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Background: The cost and complexity of current approaches to therapeutic drug monitoring during tuberculosis (TB) therapy limits widespread use in areas of greatest need. We sought to determine whether urine colorimetry could have a novel application as a form of therapeutic drug monitoring during anti-TB therapy., Methods: Among healthy volunteers, we evaluated 3 dose sizes of rifampin (150 mg, 300 mg, and 600 mg), performed intensive pharmacokinetic sampling, and collected a timed urine void at 4 h post-dosing. The absorbance peak at 475 nm was measured after rifamycin extraction. The optimal cutoff was evaluated in a study of 39 HIV/TB patients undergoing TB treatment in Botswana., Results: In the derivation study, a urine colorimetric assay value of 4.0 × 10(-2) Abs, using a timed void 4 h after dosing, demonstrated a sensitivity of 92 % and specificity of 60 % to detect a peak rifampin concentration (Cmax) under 8 mg/L, with an area under the ROC curve of 0.92. In the validation study, this cutoff was specific (100 %) but insensitive (28 %). We observed similar test characteristics for a target Cmax target of 6.6 mg/L, and a target area under the drug concentration-versus-time curve (AUC0-8) target of 24.1 mg•hour/L., Conclusions: The urine colorimetric assay was specific but insensitive to detect low rifampin serum concentrations among HIV/TB patients. In future work we will attempt to optimize sampling times and assay performance, with the goal of delivering a method that can translate into a point-of-care assessment of rifampin exposure during anti-TB therapy.

Background: Rifampicin or rifampin (R) is a common drug used to treat inactive meningitis, cholestatic pruritus and tuberculosis (TB), and it is generally prescribed for long-term administration under regulated dosages. Constant monitoring of rifampicin is important for controlling the side effects and preventing overdose caused by chronic medication. In this study, we present an easy to use, effective and less costly method for detecting residual rifampicin in urine samples using protein (bovine serum albumin, BSA)-stabilized gold nanoclusters (BSA-Au NCs) adsorbed on a paper substrate in which the concentration of rifampicin in urine can be detected via fluorescence quenching. The intensity of the colorimetric assay performed on the paper-based platforms can be easily captured using a digital camera and subsequently analyzed., Results: The decreased fluorescence intensity of BSA-Au NCs in the presence of rifampicin allows for the sensitive detection of rifampicin in a range from 0.5 to 823 µg/mL. The detection limit for rifampicin was measured as 70 ng/mL. The BSA-Au NCs were immobilized on a wax-printed paper-based platform and used to conduct real-time monitoring of rifampicin in urine., Conclusion: We have developed a robust, cost-effective, and portable point-of-care medical diagnostic platform for the detection of rifampicin in urine based on the ability of rifampicin to quench the fluorescence of immobilized BSA-Au NCs on wax-printed papers. The paper-based assay can be further used for the detection of other specific analytes via surface modification of the BSA in BSA-Au NCs and offers a useful tool for monitoring other diseases.

Adsorptive stripping voltammetry of antibiotics of rifamycin SV (RSV) and rifampicin (RIF) was investigated by cyclic voltammetry and differential pulse voltammetry using a renewable pencil graphite electrode (PGE). The nature of the oxidation process of RSV and RIF taking place at the PGE was characterized. The results show that the determination of highly sensitive oxidation peak current is the basis of a simple, accurate and rapid method for quantification of RSV and RIF in bulk forms, pharmaceutical formulations and biological fluids by differential pulse adsorptive stripping voltammetry (DPASV). Factors influencing the trace measurement of RSV and RIF at PGE are assessed. The limits of detection for the determination of RSV and RIF in bulk forms are 6.0 × 10(-8) mol/L and 1.3 × 10(-8) mol/L, respectively. Moreover, the proposed procedure was successfully applied to assay both RSV and RIF in pharmaceutical formulations and in biological fluids. The capability of the proposed procedure for simultaneous assay of antibiotics RSV-isoniazid and RIF-isoniazid was achieved. The statistical analysis and calibration curve data for trace determination of RSV and RIF are reported.

