Diet and risk of ethanol-induced hepatotoxicity: carbohydrate-fat relationships in rats.
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Nutritional status is a primary factor in the effects of xenobiotics and may be an important consideration in development of safety standards and assessment of risk. One important xenobiotic consumed daily by millions of people worldwide is alcohol. Some adverse effects of ethanol, such as alcohol liver disease, have been linked to diet. For example, ethanol-induced hepatotoxicity in animal models requires diets that have a high percentage of the total calories as unsaturated fat. However, little attention has been given to the role of carbohydrates (or carbohydrate to fat ratio) in the effects of this important xenobiotic on liver injury. In the present study, adult male Sprague-Dawley rats (8-10/group) were infused (intragastrically) diets high in unsaturated fat (25 or 45% total calories), sufficient protein (16%) and ethanol (38%) in the presence or absence of adequate carbohydrate (21 or 2.5%) for 42-55 days (d). Animals infused ethanol-containing diets adequate in carbohydrate developed steatosis, but had no other signs of hepatic pathology. However, rats infused with the carbohydrate-deficient diet had a 4-fold increase in serum ALT levels (p < 0.05), an unexpectedly high (34-fold) induction of hepatic microsomal CYP2E1 apoprotein (p < 0.001), and focal necrosis. The strong positive association between low dietary carbohydrate, enhanced CYP2E1 induction and hepatic necrosis suggests that in the presence of low carbohydrate intake, ethanol induction of CYP2E1 is enhanced to levels sufficient to cause necrosis, possibly through reactive oxygen species and other free radicals generated by CYP2E1 metabolism of ethanol and unsaturated fatty acids. (+info)
Pharmacokinetics of ethambutol under fasting conditions, with food, and with antacids.
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Ethambutol (EMB) is the most frequent "fourth drug" used for the empiric treatment of Mycobacterium tuberculosis and a frequently used drug for infections caused by Mycobacterium avium complex. The pharmacokinetics of EMB in serum were studied with 14 healthy males and females in a randomized, four-period crossover study. Subjects ingested single doses of EMB of 25 mg/kg of body weight under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. Serum was collected for 48 h and assayed by gas chromatography-mass spectrometry. Data were analyzed by noncompartmental methods and by a two-compartment pharmacokinetic model with zero-order absorption and first-order elimination. Both fasting conditions produced similar results: a mean (+/- standard deviation) EMB maximum concentration of drug in serum (Cmax) of 4.5 +/- 1.0 micrograms/ml, time to maximum concentration of drug in serum (Tmax) of 2.5 +/- 0.9 h, and area under the concentration-time curve from 0 h to infinity (AUC0-infinity) of 28.9 +/- 4.7 micrograms.h/ml. In the presence of antacids, subjects had a mean Cmax of 3.3 +/- 0.5 micrograms/ml, Tmax of 2.9 +/- 1.2 h, and AUC0-infinity of 27.5 +/- 5.9 micrograms.h/ml. In the presence of the Food and Drug Administration high-fat meal, subjects had a mean Cmax of 3.8 +/- 0.8 micrograms/ml, Tmax of 3.2 +/- 1.3 h, and AUC0-infinity of 29.6 +/- 4.7 micrograms.h/ml. These reductions in Cmax, delays in Tmax, and modest reductions in AUC0-infinity can be avoided by giving EMB on an empty stomach whenever possible. (+info)
Cimetidine transport in brush-border membrane vesicles from rat small intestine.
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In previous studies, sulfoxide metabolite was observed in animal and human intestinal perfusions of cimetidine and other H2-antagonists. A sequence of follow-up studies is ongoing to assess the intestinal contributions of drug metabolism and drug and metabolite transport to variable drug absorption. An evaluation of these contributions to absorption variability is carried out in isolated fractions of the absorptive cells to uncouple the processes involved. In this report, data is presented on the drug entry step from a study on [3H]cimetidine uptake into isolated brush-border membrane vesicles from rat small intestine. A saturable component for cimetidine uptake was characterized with a Vmax and Km (mean +/- S.E.M.) of 6.1 +/- 1.5 nmol/30s/mg protein and 8.4 +/- 2.0 mM, respectively. Initial binding, and possibly intravesicular uptake, was inhibited by other cationic compounds including ranitidine, procainamide, imipramine, erythromycin, and cysteamine but not by TEA or by the organic anion, probenecid. Initial uptake was not inhibited by amino acids methionine, cysteine, or histidine, by the metabolite cimetidine sulfoxide, or by inhibitors of cimetidine sulfoxidation, methimazole, and diisothiocyanostilbene-2,2'-disulfonic acid. Equilibrium uptake was inhibited by ranitidine, procainamide, and cysteamine but not by erythromycin or imipramine. Initial cimetidine uptake was stimulated by an outwardly directed H+ gradient, and efflux was enhanced by an inwardly directed H+ gradient. Collapse of the H+ gradient as well as voltage-clamping potential difference to zero significantly reduced initial cimetidine uptake. The data is supportive of both a cimetidine/H+ exchange mechanism and a driving-force contribution from an inside negative proton or cation diffusion potential. (+info)
Impact of food intake on the antisecretory effect of low-dose ranitidine and famotidine.
