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Biomedical subjects

A Yacobi

Publications and source records attributed to A Yacobi.

At least 109 records · Page 6Linked to original sources
PubMed1976

Serum protein binding as a determinant of warfarin body clearance and anticoagulant effect.

The serum protein binding and elimination kinetics of warfarin were determined in 31 patients with cardiovascular disease who were taking warfarin regularly. The free fraction of warfarin in the serum ranged from 0.00436 to 0.0189, indicating 98.11% to 99.56% protein binding. There was no apparent relationship between the extent of protein binding of warfarin and the concentration of albumin or total protein in the serum. The estimated total body clearance of warfarin in the patients ranged from 1.16 to 4.35ml/hr/kg of body weight and correlated significantly with the free fraction of warfarin in serum. This correlation has been predicted on theoretical grounds and shows that serum protein binding is a major determinant of the elimination kinetics of warfarin in man and an important cause of interindividual variations in its body clearance. The interindividual variation of free warfarin concentrations in the serum of patients with similar prothrombin times was somewhat smaller than the variations in total serum-warfarin concentrations and in the daily dose of warfarin. There was no correlation between prothrombin time and the concentration of free warfarin in serum, indicating that variables other than protein binding also affect the anticoagulant response of patients.

Adult↗
PubMed1976

Intrasubject variation of warfarin binding to protein in serum of patients with cardiovascular disease.

A study of 31 patients with cardiovascular disease who were taking warfarin regularly had shown pronounced intersubject differences in serum protein binding of warfarin and a highly significant correlation between the body clearance of warfarin and the free fraction of the drug in serum. Similar observations have been made in experimental animals and are consistent with predictions based on theoretical considerations. The purpose of this investigation was to determine the intrasubject variation in the free fraction of warfarin in serum. Samples of serum were obtained from 23 of the 31 patients previously studied. The time interval between the two studies was 3.4 to 5.7 mo. The daily dose of warfarin had been changed by 10.6% on the average. With two exceptions, there was no change in concurrent medications. The ratio of free fraction values of warfarin in serum, second/first study, was 0.948 +/- 0.297 (mean +/- S.D.), and there was a highly significant correlation (P less than 0.001) between the individual free fraction values in the first and second studies.

Adult↗
PubMed1976

Relationship between dicumarol distribution and the effect of enzyme induction on dicumarol elimination in rats.

Pronounced intersubject differences in the apparent first-order elimination rate constant (kapp) for dicumarol in rats have been found to be due to corresponding differences in the distribution of dicumarol between the liver (the site of dicumarol biotransformation) and the rest of the body. From theoretical considerations and experimental results in animals given only dicumarol, it has been shown that kapp is linearly related to the fraction of drug in the liver (FL). The proportionality constant (k) for these variables was defined as the intrinsic elimination rate constant for dicumarol which should reflect the activity of the enzyme system(s) involved in the elimination of this drug. The purpose of this investigation was to determine the effect of enzyme induction on dicumarol distribution and on the relationship between kapp and FL in rats. It was found that pretreatment with phenobarbital caused a substantial increase in kapp, but that it had no apparent effect on the serum/liver and serum/kidney concentration ratios of dicumarol. The relative weight of the liver was significantly increased by phenobarbital treatment but the weight of the kidneys was not affected. Linear relationships between kapp and FL were found for both the control and the phenobarbital treated groups, but with a significant difference in the slopes of the regression lines. This study illustrates the application of a pharmacokinetic technique which permits a clear and quantitative distinction between the relative contributions of enzyme activity and body distribution to the in vivo elimination kinetics of a drug.

Animals↗
PubMed1976

Intersubject variation of warfarin binding to protein in serum of normal subjects.

The protein binding of warfarin was determined in the serum of 18 normal adult subjects (8 males and 10 females). A statistically significant negative correlation between free fraction of warfarin and albumin concentration was found. The free fraction of warfarin in the serum of women was significantly larger than that in the serum of men, apparently due to the lower albumin concentration in the serum of women.

Adult↗
PubMed1976

Effect of naproxen on protein binding of warfarin in human serum.

The effect of the non-steroidal anti-inflammatory agent naproxen on the protein binding of racemic warfarin in pooled human serum was determined by equilibrium dialysis. The free fraction of warfarin in serum increased practically linearly with increasing naproxen concentration. At the highest naproxen concentration tested (400 mcg/ml), the warfarin free fraction was 74% larger than the control free fraction value.

Anti-Inflammatory Agents↗
PubMed1975

Assessment of aspirin absorption rate from urinary excretion rate measurements.

It is shown on the basis of pharmacokinetic simulations and experimental data that adequate evaluation of aspirin dosage forms with different absorption rates by urinary excretion measurements in man requires that such measurements be made during the first hour after drug administration. Measurements made only after 3 hours are totally inadequate for that purpose. An assessment of the completeness of absorption obviously does not require serial measurements but needs only a determination of the total amount excreted.

