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Biomedical subjects

G Levy

Publications and source records attributed to G Levy.

At least 433 records · Page 24Linked to original sources
PubMed1977

Frequency distribution of free warfarin and free phenytoin fraction values in serum of healthy human adults.

The protein binding of racemic warfarin was determined in serum from 57 normal adults (27 men and 30 women). The free fraction of warfarin (total concentration, 0.8 mug/ml) ranged from 0.0050 to 0.0186 and was log-normally distributed. The frequency distribution differs from that in rats in which the serum free fraction values of warfarin are trimodally distributed. The protein binding of phenytoin was determined in serum from 39 of the subjects. The free fraction of phenytoin (total concentration, 15 mug/ml) ranged from 0.111 to 0.155 and was unimodally distributed. There was no apparent correlation between the extent of protein binding of warfarin and phenytoin in individual serum samples. The pronounced intersubject variation in serum free fraction of warfarin observed in consistent with our previous finding that serum protein binding is an important determinant of interindividual differences in the total clearance of warfarin in man. On the other hand, the relatively narrow distribution of free phenytoin fraction values suggests that differences in serum protein binding of phenytoin are not an important cause of the prounounced interindividual differences in the total clearance of phenytoin by subjects with normal renal function.

Adolescent↗
PubMed1977

Interindividual differences in the effect of drugs on bilirubin plasma binding in newborn infants and in adults.

The nonprotein-bound fraction of bilirubin was determined in undiluted plasma or serum from healthy adult volunteers and newborn infants after addition of unconjugated bilirubin, 12 mg/100 ml. There were significant interindividual difference (2-fold in 13 adults, 2.6-fold in 9 full-term newborn infants) in the free fraction value. Sulfisoxazole, salicylic acid, and salicyluric acid had a pronounced displacing effect on bilirubin in the 10 to 30 mg/100 ml drug concentration range. Aspirin had only a small effect at concentrations below 20 mg/100 ml. There was a very strong correlation between the free fraction value of bilirubin in individual samples of drug-free plasma and in the same plasmas after addition of any one of the 4 drugs studied. This shows that the relative increase of the free fraction of bilirubin induced by any one of the drugs was essentially the same but that the absolute increase varied greatly between subjects. It may be possible, therefore, to predict quanitatively the bilirubin-displacing effect of drugs in individual patients before drug administration by determining the free fraction of bilirubin in a plasma or serum sample obtained prior to initiation of drug therapy.

Adult↗
PubMed1977

Comparative pharmacokinetics of coumarin anticoagulants XXI: effect of plasma protein binding on distribution kinetics of warfarin in rats.

The purpose of this investigation was to determine the effect of plasma protein binding on the pharmacokinetic parameters for warfarin that are used conventionally to describe its distribution kinetics on the basis of the time course of plasma warfarin concentrations. Following rapid intravenous injection, warfarin concentrations in the plasma of 14 selected adult male rate declined triexponentially, with the terminal exponential phase starting at about 5 hr. The free fraction, f, of warfarin in the serum of individual animals ranged from 0.303 X 10(-2) to 2.89 X 10(-2). The parameters of the equation Ct = Pe-theta + Ae-alphat + Be-betat for plasma concentration Ct at time t were obtained from the experimental data by nonlinear least-squares computer fitting and varied markedly between animals. Strong and highly statistically significant positive correlations with f were obtained for P, B, and beta, but no significant correlation was found for A, theta, and alpha. Rate constants and apparent volumes for a three-compartment open mammillary model with elimination from the central compartment were calculated. No apparent correlation was found between f and the intercompartment distribution rate constants. However, strong positive correlations between f and the elimination rate constant, the volume of the central compartment, and the volume of distribution, V area, were observed. There also was a strong linear correlation between f ant total clearance. Excellent replication of the experimental data was obtained when the experiment were repeated in some animals after 2 weeks. A detailed analysis of practical pharmacokinetic problems associated with and revealed by such repeated experiments is presented.