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BACKGROUND: Over-the-counter status has recently been approved for low-dose H2-antagonists in several countries. Insufficient information is currently available on the effect of food in low-dose H2-antagonist therapy. AIM: Compare the antisecretory efficacy of low-dose ranitidine and famotidine in fasting and non-fasting volunteers. METHODS: Twenty volunteers were randomized into a double-blind, placebo-controlled, multiple-step crossover study comparing the antisecretory efficacy of 75 mg ranitidine, 10 mg famotidine and placebo over 12 h using intragastric pH-metry. Two standard meals were given after 4 h and 8 h of medication. Fifteen volunteers also participated in a second study comparing the antisecretory effect of both drugs, both with and without meals. RESULTS: In non-fasting subjects, the percentage of time with pH > 4 was similarly elevated for both drugs compared with placebo over the first 8 h: ranitidine 39.3%, famotidine 29.5%, placebo 9.5% (P < 0. 001); but not for the last 4 h after the second meal (P > 0.05). Comparing the first 4-h period with the second, the percentage of pH > 4 was significantly reduced for both drugs in the second period in the subjects given food at the end of the initial 4-h period (ranitidine 56.9% vs. 26.6%, P = 0.005; famotidine 46.6% vs. 13.3%, P < 0.001). It remained more or less constant, however, for the second 4-h period in fasting subjects (ranitidine 41% vs. 28.1%, P = 0.46; famotidine 52.7% vs. 52.2%, P = 0.12). CONCLUSION: In non-fasting volunteers both low-dose H2-antagonists had comparable antisecretory effects and were superior to placebo over the first 8 h of therapy. Both drugs achieved a slightly higher antisecretory effect without food intake compared to with food intake. (+info)
Oral bioequivalence of three ciprofloxacin formulations following single-dose administration: 500 mg tablet compared with 500 mg/10 mL or 500 mg/5 mL suspension and the effect of food on the absorption of ciprofloxacin oral suspension.
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The oral bioequivalence and tolerability of two ciprofloxacin formulations (tablet and suspension) and the effect of food on the absorption of ciprofloxacin oral suspension were investigated. Sixty-eight young, healthy male subjects participated in two separate, randomized, crossover studies. In study 1, ciprofloxacin as a single 500 mg tablet or as 500 mg/10 mL oral suspension was administered in a fasted state on day 1. In study 2, subjects participated in a three-way crossover study in which ciprofloxacin suspension was administered as 500 mg/10 mL in a fasted state, or 500 mg/10 mL with food, or 500 mg/5 mL in a fasted state. Plasma ciprofloxacin concentrations were measured by high-performance liquid chromatography. Standard pharmacokinetic parameters were estimated using non-compartmental methods. In study 1, geometric mean Cmax values of ciprofloxacin following the single 500 mg tablet and 500 mg/10 mL suspension doses were 2.36 and 2.18 mg/L, respectively; corresponding geometric mean t(max) values were 1.1 and 1.6 h, respectively. Geometric mean AUC(0-infinity) values were 12.0 and 11.8 mg x h/L, respectively. In study 2, geometric least squares mean Cmax values following ciprofloxacin 500 mg/10 mL and 500 mg/5 mL suspension during fasted conditions were 1.54 and 1.59 mg/L, respectively. Corresponding geometric least squares mean AUC(0-infinity) values were 7.3 and 8.0 mg x h/L. Administration of ciprofloxacin 500 mg/10 mL suspension, in either a fasted or fed state, was not associated with significant changes in Cmax (1.54 mg/L for fasted vs 1.37 mg/L for fed) or AUC(0-infinity) values (7.28 mg x h/L for fasted vs 8.19 mg x h/L for fed). Each ciprofloxacin formulation was well tolerated for the duration of each study. These studies demonstrated bioequivalence between ciprofloxacin 500 mg tablet and two strengths of ciprofloxacin suspension (500 mg/10 mL and 500 mg/5 mL). Bioavailability was unaltered by food. (+info)
The effect of dosing regimen on the pharmacokinetics of risedronate.
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AIMS: To examine the effect of timing of a risedronate dose relative to food intake on the rate and extent of risedronate absorption following single-dose, oral administration to healthy male and female volunteers. METHODS: A single-dose, randomized, parallel study design was conducted with volunteers assigned to four treatment groups (31 or 32 subjects per group, 127 subjects total). Each subject was orally administered 30 mg risedronate. Group 1 was fasted for 10 h prior to and 4 h after dosing (fasted group); Groups 2 and 3 were fasted for 10 h and were dosed 1 and 0.5 h, respectively, before a high-fat breakfast; and Group 4 was dosed 2 h after a standard dinner. Blood and urine samples were collected for 168 h after dosing. Pharmacokinetic parameters were estimated by simultaneous analysis of risedronate serum concentration and urinary excretion rate-time data. RESULTS: Extent of risedronate absorption (AUC and Ae ) was comparable (P=0.4) in subjects dosed 2 h after dinner and 0.5 h before breakfast; however, a significantly greater extent of absorption occurred when risedronate was given 1 or 4 h prior to a meal (1.4- to 2.3-fold greater). Administration 0.5, 1, or 4 h prior to a meal resulted in a significantly greater rate of absorption (Cmax 2.8-, 3.5-, and 4.1-fold greater, respectively) when compared with 2 h after dinner. CONCLUSIONS: The comparable extent of risedronate absorption when administered either 0.5-1 h before breakfast or 2 h after an evening meal support previous clinical studies where risedronate was found to have similar effectiveness using these dosing regimens. This flexibility in the timing of risedronate administration may provide patients an alternative means to achieve the desired efficacy while maintaining their normal daily routine. (+info)
Clinical pharmacokinetics of doxazosin in a controlled-release gastrointestinal therapeutic system (GITS) formulation.