A novel electrochemiluminescence (ECL) type was proposed based on successive electro- and chemo-oxidation of oxidable analyte, which was different from both annihilation and coreactant ECL types in mechanism. Rifampicin was used as a model compound. No any chemiluminescence (CL) was produced by either electrochemical oxidation or chemical oxidation of rifampicin in KH(2)PO(4)--Na(2)B(4)O(7) (pH 6.6) buffer-dodecyl trimethyl ammonium chloride (DTAC) solution. However, an ECL was observed by electrochemical oxidization of rifampicin in the same solution in the presence of oxidant such as dissolved oxygen, activated oxygen and potassium peroxydisulfate (K(2)S(2)O(8)). The ECL was attributed to electrochemical oxidation of rifampicin to form semiquinone free radical, and then subsequently chemical oxidation of the formed radical by oxidant to form excited state rifampicin quinone. The proposed ECL type introduced additional advantages such as high selectivity, simple and convenient operation, and effective avoidance of side reaction that often took place in homogenous CL reaction, and will open a novel application field. In addition, with the ECL in the presence of K(2)S(2)O(8) as oxidant, a flow injection ECL method for the determination of rifampicin was proposed. The ECL intensity was linear with rifampicin concentration in the range of 1.0 x 10(-7) to 4.0 x 10(-5) mol l(-1) and the limit of detection (s/n=3) was 3.9 x 10(-8) mol l(-1). The proposed method was applied to the determination of rifampicin in pharmaceutical preparations and human urine.

Background & Objective: AIDS and its associated gastrointestinal complications may impair the absorption of anti-tuberculosis (TB) drugs. Impaired absorption of anti-TB drugs could lead to low drug exposure, which might contribute to acquired drug resistance and reduced effectiveness of anti-TB treatment. The aim of this study was to obtain information on the status of absorption of rifampicin (RMP) and isoniazid (INH) in asymptomatic HIV- positive individuals, who are less immunocompromised. The D-xylose absorption test was also carried out to assess the absorptive capacity of intestive., Methods: The absorption of RMP, INH and D-xylose was studied in 15 asymptomatic HIV-positive individuals with CD4 cell counts>350 cells/mm3 and 16 healthy volunteers, after oral administration of single doses of RMP (450 mg), INH (300 mg) and D-xylose (5 g). Urine was collected up to 8 h after drug administration. Percentage dose of the drugs and their metabolites and D-xylose excreted in urine were calculated., Results: A significant reduction in the urinary excretion of INH and D-xylose in HIV-positive persons compared to healthy volunteers was observed. The per cent dose of RMP and its metabolite, desacetyl RMP was also lower in HIV-positive persons compared to healthy volunteers, but this difference was not statistically significant., Interpretation & Conclusion: Decreased urinary excretion of D-xylose and INH are suggestive of intestinal malabsorption in HIV-positive individuals. HIV infection could cause malabsorption of anti-TB drugs even at an early stage of the disease. The clinical implications of these findings need to be confirmed in larger studies.

Two simple and accurate spectrophotometric methods for determination of Rifampicin (RIF) are described. The first method is based on charge transfer (CT) complex formation of the drug with three pi-electron acceptors either 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), 7,7,7,8-Tetracyanoquinodimethane (TCNQ) or 2,3,5,6-Tetrachloro-1,4-benzoquinone (p-chloranil) in acetonitrile. The method is followed spectrophotometrically by measuring the maximum absorbance at 584 nm, 761 nm (680 nm) or 560 nm for DDQ, TCNQ and p-chloranil, respectively. Under the optimized experimental conditions, the calibration curves showed a linear relationship over the concentration ranges of 5-140 microg/ml, 2-45 microg/ml (5-120 microg/ml) and 15-200 microg/ml, respectively. The second method is based on the reaction of RIF with iron(III) forming a water insoluble violet complex which is extracted into chloroform. The method determines RIF in concentration range of 10-240 microg/ml at 540 nm. The proposed methods applied to determination of RIF in capsule, human serum and urine samples with good accuracy and precision. The results were compared statistically with the official method and showed no significant different between the methods compared in terms of accuracy and precision.

This investigation retrospectively assessed inexpensive non-invasive qualitative methods to monitor the ingestion of anti-tuberculosis drugs isoniazid, rifampicin and rifapentine. Results showed that commercial test strips detected the isoniazid metabolites isonicotinic acid and isonicotinylglycine as efficiently as the isonicotinic acid method in 150 urine samples. The presence of rifamycins in urine samples (n=1085) was detected by microbiological assay techniques and the sensitivity compared to the n-butanol extraction colour test in 91 of these specimens. The proportions detected by the two methods were significantly different and the sensitivity of the n-butanol procedure was only 63.8% (95% CL 51.2-76.4%) as compared to that of the superior microbiological method. Final validation (n=691) showed that qualitative assays measure isoniazid and rifamycin ingestion with an efficiency similar to high-performance liquid chromatography. The qualitative procedures may therefore be valuable in clinical trials and in tuberculosis clinics to confirm drug ingestion.

Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may underlie many herb-drug interactions. Serial serum concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with milk thistle or black cohosh modified P-gp activity in vivo. Sixteen healthy volunteers were randomly assigned to receive a standardized milk thistle (900 mg daily) or black cohosh (40 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxicaps, 0.4 mg) was administered orally before and at the end of each supplementation and control period. Serial digoxin serum concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the serum concentration time curves from 0 to 3 h (AUC(0-3)), AUC(0-24), Cmax, apparent oral clearance of digoxin (CL/F), and elimination half-life were used to assess the effects of milk thistle, black cohosh, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC(0-3), AUC(0-24), and Cmax, whereas clarithromycin increased these parameters significantly (p < 0.01). Significant changes in digoxin half-life and CL/F were also observed with clarithromycin. No statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either milk thistle or black cohosh, although digoxin AUC(0-3) and AUC(0-24) approached significance (p = 0.06) following milk thistle administration. When compared with rifampin and clarithromycin, supplementation with these specific formulations of milk thistle or black cohosh did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.

Rapid, specific and simple methods for determining levofloxacin and rifampicin antibiotic drugs in pharmaceutical and human urine samples were developed. The methods are based on (1)H NMR spectroscopy using maleic acid as an internal standard and DMSO-d6 as NMR solvent. Integration of NMR signals at 8.9 and 8.2 ppm were, respectively, used for calculating the concentration of levofloxacin and rifampicin drugs per unit dose. Maleic acid signal at 6.2 ppm was used as the reference signal. Recoveries of (97.0-99.4)+/-0.5 and (98.3-99.7)+/-1.08% were obtained for pure levofloxacin and rifampicin, respectively. Corresponding recoveries of 98.5-100.3 and 96.8-100.0 were, respectively, obtained in pharmaceutical capsules and urine samples. Relative standard deviations (R.S.D.) values < or =2.7 were obtained for analyzed drugs in pure, pharmaceutical and urine samples. Statistical Student's t-test gave t-values < or =2.87 indicating insignificant difference between the real and the experimental values at the 95% confidence level. F-test revealed insignificant difference in precisions between the developed NMR methods and each of fluorimetric and HPLC methods for analyzing levofloxacin and rifampicin.

To investigate the effect of the ciprofloxacin on the urinary excretion of the rifampicin in humans, ciprofloxacin and rifampicin were coadministered. Five healthy volunteers between the ages of 20 and 35 years received, on 2 separate occasions (phases 1 and 2) and at weekly intervals, 600 mg rifampicin and 600 mg plus 500 mg ciprofloxacin, respectively, with 350 mL of water. Urinary levels of rifampicin were measured from 1-72 hours later. In phase 1, 15.6% urinary rifampicin was recovered compared with 15.5% urinary rifampicin recovered in the second phase. An increased excretion rate and higher plateau were obtained in ciprofloxacin plus rifampicin treatment. The study indicates that rifampicin may be coadministered with ciprofloxacin to check the development of drug resistance to single-drug therapy by susceptible organisms.

The effect of pefloxacin on the urinary excretion of rifampicin was investigated in 5 healthy volunteers between the ages of 20 and 35 years. The investigation was carried out in 2 different phases, with a 1-week drug washout separating the phases. Each subject received 600 mg rifampicin with 350 mL of water. After 1 week, the subjects were given 600 mg rifampicin plus 500 mg pefloxacin with 350 mL of water. Urinary levels of rifampicin were measured spectrophotometrically for the 2 phases from 0 to 72 hours. Coadministration of rifampicin with pefloxacin led to 20.1% urinary recovery of rifampicin. The increased rifampicin excretion rate following pefloxacin coadministration is supported by the competitive liver clearance between rifampicin and pefloxacin, which favors pefloxacin and causes rifampicin secretion, thus increasing its elimination through the kidney. Pefloxacin increases the absorption and urinary excretion of rifampicin by decreasing the gastrointestinal motility through chelation mechanisms.

