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Biomedical subjects

G Levy

Publications and source records attributed to G Levy.

At least 361 records · Page 20Linked to original sources
PubMed1980

Comparative pharmacokinetics of coumarin anticoagulants XLIV: Dose-dependent pharmacokinetics of warfarin in rats.

The purpose of this investigation was to determine the effect of dose on warfarin pharmacokinetics in rats. First, in a crossover experiment, rats received 14C-warfarin, 0.2 mg/kg iv, 12 hr after an injection of either nonradioactive warfarin (0.5 mg/kg) or saline solution. Warfarin concentrations in plasma declined triexponentially as a function of time. Pharmacokinetic analysis revealed that pretreatment with warfarin significantly decreased the apparent volume of distribution, total plasma clearance, and intrinsic plasma clearance of the drug. In the second part of the investigation, rats received single intravenous warfarin injections in the order of 0.1-1.0-0.1 or 1.0-0.1-1.0 mg/kg at 2-week intervals. The apparent volume of distribution, total plasma clearance, and intrinsic plasma clearance of the 1.0-mg/kg warfarin dose were appreciably lower than those of the 0.1-mg/kg dose. The decrease in the apparent volume of distribution of warfarin with increasing dose is consistent with the previously observed concentration dependence in hepatic uptake of the drug.

Animals↗
PubMed1980

Comparative pharmacokinetics of coumarin anticoagulants. XLVI: Effect of treatment of phenobarbital on pharmacokinetics of (S)-(-)-warfarin in rats.

This investigation was carried out (a) to determine if the enzyme inductive effect produced by phenobarbital reduces the interindividual variability in the biotransformation of a drug, as suggested in the literature; (b) to test whether the intrinsic clearance of free drug, for drugs exhibiting restrictive clearance, reflects the activity of drug-metabolizing enzyme systems; and (c) to determine if enzyme induction affects the apparent volume of distribution of a drug that tends to concentrate in the liver. Twelve pairs of adult male rats, matched with respect to their serum warfarin free fraction, received an intravenous injection of (S)-(-)-warfarin, 0.6 mg/kg, after four daily injections of either saline solution or phenobarbital (75 mg/kg). Phenobarbital treatment increased both the total and intrinsic clearance of (S)-(-)-warfarin almost threefold but did not reduce the coefficient of variation of the intrinsic clearance. Serum protein binding of (S)-(-)-warfarin was not affected by phenobarbital treatment. The biological half-life of warfarin and the duration of its anticoagulant effect were reduced substantially by treatment with phenobarbital. Consistent with pharmacokinetic theory, the relationship between total clearance and the free fraction of warfarin in serum remained approximately linear, but the slope of the regression line was increased for the animals treated with phenobarbital.

Animals↗
PubMed1980

Effect of heparin on bilirubin clearance in rats: pharmacokinetic consequences of extensive hepatic extraction of plasma protein binding inhibitors.

The purpose of this investigation was to determine the effect of heparin-induced endogenous inhibitors of plasma protein binding on the plasma concentrations of total (free plus bound) and free bilirubin in rats with experimental hyperbilirubinemia. Adult male rats received constant-rate intravenous infusions of bilirubin and, after attaining steady state, were given either an intravenous injection of heparin, 500 units/kg, or this injection plus a maintenance infusion of hepatin. Control animals received normal saline solution instead of heparin. The free fraction of bilirubin in plasma increased substantially within 2 min after heparin injection and remained elevated when heparin concentrations were sustained by infusion of the anticoagulant. Despite the decreased plasma protein binding of bilirubin, the plasma concentration of total bilirubin did not decrease (as it does, consistent with pharmacokinetic theory, following injection or infusion of certain other inhibitors of bilirubin binding) and the plasma concentration of free bilirubin did not return to normal (as observed previously after administration of other binding inhibitors) but remained elevated. These results are consistent with the recently demonstrated rapid and extensive hepatic extraction of heparin-induced endogenous inhibitors of plasma protein binding. The heparin interaction with bilirubin may be particularly serious because of the sustained elevation of free bilirubin concentrations in plasma and the potential neurotoxicity of free bilirubin.