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AIMS: A controlled-release gastrointestinal therapeutic system (GITS) formulation of doxazosin mesylate, a long-acting selective alpha1-adrenoceptor antagonist, was developed to enhance the pharmacokinetic profile and simplify the titration schedule by precisely controlling drug delivery rate, permitting an initial dose of 4 mg once daily, compared with standard doxazosin, which is initiated at 1 mg day-1 and titrated to a higher therapeutically effective dose. The aim of the present work was to evaluate the pharmacokinetics and bioavailability of doxazosin GITS with respect to the effect of food, age and gender, and multiple dosing. In addition, in vitro performance was assessed in conditions simulating the gastrointestinal environment. METHODS: A three-way crossover study in 24 subjects assessed the comparative bioavailability of doxazosin GITS under fed and fasting conditions and doxazosin standard under fasting condition. A multiple-dose, two-way crossover study in 35 subjects assessed the comparative pharmacokinetics and bioavailability of doxazosin GITS and doxazosin standard 4 and 8 mg upon multiple dosing. A multiple-dose, four-parallel-group study was conducted to determine the steady-state pharmacokinetics and bioavailability of doxazosin GITS 4 mg in 41 young and elderly male and female subjects. The release-rate profiles of doxazosin GITS were determined in artificial gastric fluid (pH=1.2), intestinal fluid (pH=7.5), and water. The effect of agitation on the dissolution characteristics of doxazosin GITS in artificial gastric fluid was studied at stirring rates of 50, 75, and 100 rev min-1. RESULTS: In vitro studies demonstrated that release rates for the GITS tablet are independent of pH in the range of 1.2 (gastric) to 7. 5 (intestinal), and of stirring rates simulating gastrointestinal motility. Clinical pharmacology studies showed that doxazosin GITS had a lower maximum plasma concentration, prolonged time to reach maximum plasma concentration, and a higher minimum plasma concentration compared with doxazosin standard. Thus, the GITS formulation results in a more gradual absorption of doxazosin, and a reduced plasma doxazosin concentration peak-to-trough fluctuation ratio. The relative bioavailability of doxazosin GITS is approximately 60%. With a high-fat meal, the maximum plasma concentration and area under the concentration-time curve were 31% and 18% higher, respectively (P<0.05). Bioequivalence was established between the dose strengths of two 4 mg doxazosin GITS tablets and one 8 mg doxazosin GITS tablet. For both young adult and elderly subjects, and males and females, the pharmacokinetics of doxazosin GITS once daily for 7 days were comparable. Doxazosin GITS was well tolerated in the subjects studied, including young and elderly males and females. CONCLUSIONS: The GITS formulation of doxazosin enhances the pharmacokinetic profile compared with doxazosin standard, allowing more gradual absorption of doxazosin, and a reduced plasma doxazosin peak-to-trough concentration ratio. Thus, doxazosin GITS therapy can be initiated at a therapeutic dose of 4 mg with reduced haemodynamic side-effects. (+info)
Pharmacokinetic analysis of felodipine-grapefruit juice interaction based on an irreversible enzyme inhibition model.
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Aims Ingestion of grapefruit juice (GFJ) alters the pharmacokinetics of various orally administered drugs. Quantitative evaluation of this GFJ-drug interaction is required for the proper clinical management of patients. Methods Using felodipine as a model drug, we constructed a pharmacokinetic model based on irreversible inhibition of intestinal cytochrome P450 3A4 (CYP3A4) by GFJ. We fitted previously published data [5, 6] for felodipine ER (extended release formulation) to the ratio of CLGI,int before and after grapefruit juice ingestion by nonlinear least-squares regression analysis to estimate the reaction rate constant between GFJ and CYP3A4 (K) and the elimination rate constant of CYP3A4 (k ). RESULTS: The model gave a turnover rate of CYP3A4 of 0.0849 h-1, corresponding to a half-life of 8.16 h, in agreement with reported values. The AUC-time profiles of felodipine ER in the case of different amounts and schedules of GFJ ingestion were simulated using the parameter values estimated from the model. CONCLUSIONS: The modelling leads to the important conclusion that GFJ-felodipine interaction increases with increasing frequency and amount of GFJ ingestion, and that an interval of 2-3 days between GFJ intake and felodipine administration is necessary if GFJ-felodipine interaction is to be avoided. (+info)