Patient compliance should be ensured in an effective tuberculosis control programme. We measured patient compliance by detecting antituberculous drugs in the urine of 237 outpatients receiving one to three antituberculous drugs. Positive controls were 20 hospitalised patients, supervised to receive isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA), and negative controls were not on any drugs. Among the 237 study patients, only 67% were found to be taking the appropriate treatment and 8% had taken none. We conclude that a remarkable number of patients (33%) were non-compliant with treatment. The detection of antituberculous drugs in the urine is a quick, simple and inexpensive means of measuring adherence to treatment. Unless directly observed therapy (DOT) is adopted, we recommend routine urine testing for antituberculous drugs to identify defaulting patients.

Setting: Mulago Hospital, Kampala, Uganda., Objective: To evaluate the usefulness of urine dipsticks for monitoring adherence to anti-tuberculosis chemotherapy., Design: In-house urine dipsticks for detection of isoniazid (INH) metabolites were compared to commercial test strips. The value of n-butanol to detect rifampicin was compared to coloration of the urine. Non-adherence was assessed through a questionnaire and reviews of the Mulago Hospital TB register., Results: Urine was obtained from 236 patients (127 adults and 109 children) on daily chemotherapy. Using commercial test strips as standard, the sensitivity of in-house urine dipsticks was 99.5% and specificity was 96.4%. The sensitivity and the specificity of n-butanol and of coloration of urine to detect rifampicin were low (64.0% and 54.9%, and 85.5% and 64.8%, respectively). Fifty patients (21.2%) admitted non-adherence to treatment during the previous month. An additional 15 (6.8%) were detected through urine testing. Of 911 patients in the TB register of Mulago Hospital who had started treatment in the first 3 months of 2000, 39.7% did not complete their treatment. Two-thirds of these had discontinued treatment in the first 2 months., Conclusion: In-house INH test strips are as effective as commercially available strips for detecting isoniazid in the urine. They are a simple tool for monitoring adherence. Adherence to anti-tuberculosis chemotherapy as determined by the use of isoniazid test strips and review of the TB register showed poor compliance. Tests for rifampicin are less sensitive and specific.

The present study describes comparative bioavailability of rifampicin (RIF) after administration of a single component RIF (450 mg) capsule and rifampicin-isoniazid (RIF-INH) (450+300 mg) fixed dose combination (FDC) capsule formulations. Six healthy male volunteers participated in a single dose, two treatment, two period, cross-over study. A sensitive, specific and accurate HPTLC method was developed, validated and employed for estimation of RIF and its major active metabolite, 25-Desacetylrifampicin (25-DAR) levels, in urine. Using the urinary excretion data various pharmacokinetic parameters: AUC(0-24), AUC(0-infinity), cumulative amount excreted in 24 h, peak excretion rate, etc. for both RIF and 25-DAR were calculated and compared statistically (ANOVA, 90% confidence interval for ratio). Significant decrease in the bioavailability ( approximately 32% as RIF and approximately 28% as 25-DAR) of RIF from FDC capsules was observed. The present bioavailability study confirms our serious doubts about the stability of RIF in presence of INH in acidic environment of stomach, which probably is the main factor responsible for the reduced bioavailability of RIF from RIF-INH combination formulations. This study underlines the fact that there is an urgent need to reconsider the formulation of the FDC product in order to minimize or avoid the decomposition of RIF in gastrointestinal tract.

Setting: The perceived need for simple, non-invasive methods of assessing the relative bioavailability of rifampicin in fixed-dose combination (FDC) anti-tuberculosis formulations., Objective: To compare the performance of methods based on urinary excretion data with those utilising plasma concentration-time profiles to assess the relative bioavailability of rifampicin in combined and single-drug formulations., Design: A two-period randomised crossover bioequivalence study in healthy male volunteers with a 1 week washout period between treatments. Plasma rifampicin concentrations were measured at 0, 1, 2, 4, 6 and 8 hours after each drug administration using a high performance liquid chromatography (HPLC) method. The rifampicin and desacetylrifampicin content of complete urinary collections made from 0-4 and 4-8 hours after dosage were determined using both the HPLC and a much simpler colorimetric procedure., Results: There was good agreement between the relative bioavailability of the formulations using plasma and urinary excretion data, although the precision of the urinary-based estimates was slightly less than those derived from the plasma findings. There was also good agreement between the HPLC and colorimetric estimates of the combined urinary excretion of rifampicin plus desacetylrifampicin., Conclusions: Urinary excretion data may be used for ongoing quality control to confirm that commercial combined rifampicin-containing formulations that were initially shown to be satisfactory continue to be so.

