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B M Silber

Publications and source records attributed to B M Silber.

29 records · Page 2Linked to original sources
PubMed1987

Pharmacokinetics of cefixime after oral and intravenous doses in dogs: bioavailability assessment for a drug showing nonlinear serum protein binding.

Cefixime is a new oral cephalosporin which shows dose dependent absorption and concentration dependent serum protein binding in dogs. To study the absolute bioavailability of this drug in dogs, intravenous infusions of 6.25 and 25 mg/kg (each given over 2 hours), approximating the rate of appearance of the drug also given after oral dosing (12.5 and 50 mg/kg) were administered on separate occasions. The mean respective pharmacokinetic parameters obtained after the two intravenous infusions (6.25 and 25 mg/kg) were: total body clearance 4.0 and 5.2 mL/min; volume of distribution 2.2 and 2.8 L; and terminal half-lives of 6.4 hrs. Serum concentrations and area under the serum concentration time curve (AUC) after the low intravenous and oral dose were similar. At the higher doses, serum concentrations and AUC values were significantly higher after the intravenous infusion than after the oral dose. The mean absolute bioavailability (F) values after the 12.5 and 50 mg/kg oral doses using serum AUC comparisons were 52 and 58%, respectively, when calculated against the 6.25 mg/kg intravenous dose and 73 and 38%, respectively, when calculated against the 25 mg/kg intravenous dose. Based on urinary recovery data, F was 49 or 43% for the 12.5 mg/kg oral dose and 34 or 30% for the 50 mg/kg oral dose, depending on the reference intravenous dose used. These results show that because of nonlinearities in the pharmacokinetics of cefixime in the dog, comparison of AUC values obtained after oral doses to AUC values derived following intravenous administration of the drug may result in inaccurate bioavailability estimates if the concentration ranges after the two routes of administration are substantially different. Since the clearance of the drug is concentration-dependent, the absolute bioavailability of the drug must, therefore, be estimated under conditions where serum concentrations obtained after oral and intravenous doses are similar. In summary, for a drug like cefixime which shows nonlinear pharmacokinetics in the dog, estimations of absolute bioavailability, can be more accurately made using urinary excretion data.

Administration, Oral↗
PubMed1987

Liquid-chromatographic determination of five orally active cephalosporins--cefixime, cefaclor, cefadroxil, cephalexin, and cephradine--in human serum.

We report an isocratic "high-performance" liquid-chromatographic (HPLC) procedure for measurement of five orally administered cephalosporins (cefixime, cefaclor, cefadroxil, cephalexin, and cephradine) in 0.1 mL of human serum. Serum protein is precipitated with acetonitrile, the sample is centrifuged, and the supernate is evaporated under nitrogen. The residue is reconstituted in 0.1 mL of mobile phase, and 50 to 80 microL of this is injected onto a reversed-phase Altex Ultrasphere Octyl (C8) column. The five cephalosporins are resolved by elution with a pH 2.6 mobile phase of methanol/monobasic phosphate buffer (20/80) by vol), flow rate 2 mL/min. The column effluent is monitored at 240 nm. Cefixime serves as the internal standard for the analysis of the four other compounds, cephalexin as the internal standard for cefixime. We used two standard curves for all compounds: a low-range curve for concentrations commonly observed clinically and a higher-range curve for higher concentrations. The former were linear from 1.0 to 10 mg/L for cefaclor, cefadroxil, cephalexin, and cephradine and from 0.1 to 1 mg/L for cefixime. The high-concentration curves were linear from 1 to 10 mg/L for cefixime and from 10 to 100 mg/L for the other compounds. The detection limits were 0.1 mg/L for cefixime, 1 mg/L for the other cephalosporins. Mean within-run and day-to-day CVs were always less than 15% for all compounds studied.

Cefaclor↗
PubMed1984

Nonlinear formation of propranolol metabolites in dogs after portacaval transpositions.