Absorption↗
PubMed1975

Comparative pharmacokinetics of coumarin anticoagulants. XIV: relationship between protein binding, distribution, and elimination kinetics of warfarin in rats.

The relationships between the protein binding, distribution in the body, and kinetics of elimination of warfarin were studied. Individual rats eliminated warfarin by apparent first-order kinetics, with a biological half-life of 5.9-41 hr and a total plasma clearance of 2.4-22 ml kg(-1) hr(-1). There is a strong positive correlation between the apparent volume of distribution (Vd) and the elimination rate constant (kel). There was no apparent concentration dependance of warfarin binding to serum proteins over a wide concentration range, but there were pronounced intersubject variations in protein binding, with the free fraction of drug (f) in serum ranging from 0.172 x 10(-2) to 1.53 x 10(-2). There are strong positive correlations between f and kel, f and Vd, and f and the kidney-serum concentration ratio of warfarin. Consistent with theory, there is an excellent positive linear correlation between f and total plasma clearance of the drug. The intersubject variation in f is not related to variations in serum albumin or total protein concentration. There is a strong correlation between values of f for serum and liver homogenate in individual animals, consistent with the lack of correlation between f in serum and the liver-serum concentration ratio of warfarin. These results show that the pronounced intersubject variation in the elimination of warfarin observed in this investigation was related to interindividual differences in plasma protein binding of the drug. The differences in protein binding cannot be ascribed to differences in plasma protein concentrations and may reflect configurational differences of proteins or the presence of an endogenous displacing agent at different concentrations.

Animals↗
PubMed1975

Comparative pharmacokinetics of coumarin anticoagulants XV: relationship between pharmacokinetics of dicumarol and warfarin in rats.

The distribution, elimination, and anticoagulant effect of dicumarol and warfarin were determined in adult males rats following intravenous injection of single doses of these drugs in crossover experiments. The biological half-life of dicumarol ranged from 5 to 28 hr; that of warfarin ranged from 9 to 30 hr. There was a statistically significant correlation between the following pharmacokinetic characteristics of dicumarol and warfarin in individual animals: biological half-life, apparent volume of distribution, total plasma clearance, and concentration in plasma eliciting one-half the maximum anticoagulant effect (effective concentration). The mean ratio of the respective biological half-lives (warfarin/dicumarol) was 1.42, and that of the apparent volumes of distribution was 1.50. The ratio of the effective plasma concentrations (dicumarol/warfarin) was correlated negatively with the half-life of dicumarol and positively with the ratio of the half-life values (warfarin/dicumarol) in individual animals. Additional studies with serum samples from other rats showed pronounced interindividual differences in the serum protein binding of both dicumarol and warfarin and a strong correlation between the protein binding of these two drugs in serum of individual animals. The results of this study, together with the results of previous studies in this series, indicate that serum protein binding is the major determinant of interindividual differences in the pharmacokinetics of dicumarol and warfarin in rats under these experimental conditions.

Animals↗
PubMed1975

Effect of plasma protein binding on the anticoagulant action of warfarin in rats.

The relationships between the anticoagulant effect and the concentrations of free and total (sum of free and protein-bound) warfarin in plasma were determined in rats following intravenous administration of single doses of racemic warfarin or S(-)-warfarin. The concentration of total warfarin required to elicit a defined anticoagulant effect varied widely between animals while the concentration of free warfarin showed much less variation. This indicates that the anticoagulant effect of warfarin is a function of its free concentration in plasma.

Animals↗
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

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

Analytical methods validation: bioavailability, bioequivalence and pharmacokinetic studies. Conference report.

This is a summary report of the conference on Analytical Methods Validation: Bioavailability, Bioequivalence and Pharmacokinetic Studies. The conference was held from December 3 to 5, 1990 in the Washington, DC area and was sponsored by the American Association of Pharmaceutical Scientists, US Food and Drug Administration, Federation International Pharmaceutique, Health Protection Branch (Canada) and Association of Official Analytical Chemists. The purpose of the report is to represent our assessment of the major agreements and issues discussed at the conference. The report is also intended to provide guiding principles for validation of analytical methods employed in bioavailability, bioequivalence and pharmacokinetic studies in man and animals. The objectives of the conference were: 1. To reach a consensus on what should be required in analytical methods validation and the procedures to establish validation; 2. To determine processes of application of the validation procedures in the bioavailability, bioequivalence and pharmacokinetic studies; 3. To develop a report on analytical methods validation (which may be referred to in developing future formal guidelines). Acceptable standards for documenting and validating analytical methods with regard to processes, parameters or data treatments were discussed because of their importance in assessment of pharmacokinetic, bioavailability and bioequivalence studies. Other topics which were considered essential in the conduct of pharmacokinetic studies or in establishing bioequivalency criteria, including measurement of drug metabolites and stereoselective determinations, were also deliberated.

Biological Availability↗