Setting: The perceived need to demonstrate whether or not the rifampicin bioavailability of commercially manufactured fixed-dose combinations is satisfactory., Objective: To establish an international laboratory network to assess rifampicin bioavailability., Design: Convenient assay kits were devised to evaluate the ability of laboratories in China, India, Italy, South Africa, Thailand and the USA to determine plasma and urinary concentrations of rifampicin and desacetyl-rifampicin., Results: Five laboratories, all of whom used high pressure liquid chromatographic methods, were shown to be able to accurately and precisely determine the two compounds., Conclusion: Such a procedure is simple, convenient and objective and could be further employed to enlarge the intended international laboratory network.

Setting: The benefits of fixed-dose combination (FDC) formulations of rifampicin, isoniazid and pyrazinamide over individual formulations are well recognised., Objectives: To evaluate the comparative bioavailability of antituberculosis drugs in FDC formulations and the same doses in separate formulations of antituberculosis drugs, using a simplified protocol developed by the World Health Organization (WHO)., Methods: Twenty healthy volunteers were included in the study and evaluated for bioequivalence of rifampicin in a cross-over experimental design. After administration of drugs the plasma concentration of rifampicin and desacetyl-rifampicin was measured repeatedly up to 8 hours in both plasma and urine. Various pharmacokinetic parameters of rifampicin, such as Cmax, Tmax, elimination rate constant, area under the curve (AUC) up to 8 hours and absorption efficiency were calculated., Results: No significant differences were observed between the FDCs and separate formulations when Cmax, Tmax, AUC and absorption efficiencies were compared by parametric test and Hauschke's analysis., Conclusion: The WHO simplified protocol is suitable for evaluating bioequivalence of antituberculosis drugs.

Setting: The present study assesses bioavailability indices for rifampicin, isoniazid and pyrazinamide when administered to healthy volunteers separately or in a fixed triple-drug formulation, Rifater 125 SCT., Objective: To compare the pharmacokinetics of rifampicin, isoniazid and pyrazinamide based on their blood concentrations up to 12 hours with the proportions of the doses of the drugs and their metabolites excreted in urine up to 12 hours, and to assess the bioavailability indices for the free and fixed triple drug formulations., Design: An open cross-over study was conducted in 18 healthy volunteers with normal hepatic and renal functions to whom the drug combinations were administered in free and fixed dose formulations a week apart, to the same subject., Results: Concentrations of the three drugs/metabolites were assessed in blood and urine. The results indicated the absence of negative pharmacokinetic interactions between the drugs when administered in both the free and the new fixed triple drug formulation., Conclusion: Human bioavailability studies provide direct straightforward information, particularly when studying compounds such as rifampicin and other major anti-tuberculosis drugs. The results of the present study indicate that the pharmacokinetic properties of rifampicin, isoniazid and pyrazinamide as assessed after individual and combined administration do not change when combined in a single pharmaceutical preparation. The bioavailability indices calculated based on plasma concentrations and urinary levels for all three drugs compared well.

A reversed phase HPLC method is described for the simultaneous estimation of rifampicin and its major metabolite desacetyl rifampicin, in the presence of isoniazid and pyrazinamide, in human plasma and urine. The assay involves simple liquid extraction of drug, metabolite and internal standard (rifapentine) from biological specimens and their subsequent separation on a C18 reversed phase column and single wavelength UV detection. In plasma as well as in urine samples, all the three compounds of interest eluted within 17 min. Using methanol-sodium phosphate buffer (pH 5.2; 0.01 M) (65:35, v/v) as mobile phase under isocratic conditions, it was established that isoniazid, pyrazinamide and ascorbic acid (added to prevent oxidative degradation of analytes) did not interfere with the analyte peaks. Recoveries (extraction efficiency) for drug were greater than 90% in both plasma and urine, whereas for metabolite the values were found to be 79 and 86% in plasma and urine, respectively. The plasma and urine methods were precise (total coefficient of variation ranged from 5 to 23%) and accurate (-7 to 5% of the nominal values) for both the analytes. Individual variance components, their estimates and their contribution to the total variance were also determined. Using the same method, unknown samples supplied by WHO were assayed and good correlations were obtained between the found and intended values. The method developed proved to be suitable for simultaneous estimation of rifampicin and desacetyl rifampicin in plasma and urine samples.