The formation of four major metabolites of propranolol by the liver was examined at steady state in three dogs that had undergone surgical portacaval transposition, following which injection of drug into the hindlimb delivers the total dose to the liver. Propranolol was infused directly into the liver via a hindlimb vein at dose rates ranging from 1.01 to 6.3 mg/min. In all dogs the formation of 4-hydroxypropranolol, alpha-naphthoxylactic acid, and propranolol glycol was saturable. Vmax and Km values were determined at steady state by relating the rate of excretion of each metabolite into bile and urine to the blood concentration of propranolol. The formation of propranolol glucuronide was a first order process. The use of a dog with a portacaval transposition has permitted development of a method to estimate, in vivo, the kinetic properties of enzymes responsible for hepatic first-pass metabolism of drugs.

Animals↗
PubMed1983

Chemical aspects of propranolol metabolism. Synthesis and identification of 3-(4-hydroxy-1-naphthoxy)propane-1,2-diol as a metabolite of propranolol in the dog, in man and in the rat liver 9000g supernatant fraction.

4-Hydroxypropranolol glycol (2), a suspected metabolite of propranolol was synthesized from 4-allyloxy-1-naphthaldehyde (4). Osmium tetroxide oxidation of 4 afforded a glycol (5) and subsequent Baeyer-Villiger rearrangement afforded 2. Its presence as a biliary metabolite in a dog maintained on a constant infusion of pseudoracemic propranolol (made up of equal molar 2S-propranolol-3',3'-d2 and 2R-propranolol-d0) into the portal vein was confirmed based on GC-MS data of the TFA and TMS derivatives of the standard and biliary metabolites. Greater amounts of 2 arose from 2R-propranolol than from 2S-propranolol (1.5:1). Similarly, 2 was formed as a urinary metabolite in one subject maintained on oral propranolol, 80 mg every 6 hours. Compound 2 was also formed when propranolol and propranolol glycol were incubated in the presence of the rat liver 9000g supernatant fraction. In addition to 2, an isomeric ring-hydroxylated propranolol glycol, perhaps 7-hydroxypropranolol glycol, was formed when propranolol glycol was the substrate.

Aged↗
PubMed1982

A technique to study hepatic and intestinal drug metabolism separately in the dog.

A model to study hepatic and intestinal drug metabolism in the dog has been evaluated. The model is made by performing a portacaval transposition, cholecystectomy and inserting a Thomas cannula into the duodenum. The result is a healthy animal in which drugs can be infused either in a normal i.v. (forelimb) fashion, directly into the liver (hindlimb) or given orally. Blood can be sampled from a peripheral vein, peripheral artery or hepatic vein. Bile and urine can be collected continuously. Pharmacokinetics can be studied in awake, unmedicated animals. The model can be used to assess oral, i.v. or hepatic infusion of drugs and their hepatic, intestinal or pulmonary metabolism.

Animals↗
PubMed1982

Lack of gastrointestinal metabolism of propranolol in dogs after portacaval transposition.

We studied whether or not propranolol underwent presystemic metabolism in the gastrointestinal wall in five dogs. The dogs were studied before and four weeks after creation of a portacaval transposition. Before surgery, systemic bioavailability of the oral dose was 8 +/- 8% (mean +/- S.D.), whereas after transposition the bioavailability was 102 +/- 9%. The systemic plasma clearance increased from 766 +/- 192 to 976 +/- 280 ml/min. The terminal half life and apparent volume of distribution after transposition were not significantly different from those obtained preoperatively. Our results indicate that there is complete absorption but no metabolism of propranolol by the gastrointestinal wall.

Administration, Oral↗
PubMedDate not supplied

The relationship between drug input and mean residence time in the body.

