This study was conducted in order to (i) determine the effect of food, orange juice, or antacids on the absorption of a single oral 500-mg dose of ethionamide (ETA) in healthy volunteers, including an assessment of bioequivalence, and (ii) determine ETA population pharmacokinetic (PK) parameters. The pharmacokinetics of ETA in serum was determined for 12 healthy males and females in a randomized, four-period crossover study. Volunteers received single 500-mg doses of ETA either on an empty stomach (reference) or with food, orange juice, or antacids. Serum samples were collected for 48 h and assayed by high-performance liquid chromatography. Data were analyzed by noncompartmental and population methods. Mean test/reference ratios and 90% confidence intervals were determined. No statistically significant differences were seen in the maximum concentration of ETA (C max ), time to maximum concentration (T max ), or area under the concentration-time curve from 0 h to infinity (AUC 0-ؕ ) between the four treatments (P > 0.05 by analysis of variance). The least-squares mean ratios (with confidence intervals in parentheses) for C max were 105% (81.2 to 135%) after orange juice, 94% (72.8 to 121%) after food, and 88% (68.4 to 114%) after antacids. The least-squares mean ratios (with confidence intervals is in parentheses) for AUC 0-ؕ were 91% (72.7 to 115%) after orange juice, 96% (76.4 to 121%) after food, and 95% (75.5 to 120%) after antacids. The mean T max was slightly prolonged following antacid or food administration (2.3 to 2.6 h) compared to administration on an empty stomach or with juice (1.7 to 1.9 h). The median population PK parameters were as follows: K a ؍ 0.37 to 0.48 h ؊1 , V/F ؍ 2.0 to 2.8 liters/kg, CL/F ؍ 56.5 to 72.2 liters/h, and terminal half-life ؍ 1.7 to 2.1 h, where K a is the absorption rate constant, V is the volume of distribution, and CL is clearance. The PK behavior of ETA was not significantly modified by the different conditions studied. Mean ratios for AUC ranged from 0.91 to 0.96 for the orange juice, food, and antacid treatments, indicating a minimal effect on relative bioavailability. ETA can, therefore, be administered with food if tolerance is an issue.Ethionamide (ETA) is a bacteriostatic, isonicotinic acidderived antituberculosis agent (10, 28). It is used in combination for the treatment of clinical tuberculosis that has failed to respond to adequate first-line therapy (1). Very limited information exists in the literature regarding the pharmacokinetics (PK) of ETA in healthy volunteers or in patients with tuberculosis. ETA is often administered with meals to reduce gastrointestinal intolerance (1). However, to our knowledge, the effects of food, as well as those of antacids or acidic beverages on the PK of ETA have not been evaluated in a crossover study. We have previously demonstrated that food has minimal effect on the absorption of ethambutol and pyrazinamide, while antacids should be avoided near the time of ethambutol dosing (17, 18). Similarly, we have found that ...
The purpose of this study was to assess the ability of our previously constructed pharmacokinetic (PK) model to describe nitroglycerin (GTN), 1,2-dinitroglycerin (1,2-GDN), and 1,3-dinitroglycerin (1,3-GDN) plasma concentrations after a single-dose application of a GTN transdermal matrix delivery system. GTN, 1,2-GDN, and 1,3-GDN plasma concentrations were simultaneously fitted using a first-pass, mixed-order release, one-compartment PK model. Population PK parameter values were derived using an iterative two-stage methodology (IT2S). Some of the mean PK parameters estimates and their interindividual variability (CV%) were the percentage of the delivered GTN dose reaching the systemic circulation released by a first-order process A, 53% (44); the 1,2-GDN and 1,3-GDN formation rate constants, k(f1)9 h(-1) (67) and k(f2) 0.5 h(-1) (38), respectively; the metabolite elimination rate constant, k(m) 1 h(-1) (27); GTN, 1,2-GDN, and 1,3-GDN volumes of distribution (Vc/F 6 L [45]), V2/F 78 L [51]), and V3/F 29 L [40]), respectively). Mean calculated elimination half-lives (t1/2+/-standard deviation [SD]) for GTN and the GDN metabolites were 7+/-4 minutes and 33+/-7 minutes, respectively. The proposed PK model fitted the observed plasma concentrations of GTN, 1,2-GDN, and 1,3-GDN very well. This new transdermal matrix delivery system appears to behave pharmacokinetically in the same manner as a transdermal reservoir delivery system (Transderm-Nitro, Ciba-Geigy, Mississauga, Canada).
Three patients negative for human immunodeficiency virus infection were admitted for pulmonary Mycobacterium avium complex (MAC) and aspergillosis infections. They were treated with different drug combinations, but all regimens included clarithromycin for MAC and itraconazole for aspergillosis. All patients experienced an increase in clarithromycin concentrations and clarithromycin: 14-OH-clarithromycin ratio compared with expected range values. They had no clinical side effects. The time course suggested a possible interaction between clarithromycin and itraconazole, presumably through itraconazole's effects on cytochrome P450 3A4 activity. A bidirectional interaction cannot be ruled out. The data suggest that, when necessary, these two drugs can be administered together safely. Further investigation is necessary to determine the extent and clinical consequences of coadministration in humans.
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