Animals↗
PubMed1977

Comparative pharmacokinetics of coumarin anticoagulants XXIV: Effect of treatment with phenobarbital on serum protein binding of warfarin and dicumarol in rats.

Rats were treated with the enzyme inducer phenobarbital to determine if it would affect the serum protein binding of warfarin and dicumarol, possibly by changing the rate of formation or elimination of endogenous inhibitor(s). Daily administration of phenobarbital, 75 mg/kg, for 4 days increased relative liver size (a concomitant of enzyme induction) but had no apparent effect on the serum protein binding of warfarin and dicumarol.

Animals↗
PubMed1977

Comparative pharmacokinetics of coumarin anticoagulants XXV: Warfarin-ibuprofen interaction in rats.

The effect of ibuprofen on the pharmacokinetics and anticoagulant action of racemic warfarin was determined in a crossover study on male Sprague-Dawley rats. At average plasma concentrations of 24-83 mg/liter, ibuprofen decreased the biological half-life and increased the total clearance of warfarin. It also increased the anticoagulant effect produced by a given plasma concentration of total (free and protein-bound) warfarin. These effects of ibuprofen appear to be a consequence of its displacing effect on warfarin in plasma.

Animals↗
PubMed1977

Relationship between protein binding of bilirubin, salicylic acid, and sulfisoxazole in serum of unmedicated and phenobarbital-treated rats.

The relationship between the protein binding of bilirubin, salicylic acid, and sulfisoxazole in the serum of phenobarbital-treated and untreated rats was studied. The free fraction of bilirubin in serum varied about threefold between animals but was not related to the albumin concentration, the free fraction of salicylate, or the free fraction of sulfisoxazole. However, there was a strong positive correlation between the free fraction values of salicylate and sulfisoxazole. The free fraction value for each of these drugs showed a significant negative correlation with the serum albumin concentration. Treatment of the animals with phenobarbital had no apparent effect on the serum protein binding of bilirubin, salicylic acid, and sulfisoxazole.

Animals↗
PubMed1977

Comparative pharmacokinetics of coumarin anticoagulants XXIX: Elimination kinetics and anticoagulant activity of (S)-(-)-warfarin in rats before and after chronic administration.

The kinetics of elimination and the anticoagulant effect of (S)-(-)-warfarin were determined in adult male rats before and after daily drug administration for 13 days. There was a small but statistically significant (p less than 0.05) decrease in the body clearance of (S)-(-)-warfarin (from 4.84 to 4.37 ml/hr/kg) and an increase in the serum free fraction of racemic warfarin (added to serum in vitro) from 0.00850 to 0.0107 (p less than 0.05). The concentration of (S)-(-)-warfarin in serum at which the synthesis rate of prothrombin complex activity is one-half of the pre-warfarin rate increased from 0.532 to 0.655 microgram/ml on the average (p less than 0.05).

Animals↗
PubMed1977

Intraindividual relationships between serum protein binding of drugs in normal human subjects, patients with impaired renal function, and rats.

The serum protein binding of phenytoin, salicylic acid, sulfisoxazole, and warfarin was determined in normal human adults, in patients with impaired renal function (kidney donor and recipient), and in adult male Sprague--Dawley rats. The free fraction values for salicylate and sulfisoxazole were significantly correlated in all three groups. The other correlations were statistically significant in only one or two of these groups. There was a statistically significant negative correlation between albumin concentration and the free fraction values of salicylic acid and sulfisoxazole (but not of phenytoin and only under special circumstances with warfarin) in normal subjects and of phenytoin, salicylic acid, and sulfisoxazole (but not warfarin) in rats. No such correlation was observed for any of the drugs in patients with impaired renal function. These observations show that no single weakly acidic drug can serve as an index for quantitatively determining the effect of disease or species differences on the serum protein binding of other weakly acidic drugs.

Adolescent↗
PubMed1977

Comparative pharmacokinetics of coumarin anticoagulants XXX: Relationship between total clearance and serum protein binding of dicumarol in rats.