Animals↗
PubMed1980

Serum protein binding of drugs during and after pregnancy in humans.

The serum protein binding of three weakly acidic drugs (salicylic acid, sulfisoxazole, and phenytoin), one week base (diazepam), and one steroid (dexamethasone) was determined in pregnant women at seven time periods during pregnancy and at two periods post partum, as well as in a group of nonpregnant women of childbearing age. The serum free fraction values (ratio of concentrations, free to total drug) of all drugs rose during pregnancy, primarily after 15 wk of gestation, and remained elevated for at least 1 to 5 days post partum. Pregnancy had the greatest effect on protein binding of sulfisoxazole, diazepam, and salicylic acid. The magnitude of this effect is such that quantitatively significant changes in the pharmacokinetic and pharmacodynamic characteristics of certain drugs may be expected to occur during pregnancy (in addition to possible changes caused by other pregnancy-related effects such as altered activity of drug-metabolizing enzyme systems). All drugs but dexamethasone exhibited significant negative correlations between free fraction values and serum albumin concentrations during pregnancy. The serum protein binding of salicylic acid, but not the other drugs tested, was more extensive in nonpregnant women who were not taking oral contraceptives than in those who were.

Adolescent↗
PubMed1980

Propoxyphene and norpropoxyphene plasma concentrations after oral propoxyphene in cirrhotic patients with and without surgically constructed portacaval shunt.

Plasma concentrations of propoxyphene and its major metabolite, norpropoxyphene, were determined over at least 12 hr after oral administration of 130 mg dextropropoxyphene hydrochloride to eight men with hepatic cirrhosis, of whom four had a surgically constructed portacaval shunt, and to seven healthy men. Propoxphene concentrations were appreciably higher and norpropoxyphene concentrations were much lower in the patients than in the normal subjects. The ratio of areas under the plasma concentration-time curve from 0 to 12 hr, norpropoxyphene: propoxyphene, was 0.70 +/- 0.46 (x +/SD) in patients and 3.94 +/ 0.83 in normal subjects. A similar decrease in this ratio was observed previously in otherwise healthy dogs after surgical construction of portacaval shunt when propoxyphene was given orally, but not after intravenous injection of the drug. A woman with portacaval shunt and essentially complete renal failure was also studied; she exhibited the highest propoxyphene peak concentration in this investigation and had no detectable norpropoxyphene in plasma. Most of the patients, unlike the normal subjects, experienced considerable sedation after propoxyphene. These results are probably due to increase systemic availability of orally administered propoxyphene in patients with hepatic cirrhosis and possibly to increased receptor response to the drug by these patients. It is concluded that propoxyphene should be administered cautiously and in reduced doses to patients with hepatic dysfunction.

Adult↗
PubMed1980

Relationship between concentration and anticoagulant effect of heparin in plasma of normal subjects: magnitude and predictability of interindividual differences.

The purposes of this investigation were to determine the magnitude of inter- and intraindividual variations in the relationship between heparin concentration and anticoagulant effect in normal adults, and to determine whether these variations are asociated with, and therefore predictable from, certain physiologic characteristics of individual subjects. Citrated plasma was obtained from 12 men and 5 women, 21 to 35 yr old. Heparin was added to the plasma to yield concentrations of 0.05 to 1.0 U/ml and the activated partial thromboplastin time (APTT) was determined. These studies were repeated once or twice over 65 days. Baseline APTT values (i.e., ATPP without added heparin) ranged from 25.6 to 36.2 sec and the hematocrit ranged from 39% to 50%. Both measures showed little intrasubject variation on the same day or on different days. There was an excellent linear relationship between In APTT and heparin concentration in the 0.05- to 0.8-U/ml range (r2 > 0.987 in all cases). The slope value for this relationship ranged from 1.51 to 3.88 ml/U and these interindividual differences were well reproducible on repeated testing. Women had lower hematocrits (p < 0.05) and higher slope values (p < 0.01) than men. Multiple linear regression analysis revealed a linear relationship between observed slope values and slope values calculated as a function of both hematocrit and baseline APTT. Age, weight, and the concentrations of various plasma proteins did not contribute significantly to the predictability of the slope. A multiple linear regression equation with hematocrit and baseline APtt as independent variables yielded a multiple correlation coefficient of 0.875 (p < 0.01). Thus, it may be possible to predict the APTT value produced by a given concentration of heparin in an individual subject from the subject's baseline APTT and hematocrit.

