[Antibiotic assay. Indications and application].
Explore the source record for details and available documents.
Acquired Immunodeficiency Syndrome↗
Biomedical subjects
J F Westphal
Publications and source records attributed to J F Westphal.
Adaptive computer program for determination of absorption profiles by numerical deconvolution: application to amoxicillin absorption.
We have developed a specific numerical deconvolution program for the Apple Macintosh microcomputer. After comparison with other methods, we used the program to evaluate the influence of nifedipine on the absorption and bioavailability of amoxicillin. The technique provided a model-independent approach. This study shows that the simultaneous administration of nifedipine with amoxicillin leads to a significant increase in both the total quantity of amoxicillin absorbed (+22%) and the rate of absorption. Parameters of clearance, volume of distribution, and elimination were unaffected. Numerical deconvolution analysis showed that nifedipine did not modify the absorption kinetics of amoxicillin, which are characterized by a lag time followed by a constant rate of absorption, suggesting zero-order kinetics with first-order kinetics at the end of the process. The results suggest the existence of a specialized, saturable transport molecule for this antibiotic.
Adult↗
Modification of cefixime bioavailability by nifedipine in humans: involvement of the dipeptide carrier system.
We studied the action of nifedipine on the bioavailability of cefixime, a molecule absorbed via the gut wall dipeptide carrier system in the rat, and on the bioavailability of D-xylose, which is absorbed via a pH (and Na(+)-)-dependent transporter. Each compound was administered alone or in combination with 20 mg of nifedipine to eight healthy male volunteers. Nifedipine significantly increased the absorption rate of cefixime (20.7 +/- 4.3 versus 16 +/- 3.5 mg/h in the absence of nifedipine). The absolute bioavailability of cefixime alone was 31% +/- 6% compared with 53% +/- 1% (P < 0.01) in the presence of nifedipine. The observed peak concentrations in serum were significantly different (2.5 +/- 0.3 mg/liter without nifedipine and 3.7 +/- 1.1 mg/liter with nifedipine; P < 0.02). In contrast, nifedipine induced no significant differences in the pharmacokinetic profile of xylose following oral administration. We conclude that (i) cefixime is absorbed in humans by an apparently active process which can be enhanced by a calcium channel blocker, in this case, nifedipine; and (ii) nifedipine does not modify the activity of the pentose transporter.
Administration, Oral↗
Evaluation of cefixime biliary disposition in the isolated perfused rabbit liver model and in humans.
Cefixime is a new orally effective third-generation cephalosporin. It inhibits a wide variety of Gram-positive and Gram-negative bacteria, especially most of the Enterobacteriaceae. Since extrarenal excretion processes have been reported to account for 60% of cefixime systemic clearance we have endeavoured to determine the place taken up by biliary excretion of unchanged cefixime in this pattern. We initially used the isolated perfused rabbit liver technique. Six perfusions were performed. Cefixime concentrations were measured by HPLC chromatography. After addition of a single 10-mg dose of cefixime to the circulating blood, biliary elimination of the drug proved to be very low, since only 0.28 +/- 0.15% of the dose was recovered during the 3-h perfusion period. The rate of cefixime biotransformation in the liver was found to be 16.2%. In contrast, the data obtained in humans highlight substantial biliary excretion of the drug. In six healthy volunteers submitted to duodenal aspiration and receiving a single 200-mg i.v. dose of cefixime, drug levels in duodenal fluid were at least fivefold greater than the simultaneous concentrations in serum. Biliary excretion of cefixime was further investigated in ten cholecystectomized patients provided with T-tube drainage: following a single 200 mg oral dose of cefixime, Cmax in bile reached 56.9 +/- 70 mg/l, that is about 25 times as high as Cmax in serum, 2.3 +/- 0.85 mg/l. Drug levels in choledochal bile proved to be sustained, since a concentration of 4.3 +/- 3.7 mg/ml was still observed 20 h after dosing.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Biliary excretion and hepatic disposal of cefixime: experimental and clinical study].
