenic Compounds; Drug Interactions; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Pharmacokinetics of rifampicin studied in 15 patients after its intravenous administration in a dose of 10 mg/kg was described by a two-compartment model. The drug levels in serum and urine were determined with a chemical method. At the moment of the infusion discontinuation the maximum drug levels in serum averaged to 14.05 micrograms/ml. The mean values of the total clearance, distribution of the kinetic volume and half-lives were 93.2 ml/(h X kg), 1016.1 ml/kg and 8.1 h respectively. Cumulative excretion of the total rifampicin within 24 hours amounted to 19.4 per cent of the administered dose, the proportions of the main metabolite (25-O-desacetyl rifampicin) and intact rifampicin being equal to 29 and 71 per cent respectively. The renal and nonrenal clearance of rifampicin amounted to 14.2 and 79 ml/(h X kg) respectively.

Topics: Adult; Humans; Infusions, Intravenous; Kinetics; Male; Rifampin; Time Factors; Tuberculosis, Pulmonary

Four rates of rifampicin infusion ranging from 3.3 to 15 mg/min in 12 tuberculous patients were studied. Blood samples (n = 10) were drawn during infusion and 8 h later. Urine samples were collected in six fractions during a 24-h period. Rifampicin and desacetylrifampicin were measured by high-pressure liquid chromatography. Results show that the maximum plasma concentrations increase linearly for each dose with the rate of infusion, and that the amounts excreted in the urines are highly dependent on the administered dose. Simulation of plasma concentrations after different dosage regimens shows that a double rate of infusion--20 mg min-1 during 1 h and then 200 mg h-1--allows plasma concentrations to be quickly reached and maintained at a 20 mg L-1 level, far higher than the minimum inhibitory concentrations of most germs.

Topics: Adult; Aged; Female; Half-Life; Humans; Infusions, Parenteral; Kinetics; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

A method for the determination of rifampicin, desacetylrifampicin, isoniazid, and acetylisoniazid by high-performance liquid chromatography and using the same extract of the same sample is reported. After protein precipitation and extraction of these antituberculous drugs, two reversed-phase chromatographies were necessary. The technique was applied to serum extracts, polymorphonucleocytes and alveolar macrophages from patients treated for tuberculosis.

Topics: Chromatography, High Pressure Liquid; Humans; Isoniazid; Macrophages; Neutrophils; Rifampin; Tuberculosis, Pulmonary