Rifapentine is a long-acting cyclopentyl-derivative of rifampin. This study was designed to investigate the mass balance and biotransformation of 14C-rifapentine in humans. Four healthy male volunteers received a single 600-mg oral dose of 14C-rifapentine in a hydroalcoholic solution. Whole blood, urine, and fecal samples were collected before and at frequent intervals after drug administration. Amount of radioactivity recovered in urine and feces was assessed for up to 18 days postdose. Metabolite characterization in urine and feces was conducted using high-performance liquid chromatography with radiometric detection and liquid chromatography/mass spectroscopy. The total recovery of radioactive dose was 86.8%, with the majority of the radioactive dose recovered in feces (70.2%). Urine was a minor pathway for excretion (16.6% of the dose recovered). More than 90% of the excreted radioactivity was profiled as 14C chromatographic peaks and 50% was structurally characterized. These characterized compounds found in feces and urine were rifapentine, 25-desacetyl-rifapentine, 3-formyl-rifapentine, and 3-formyl-25-desacetyl-rifapentine. The 25-desacetyl metabolite, formed by esterase enzymes found in blood, liver, and other tissues, was the most abundant compound in feces and urine, contributing 22% to the profiled radioactivity in feces and 54% in urine. The 3-formyl derivatives of rifapentine and 25-desacetyl-rifapentine, formed by nonenzymatic hydrolysis, were also prominent in feces and, to a lesser extent, in urine. In contrast to the feces and urine, rifapentine and 25-desacetyl-rifapentine accounted for essentially all of the plasma radioactivity (99% of the 14C area under the concentration-time curve), indicating that 25-desacetyl-rifapentine is the primary metabolite in plasma. It appears, therefore, that the nonenzymatic hydrolysis of rifapentine to 3-formyl byproducts occurs primarily in the gut and the acidic environment of the urine.

Rifapentine is a cyclopentyl derivative of rifampin under development for the treatment of Mycobacterium tuberculosis and Mycobacterium avium complex infections. These studies were designed to investigate the disposition and biotransformation of single iv and oral doses of 14C-rifapentine in mice, bile duct-cannulated and uncannulated rats, and monkeys. Mass balance studies included 14C analyses of urine, feces, bile, cage wash, carcasses, and cage air collected for up to 120 hr postdose. Separation of radioactive compounds extracted from urine, bile, and feces was conducted using high-performance liquid chromatography and radioisotope detection. The mass spectra of selected chromatographic peaks were obtained. Disposition results were similar for all three species. Less than 5% of the radioactive dose of 14C-rifapentine was recovered in urine, indicating that renal excretion is a minor route of elimination in these species. The major route of elimination of radioactivity was into the feces, where more than 75% of the radioactivity was recovered. Biliary excretion was the major route of elimination of radioactivity in bile duct-cannulated rats dosed either po or IV. Radiochromatograms were similar for fecal samples from animals dosed by IV or orally. Ten regions of radioactivity were observed in mouse and rat fecal sample radiochromatograms, and seven regions of radioactivity were observed in monkey fecal sample radiochromatograms. The most abundant compound identified in feces was usually intact rifapentine (27%-41% of dose in mouse, 3%-35% of dose in rat, and 17%-29% of dose in monkey). Other peaks identified or characterized in feces based on liquid chromatography/ultraviolet/14C and/or liquid chromatography/mass spectrometry methods included 25-desacetyl-rifapentine, 3-formyl-25-desacetyl-rifapentine, and 3-formyl-rifapentine. The compounds rifapentine, 25-desacetyl-rifapentine, and 3-formyl-rifapentine were present in rat bile samples. These studies show that the metabolism and disposition of rifapentine in mice, rats, and monkeys were similar.

The treatment of tuberculosis usually includes the antibiotic rifampicin, especially in patients with concomitant human immunodeficiency virus infection. Some of these patients are in withdrawal therapy for drug abuse. When opiate screening is carried out in patients receiving rifampicin, false positive results are detected with the kinetic interaction of microparticles in solution method. We evaluated this interference in a Cobas-Integra analyzer and found a 12% cross-reactivity of rifampicin for antibiotic concentrations ranging from 0.19 to 6.08 mumol/l (156 to 5000 micrograms/l). This effect is not explained by the colour of the rifampicin solutions. Calculations assuming first order kinetics of elimination show that more than 18 hours after a single oral dose of 600 mg of rifampicin, a false positive result for opiates could be obtained. This indicates that the risk of a false positive result must always be considered when urine samples from these patients are analyzed.