Cefixime is a new oral cephalosporin with in vitro activity similar to that of third-generation cephalosporins. Renal excretion accounts for only 40% of systemic clearance of cefixime, suggesting that biliary excretion of the drug may be significant. This study was designed to determine to what extent nonrenal clearance of cefixime is due to biliary excretion of the parent compound. In an isolated perfused rabbit liver model, biliary excretion of cefixime was very low, with only 0.28 +/- 0.15% of a single 10 mg dose injected in the system being recovered in the bile after three hours perfusion. The liver biotransformation rate for cefixime was found to be 16.2%. These results are in striking contrast with those obtained in human studies. Cefixime levels in duodenal juice aspirates collected over four hours following an intravenous injection of 200 mg cefixime in six healthy volunteers were at least fivefold concomitant serum levels. Studies of bile collected by external biliary drainage during 24 hours following an oral dose of 200 mg cefixime in ten cholecystectomized patients showed that the Cmax was 56.9 +/- 70 mg/l, i.e., 25-fold the serum Cmax (2.3 +/- 0.85 mg/l). The bile AUC/serum AUC ratio was 20.4 +/- 20.3. Mean bile level of cefixime was still as high as 4.3 +/- 3.7 mg/l 20 hours after dosing. The amount of cefixime excreted in the bile over 24 hours was 10.0 +/- 12.3 mg i.e., 5% of the dose administered. Twenty-four hour renal excretion of cefixime was 53.3 +/- 26.2 mg.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Reappraisal of amoxycillin absorption kinetics.
Interest in the intestinal absorption mechanisms of drugs has increased because transepithelial passage across the gut does not necessarily follow a passive diffusion process. Amoxycillin, like other amino-beta-lactam antibiotics, has been demonstrated in vitro to use the dipeptide carrier-mediated system in rodent small intestine. In order to assess the in-vivo relevance of these data, we applied the Loo-Riegelman method for a reappraisal of amoxycillin absorption kinetics in healthy human volunteers. The results showed evidence of a saturable carrier-mediated uptake of this antibiotic. With respect to the in-vitro data previously published, the dipeptide carrier system would appear to be the most likely transport mechanism.
Administration, Oral↗
Management of biliary tract infections: potential role of the quinolones.
Explore the source record for details and available documents.
4-Quinolones↗
[Experimental study on the hepatobiliary kinetics and excretion of temafloxacin. Evidence for production of active metabolites by the rabbit liver].
Temafloxacin is a new fluoroquinolone derivative currently under evaluation. Its hepatobiliary disposition remains undefined as yet. The present study represents an experimental approach to this issue. Six isolated rabbit liver preparations were perfused for three hours with reconstituted and oxygenated blood in a closed circuit. A the onset of the procedures, temafloxacin 10 mg were added to the circulating blood. Both bile and blood were sampled throughout the perfusion time, and liver fragments were taken at the end of the experiments. Temafloxacin levels were measured by HPLC in serum and hepatic tissue, and by both HPLC and microbiological assay in bile. The percentage of drug undergoing hepatic biotransformation appeared to be high, i.e. 58.3%. This finding is substantiated by the comparison of temafloxacin levels in bile, as provided by HPLC and microbiological assay, the latter yielding concentrations twice as high (biliary peak: 33.5 +/- 2.8 micrograms/ml versus 19.3 +/- 3.1 micrograms/ml by HPLC assay) as those obtained by HPLC (p less than 0.05). Consistently, the average amount of temafloxacin excreted into the bile (0-3 h) was, respectively, 92 micrograms (0.9% of the dose) and 204 micrograms (2.0%) as determined by HPLC and microbiological methods (p less than 0.05); this statistically significant difference suggests the presence of active metabolites in bile. The presented results bring out evidence for substantial biotransformation of temafloxacin by Rabbit liver. Extrapolation to other species, however, would be hazardous; further pharmacokinetic studies are needed in order to assess the relevance of these findings in humans.