Adult↗
PubMed1980

Protein binding of several drugs in serum and plasma of healthy subjects.

The protein binding of phenytoin, propranolol, salicylic acid, warfarin, and bilirubin was determined in heparinized plasma and serum obtained from the same healthy adult subjects. There were no significant differences in the free fraction values of these compounds in plasma and serum. Addition of heparin to serum had no significant effect on protein binding. Contact with Vacutainer stoppers increased the free fraction of the weak base propranolol in serum and plasma but no significant effect on the protein binding of the other, weakly acidic compounds tested. The lack of differences in the protein binding of phenytoin, salicylic acid, warfarin, and bilirubin in human plasma and serum is in contrast with the pronounced differences observed previously in rat serum and plasma.

Adult↗
PubMed1980

Effect of hemodialysis on propoxyphene and norpropoxyphene concentrations in blood of anephric patients.

Our purpose was to determine whole-blood hemodialysis clearances and the effect of hemodialysis on blood propoxyphene concentrations and of its major metabolite, norpropoxyphene, in anephric patients under apparent steady-state conditions with respect to propoxyphene. Propoxyphene hydrochloride 130 mg was given orally every 8 hr for 7 doses to 4 patients. Blood propoxyphene and norpropoxyphene levels were determined repeatedly during the sixth dosing interval (before hemodialysis) and during the seventh dosing interval (during hemodialysis). There were no statistically significant differences in the areas under the blood level/time curves of propoxyphene and norporopoxyphene during the sixth and seventh dosing intervals, indicating that hemodialysis contributes negligible to their total clearance from the body. The low hemodialysis clearances of propoxyphene and norpropoxyphene were confirmed by direct in vivo determination of their hemodialyzer extraction ratios. Propoxyphene produces much higher propoxyphene plasma levels and higher as well as more persistent norpropoxyphene plasma levels in anephric patients than in normal subjects. In view of their substantive cumulation during repeated propoxyphene administration, their central nervous system and cardiac toxicity at high concentrations, their low hemodialysis clearance, and the apparent sensitivity of patients with renal failure to narcotics, propoxyphene should be used cautiously in anephric patients.

Adult↗
PubMed1980

Propoxyphene and norpropoxyphene plasma concentrations in the anephric patient.

The widely used analgesic propoxyphene is subject to extensive presystemic (first-pass) biotransformation after oral administration. There have been indications that presystemic biotransformation of a drug may be less in anephric patients than in healthy subjects. Plasma concentrations of propoxyphene (a drug with dangerous adverse effects at high concentrations) and its major and pharmacologically active metabolite norpropoxyphene have been compared in 7 anephric patients and 7 healthy subjects after oral administration of a 130-mg dose. Maximum propoxyphene concentrations were much higher (177 +/- 16 vs 81 +/- 35 ng/ml, mean +/- SD, p less than 0.001), and areas under the concentration-time curve over 12 hr were much larger (4,310 +/- 1,520 vs 2,250 +/- 1,050 ng hr/ml, p less than 0.02) in the anephric patients than in the normal subjects. These differences were statistically significant even after normalization for dose per body weight. Norpropoxyphene concentrations were also higher and more persistent in the anephric patients. These differences, which appear to result from decreased presystemic biotransformation of propoxyphene and decreased elimintation of norpropoxyphene, indicate that propoxyphene should be used cautiously and at reduced doses in patients with renal failure.

Absorption↗