The in vitro bactericidal interaction of trovafloxacin and rifampin against Enterococcus spp. has indicated that antagonism occurs between these two antimicrobial agents. This drug combination was examined in vivo in rats with experimental pyelonephritis. The rats received trovafloxacin, rifampin, or both drugs. On the basis of the mean log10 CFU of Enterococcus faecalis from the kidneys, there was no evidence that trovafloxacin and rifampin were antagonistic in vivo.

Aim: To determine the prevalence of non-compliance with tuberculosis treatment at Freegold Mines., Objectives: 1. To establish the rates of attendance and collection of anti-tuberculosis drugs. 2. To determine prevalence of non-compliance by means of urine tests., Design: A cross-sectional study conducted over 2 weeks at mine medical stations., Method: Urine samples were collected from tuberculosis patients 3 hours after drug ingestion. Non-compliance was established by testing these samples for rifampicin and/or isoniazid (INH) metabolites. Non-compliance was defined as a negative urine test result for these drugs in participants whose treatment regimens included one or both. Daily attendance and collection of drugs statistics are recorded in the medical station tuberculosis register. The patient rate of adherence was calculated as the observed number of days on which medication had been collected over the expected treatment days in a given period., Results: Urine test results showed an overall prevalence of non-compliance of 14.6 +/- 3.3%. The study showed that non-compliance with tuberculosis treatment was underestimated by the surveillance data. The rate of non-adherence with treatment established from the formal surveillance procedure was 0.2%. The poor response rate of patients was found to be a major problem and fewer than 40% per day returned to bring urine specimens. The mean prevalences of non-compliance established by rifampicin and INH tests were 19.5 +/- 5.3% and 9.8 +/- 3.9%, respectively, and these were significantly different (Chi 2 = 7.44; P < 0.05). The proportion of false-positive results for INH and rifampicin urine tests were 21% (11/53) and 35% (17/48), respectively, showing that some patients were taking the wrong treatment., Conclusions: It is clear that attendance at the clinics does not accurately reflect compliance. Both programme compliance (dispensing of the correct treatment) and patient compliance need to be improved. This has important implications for the new national tuberculosis control policy adopted by the South African government that stresses the importance of directly observed therapy, short-course (DOTS) and a patient-centred approach.

The saliva and plasma concentrations of rifampicin were determined following oral administration of 600 mg of the drug to healthy human subjects. Rifampicin is a zwitterion with PKa's of 1.7 and 7.9. The saliva-plasma concentration ratios calculated on the basis of the PKa of 1.7 was 1.6346. The saliva concentrations were much higher than the MICs of a variety of organisms, indicating the possible usefulness of rifampicin in the treatment of susceptible oropharyngeal and nasopharyngeal pathogens. After 24 hrs, when rifampicin was completely absent in the urine, the saliva and plasma concentrations also had fallen almost to zero.

The effect of activated charcoal (AC) on rifampicin excretion was investigated in six healthy volunteers. On three occasions, at weekly intervals, each subject received a 600 mg rifampicin with 350 ml of water; b+c one and two weeks later, 600 mg of rifampicin plus 7.5 and 15 g AC, respectively, in 350 ml of water as a charcoal slurry. Urinary levels of rifampicin were measured form 1-36 hr after ingestion. Treatment with AC led to 1.2 per cent urinary recovery of rifampicin; decreased excretion rate; and a much lower plateau indicative of reduced absorption.

Rifampicin excretion with urine and its plasma levels were studied in 46 patients with nephrophthisis treated with rifampicin alone or in combination with isoniazid in doses of 8--10 mg/kg bw with regard to the degree of renal insufficiency. It was shown that excretion of rifampicin with urine decreased with progression of renal insufficiency and had no effect on its plasma levels. The combined use of isoniazid and rifampicin in a single dose was accompanied by a decrease in the latter's excretion with urine and different changes in its plasma concentration. The use of the two drugs for 4--6 weeks resulted in a further decrease in rifampicin excretion with urine not dependent on renal function and in decreased plasma levels of the antibiotic in 1/3 of patients. The findings indicate that the use of rifampicin in a dose less than 10 mg/kg of the body weight in patients with chronic renal insufficiency is not advisable. The absence of rifampicin in the urine specimens collected during the first hours on the 2nd day after its single use or its use for 4--6 weeks indicate that rifampicin does not accumulate in patients with renal insufficiency.