4-Quinolones↗
[Cefuroxime axetil, a new oral cephalosporin for treating infections of the ORL field: clinical synthesis].
Cefuroxime axetil (C.A.E.) is a broad spectrum cephalosporin, suitable for oral route. Its antibacterial activity includes all the pathogens usually responsible for E.N.T. infection, with low M.I.C.'s: H. influenzae, S. pneumoniae, S. aureus, S. pyogene. The stability of the drug against betalactamases, especially those produced by H. influenzae, associated with good bio availability (50%) and tissue penetration (30%) account for the potent in vivo bactericidal activity and clinical efficacy of cefuroxime axetil. More than 1,000 patients had been enrolled in controlled clinical trials: the success rates yielded by C.A.E. were 98%, 96% and 91%, respectively for pharingitis/tonsilitis, otitis media and acute sinusitis. C.A.E. is at least as effective as amoxycillin/clavulanic acid and safety appears to be better.
Cefuroxime↗
Biliary elimination and hepatic disposition of a new fluoroquinolone, temafloxacin: experimental evaluation.
Temafloxacin is a new quinolone derivative presently under evaluation. Its pharmacokinetic profile, and particularly its biliary elimination and hepatic disposition, remains undefined. The present study describes an experimental approach to this issue. Six isolated rabbit liver preparations were perfused for 3h (h) with reconstituted blood in a closed circuit; 10 mg of temafloxacin were added to the circulating blood at the onset of the procedure. Bile was recovered throughout the experiments and liver fragments were taken at the conclusion. Assays were carried out by high-performance liquid chromatography. Pharmacokinetic analysis was performed with reference to a monocompartmental open model. Under these conditions, the serum half-life of temafloxacin was 3.1 and the maximal biliary concentration of 19.3 +/- SEM 3.1 micrograms/ml was reached between 30 and 60 min; the cumulative biliary elimination (0-3 h) amounted to 92 +/- 16 micrograms (0.9% of the added dose). Total and hepatobiliary clearances were calculated as respectively 134 and 2.38 ml/h and the hepatobiliary elimination rate as 0.0042 (h-1). At the end of the procedure, 25.7 +/- 3.5% of the added dose of temafloxacin was still present in the circulating blood, and 13.7 +/- 2.4% in the liver. Degradation of the antibiotic in the perfusion device concerned only 2.4% of the dose. The percentage of temafloxacin undergoing hepatic biotransformation, determined by subtraction, was high (57.3%). Under these experimental conditions, temafloxacin appears to be particularly stable in serum, poorly eliminated as parent compound in the bile, highly fixed in the liver and above all subject to a probable hepatic biotransformation. Extrapolation of these experimental data to other species or to the whole organism would be hazardous, but these results should stimulate studies on a possible hepatic metabolism of this new trifluoroquinolone in man.
4-Quinolones↗
Nifedipine enhances amoxicillin absorption kinetics and bioavailability in humans.
Intestinal absorption of aminopenicillins in vitro uses the dipeptide carrier system. Recent experiments have reported calcium ion to be a cellular mediator of the regulation of electrolyte transport through the enterocyte membrane, especially the Na/H exchange which is partly responsible for the proton gradient energizing the carrier system. In order to assess the in vivo relevance of these data, we studied, in healthy volunteers, the influence of nifedipine, a calcium channel blocking agent, on the intestinal uptake of amoxicillin, a commonly prescribed and well-absorbed aminopenicillin. Results obtained show that 1) intestinal absorption kinetics of amoxicillin follows a zero-order process, which further substantiates the existence of a saturable carrier-mediated process for this antibiotic in humans and 2) calcium channel blockade significantly enhances both absorption rate (by 70%) and bioavailability of amoxicillin (by 21.4%) without modifying its distribution or elimination. These findings might suggest that nifedipine could enhance amoxicillin intestinal uptake by stimulating its active transport.
Adult↗