The relationship between the mean residence time after oral dosing or any other non-instantaneous mode of administration (MRTni) was explored by a series of computer simulations. MRTni was calculated from the ratio of AUMC to AUC (where AUC and AUMC are the zeroth and first statistical moments, respectively, of the drug concentration-time curve). A continuous linear relationship between MRTni and 1/ka or 1/k0 was observed. In the 'flip-flop' case where ka less than K (where K is the last elimination rate constant), the extrapolation from t* to infinity (where t* is the last observed plasma concentration) should be done using ka instead of K. If K is used, underestimated values of MRTni will be obtained. The findings from this investigation have practical application in the design and pharmacokinetic evaluation of novel sustained-release dosage forms.

Administration, Oral↗
PubMedDate not supplied

Bioequivalency of oral suspension formulations of cefixime.

A study was performed in 24 healthy male subjects to establish that two suspension formulations of cefixime were bioequivalent to each other and to a reference oral solution. A single 400 mg oral dose of the drug was given in a randomized three-way crossover design as two suspensions (a research suspension (RS) used during clinical trials and a suspension intended for marketing (MS] and a reference oral solution (SOL). Each dose was separated from the other by a 3-day washout period. Mean peak serum concentrations (Cmax) were 4.67, 4.10, and 4.27 micrograms ml-1 after the MS, RS, and SOL, respectively. Although comparison (ANOVA) of the mean pharmacokinetic parameters for cefixime found significant differences (p less than 0.05) in Cmax, the time to Cmax, and area under the serum concentration time curve (AUC 0----infinity) values among the three formulations, the mean differences were less than 20 per cent. No significant differences (p greater than 0.05) were found in either the elimination half-life or renal clearance of unchanged drug. Overall, with a 98 per cent power to detect a 20 per cent difference in AUC0----infinity or urinary recovery values between the formulations tested, the results show that the MS was bioequivalent to the RS and that both suspensions were bioequivalent to the SOL.

Administration, Oral↗
PubMedDate not supplied

In vitro protein binding interaction studies involving cefixime.

Cefixime is a new oral cephalosporin currently undergoing clinical trials. Selected agents with the likelihood for coadministration with cefixime in man were examined for their influence on the in vitro binding of cefixime in pooled serum from dog, monkey, and man. Results from these experiments showed no significant change in cerfixime binding in any animal species studied or in man by acetaminophen, heparin, phenytoin, diazepam, ibuprofen or furosemide at their maximum reported therapeutic concentrations. In contrast, both salicylic acid and probenecid resulted in concentration-dependent increases in the free fraction of cefixime (up to 2.5-fold). These findings demonstrate the usefulness of in vitro protein binding screening procedures for studying potential drug interactions that are mediated, at least in part, by changes in the protein binding of a drug.

Animals↗
PubMedDate not supplied

Relationship between the pharmacokinetic and pharmacodynamic profile of nilvadipine in the dog.

The purpose of this study was to determine the pharmacokinetic profile of nilvadipine and, using a chronic dog model, determine whether there was a correlation between plasma concentrations of the drug and hemodynamic effects. Nilvadipine was given to four dogs as single intravenous (iv) and oral doses. Pharmacokinetic parameters were estimated after each dose using model-independent methods. The mean elimination half-life was approximately 6 hr after both iv and oral doses. The absolute bioavailability of nilvadipine decreased from 67 to 27% after increasing oral doses (6 and 24 mg), probably because of reduced drug absorption from the gastrointestinal tract. Nilvadipine produced plasma concentration-related decreases in diastolic (DBP) and systolic (SBP) blood pressure and reflex increases in heart rate. The maximum reduction in DBP and SBP ranged from 34 to 53% and 17 to 47%, respectively, from control and was attained at about 0.1 and 0.7 hr after iv and oral doses, respectively. A strong linear correlation between the per cent reduction in both DBP (r = 0.9; p less than 0.001) and SBP (r = 0.66; p less than 0.001) and log plasma concentration of nilvadipine was established. The slopes of the concentration-response relationships were virtually superimposable after both iv and oral routes of administration. A plasma concentration of about 10 and 16 ng/ml was associated with a 14% reduction in DBP or SBP, respectively. There was no clear relationship between plasma concentrations of nilvadipine and changes in heart rate.

Administration, Oral↗