The effect of serum protein binding on the elimination kinetics of dicumarol was studied. The serum free fraction of dicumarol was essentially independent of concentration over a wide concentration range and ranged from 0.00015 to 0.00079 in 10 adult rats. The total clearance of dicumarol in these animals ranged from 3.93 to 14.5 ml/kg/hr. As in previous studies, there was an excellent linear correlation between the elimination rate constant for dicumarol and the fraction of dicumarol in the liver (i.e., the amount of drug in the liver divided by the amount of drug in the body). Consistent with theoretical considerations, there was a positive and apparently linear relationship between the total clearance and the serum free fraction of dicumarol. The individual serum free fraction and the fraction in liver values for dicumarol were strongly correlated. The pharmacokinetic model based on a proportional relationship between the apparent elimination rate constant and the fraction in the liver applies to dicumarol but not to warfarin and has limited utility. On the other hand, the model relating total clearance to the serum free fraction has been found to apply to dicumarol, warfarin, and other extensively plasma protein-bound drugs and can be utilized under clinical conditions.

Animals↗
PubMed1977

Comparative pharmacokinetics of coumarin anticoagulants XXXI: Effect of plasma protein binding on distribution kinetics of dicumarol in rats.

The purpose of this investigation was to determine, with respect to dicumarol, the effect of plasma protein binding on the pharmacokinetic parameters used conventionally to describe the distribution kinetics of a drug on the basis of the time course of its plasma concentration. After rapid intravenous injection, plasma dicumarol concentrations in adult male Sprague-Dawley rats declined triexponentially, with the terminal exponential phase starting at about 4 hr. The free fraction f, of dicumarol in the serum of individual animals ranged from 0.000150 to 0.000790. The parameters of the equation Ct = Pe-pit + Ae-alphat + Be-betat for plasma concentration Ct at time t were obtained by nonlinear least-squares computer fitting of the experimental data and varied appreciably between animals. Of these parameters, only beta showed a significant correlation with f. These observations indicate that the distribution kinetics of this very extensively plasma protein-bound drug, as reflected by the time course of its plasma concentration after intravenous injection, are apparently not affected by intersubject differences in plasma protein binding. There is a remarkable similarity in the valves of P, A, B, pi, and alpha for dicumarol and warfarin, even though the serum free fraction of these drugs differs considerably.

Animals↗
PubMed1977

Pharmacokinetics in renal disease.

The physiologic perturbations associated with renal disease can have a pronounced effect on the kinetics of elimination of drugs and their metabolites from the body. Drugs are ordinarily cleared from the body by a number of routes, each of which can be characterized by a clearance value. The sum of these clearances (renal, hepatic, etc.) is the total or body clearance which is inversely proportional to the steady-state plasma concentration produced by a given drug dosage regimen. The quantitative contribution of each route of elimination to the metabolic fate of a drug is proportional to the clearance value of that route relative to the body clearance. As a first approximation, the reduction in the renal clearance of a drug caused by renal disease is proportional to the reduction in the renal clearance of creatinine. The metabolic (biotransformation) clearance of many extensively plasma protein bound drugs is proportional to their free fraction (ratio of concentrations of free to total drug) in plasma. Since severe renal disease causes a reduction in the plasma protein binding of many drugs, the metabolic clearance of such drugs will be increased. The contribution of hemodialysis to the total clearance of a drug depends on the magnitude of the clearance obtained by hemodialysis relative to the magnitude of the body clearance of the drug on a day between dialyses. To compensate for the increased elimination of a drug during hemodialysis, the dosing rate (i.e., the dose per unit of time) must be increased by the factor (hemodialysis clearance and body clearance):body clearance, where body clearance is that during a day between dialyses. Further dosage compensation may be needed if body clearance is increased during hemodialysis due to decreased plasma protein binding of the drug. Under certain conditions, an increased accumulation of pharmacologically active drug metabolites during renal failure becomes a matter of serious concern.

Biotransformation↗