Serum Rifampicin levels were determined by a microbiological assay using Staphylococcus aureus in 22 cases of leprosy after administering the drug with and without probenecid. Most of the patients showed higher serum rifampicin levels when probenecid was given along with rifampicin. Six patients showed statistically significant increase in the serum levels of the drug when given in the dose of 300 mg along with 1 g of probenecid one hour before breakfast and these levels were comparable with those obtained following administration of 450 mg of rifampicin alone two hours after breakfast. Thus administration of probenecid preceding rifampicin may be employed to reduce cost of drug as well as hepatotoxicity in patients requiring rifampicin for long duration.

This study includes 30 children below the age of 3 years, distributed in three groups of 10 children each. One group received 15 mg/kg/day of rifampicin (RAMP), the other received 15 mg/kg/day of isoniazid (INH) and the third received both drugs (RAMP + INH) at the same doses. Plasma levels of RAMP and INH were determined. At the same time, some hepatic function parameters were analyzed: bilirubin, transaminases, alkaline phosphatases and prothrombin. Plasma levels of INH administered alone show significantly higher levels on the 7th day with respect to the 1st day, thus demonstrating a marked tendency towards the accumulation of successive doses. Very significant differences exist between initial and final values of transaminases in the RAMP + INH group. There are no significant differences in the other two groups. These data suggest a hepatic overload when both drugs are simultaneously administered.

With a rifampicin (RMP) range of 600 to 1800 mg, 12.5% of the administered dose are on an average secreted in urine. In spite of this minimal portion the course of pharmacokinetic processes can distinctly be learned from its alterations. Analyses in 84 patients revealed that the age will influence the induction and the sex-specific differences of the pharmacokinetics. Compared to male subjects, an increased RMP secretion in urine can be recorded in young female subjects, whereas in older male ones an induction-reduced RMP elimination in urine becomes more obviously. Considering these multiform processes, the determination of the bioavailability of RMP preparations by means of the RMP secretion in urine is taken to be manipulatable and uncertainly. More evident results can be gained by the determination of the RMP concentration in serum or by the calculation of the AUC.

Biotransformation of rifampicin in 39 tuberculosis patients treated with the drug was studied. The studies showed that biotransformation of rifampicin was most intensive during the first 3--6 hours after its use, which was confirmed by excretion of maximum amounts of rifampicin and its metabolites with the urine. 2--4 weeks after the beginning of the treatment with rifampicin excretion of its metabolism products decreased. When rifampicin was used simultaneously in a single dose with tubazid excretion of rifampicin transformation product and desacetylation of the antibiotic slowed down.

A study was undertaken to evaluate simple, reliable urine spot tests suitable for detection of the major anti-tuberculosis (TB) drugs rifampicin, isoniazid and pyrazinamide. The discrepancy between the actual ingestion of anti-TB tablets and prescribed medication was investigated in 234 hospitalized male and female patients as well as in 85 male and female outpatients with pulmonary tuberculosis. Several factors implicated in patient non-compliance are discussed, namely the degree of supervision, the independent administration of rifampicin before the other TB medication, and patient preference for certain TB medicines because of tablet size.

Treatment compliance was assessed by testing multiple urine samples for rifampicin in 113 consecutive patients taking a rifampicin containing regimen for tuberculosis. Nineteen (16.8%) patients had at least one negative urine sample after chromatographic analysis and these patients were more likely to be from social classes IV and V, to be Asian, and to have defaulted from at least one clinic appointment without good reason. A questionnaire was completed by 70 of the patients and four (6%) admitted to having omitted at least one treatment weekly; two of these also had at least one negative urine test. Physicians were only partly successful in identifying non-compliers. The relevance of these findings is discussed.

Indication of an enhancing effect of Rifampicin on the urinary excretion of DDs has already been reported from this institution. Further observations on this aspect in 25 cases of lepromatous leprosy treated with a 15 day schedule of Rifampicin at a dose of 600 mg daily along with DDS are presented. The earlier findings that Rifampicin in the initial phase of administration enhance the urinary output of DDS are confirmed. An estimation of Rifampicin Creatinine levels in urine done concurrently also showed a quicker elimination of the drug in the earlier phase compared to later phases of the drug administration. As part of the study of drug interactions, the influence of Clofazimine administration on DDS metabolism was also studied. The findings indicate that Clofazimine does not exert any influence on DDs excretion by leprosy patients. The findings and their implications are discussed.