Biomedical subjects

G Levy

Publications and source records attributed to G Levy.

At least 307 records · Page 17Linked to original sources

PubMed1984

Renal clearance and serum protein binding of acetaminophen and its major conjugates in humans.

The renal clearances of acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate were determined in eight healthy adults 2 h after administration of 1.5 g of acetaminophen. The renal clearance ratios (relative to creatinine) were 0.058 +/- 0.026, 0.890 +/- 0.153, and 1.43 +/- 0.250 (mean +/- SD), respectively. The renal clearance of acetaminophen increased with increasing urine flow rate, and that of acetaminophen sulfate decreased with increasing serum concentration of the conjugate. A strong positive correlation was found between the renal clearances of acetaminophen glucuronide and acetaminophen sulfate, possibly due to blood perfusion rate-dependent renal tubular secretion of the two conjugates. The serum protein binding of acetaminophen (congruent to 20%) and acetaminophen glucuronide (less than 10%) are minor. Acetaminophen sulfate is greater than 50% protein bound, as determined by equilibrium dialysis and ultrafiltration. The results of these studies are (a) consistent with previous reports of animal studies, indicating that renal excretion of acetaminophen involves glomerular filtration and passive reabsorption and that acetaminophen sulfate is subject to active renal tubular secretion, and (b) compatible with the reported occurrence of renal tubular secretion of acetaminophen glucuronide in animals.

Acetaminophen↗

PubMed1984

Comparative in vivo and in vitro studies of phenytoin protein binding and in vitro lipolysis in plasma of pregnant and nonpregnant rats.

This investigation was designed to determine the cause of the changes in drug protein binding that occur in rat plasma, particularly in plasma from pregnant animals, during in vitro drug-protein binding measurements. In vivo estimates of phenytoin binding in plasma were obtained from steady-state CSF-plasma concentration ratios in pregnant and nonpregnant rats. Immediate ultrafiltration of heparin- or EDTA-anticoagulated plasma yielded phenytoin free fraction values that were in good agreement with in vivo estimates for nonpregnant rats but that were about one-third higher than in vivo estimates for pregnant animals. In vitro free fraction values tended to increase during incubation of plasma and/or during equilibrium dialysis. The concentrations of the four major endogenous free fatty acids were similar in plasma of pregnant and nonpregnant rats if determined immediately after blood collection. Six hours of incubation at 37 degrees C caused fatty acid concentrations to increase about fivefold and twofold in heparin-anticoagulated plasma from pregnant and nonpregnant animals, respectively. The corresponding increases in EDTA-anticoagulated plasma were only about twofold and 1.14-fold, respectively. These changes were associated with decreased plasma protein binding of phenytoin. The in vivo differences between pregnant and nonpregnant rats with respect to phenytoin binding in plasma are not due to differences in fatty acid concentrations, but the in vitro differences are due primarily to corresponding differences in free fatty acid concentrations if extensive in vitro lipolysis occurs.

Animals↗

PubMed1984

Effect of folic acid on the pharmacokinetics of acutely administered phenytoin in pregnant and nonpregnant rats.

The concentrations of both total and free phenytoin in the plasma of epileptic women tend to decrease during pregnancy, suggestive of a pregnancy-associated increase in the metabolic clearance of the drug. On the other hand, the metabolic clearance of free (unbound) phenytoin decreases during pregnancy in rats. One possible reason for this species difference is the routine dietary supplementation of folic acid in human pregnancy and the apparent ability of folic acid to lower phenytoin plasma concentrations even in nonpregnant humans. The purpose of this investigation was to determine the effect of treatment with folic acid on the pharmacokinetics of phenytoin in pregnant and female nonpregnant rats. In one experiment, the treated animals received folic acid in the drinking water, approximately 100-150 micrograms/kg/d, for 19 d. There was no apparent difference between the treated and untreated rats in the pharmacokinetics of a 10-mg/kg iv dose of phenytoin (which was administered to the pregnant rats on the 20th day of gestation), regardless of pregnancy status, In another experiment, pregnant and female nonpregnant rats received either folic acid, 400 micrograms/kg/d, or an equal volume of the solvent only, by gastric intubation for 19 d. The next day (which was the 20th day of gestation for the pregnant rats), the animals received an intravenous injection of phenytoin, 30 mg/kg. Again, pretreatment with folic acid had no apparent effect on the pharmacokinetics of phenytoin in both pregnant and nonpregnant rats. However, the results of this investigation confirm previous observations of dose-dependent phenytoin pharmacokinetics in rats and of decreased clearance of free phenytoin in late pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Kinetics of drug action in disease states III: Effect of pregnancy on the relationship between phenytoin concentration and antiseizure activity in rats.

The purposes of this investigation were to determine the effect of pregnancy on the susceptibility of female rats to experimentally induced seizures and on the relationship between serum phenytoin concentration and antiseizure activity. Pregnant rats (on the 18th day of gestation) were more susceptible than nonpregnant female rats to seizures produced by maximal electroshock or by a body-weight-based dose of pentylenetetrazol. There was no apparent difference between pregnant (20th day of gestation) and nonpregnant rats in the relationship between seizure protection (percent of animals protected) and the serum concentration of total (free plus protein-bound) phenytoin. The relationship between concentration and effect was essentially the same 20 min after an injection of phenytoin and 2 h after the start of a constant-rate infusion preceded by a loading dose of the drug. Since the protein binding of phenytoin is appreciably decreased in late pregnancy, the serum concentration of free phenytoin required for seizure protection tended to be higher in pregnant than in nonpregnant rats. This may be due to the increased susceptibility of pregnant rats to seizure stimuli.

Electroshock↗

PubMed1984

Pharmaceutical education and the practice of pharmacy.

Community pharmacy has undergone a process of relative deprofessionalization; most community pharmacists are now and will continue to function primarily as drug distributors. More sophisticated professional services can and will be offered mainly in hospitals and clinics. There is need for a rigorous and objective assessment of future needs and career opportunities in pharmacy. Many of the expanded roles for pharmacists have not yet been justified by proper functional and economic evaluation. The acceptance of those who fill these new and nontraditional roles cannot be ascertained adequately as long as they are supported extensively by schools of pharmacy rather than by professional fees or by salaries from the institutions in which they practice. There has been an unwillingness or inability on the part of academic pharmacy to make objective and rigorous assessments of the career potential of the various new roles envisaged for pharmacists. Other important issues that have not been explored objectively include drug information leaflets for patients and the single professional degree (Pharm.D.). A good case can be made for having physicians rather than community pharmacists provide drug information literature to patients. There must be pharmacists with one of three different levels of training: the B.S., the Pharm.D., and the Ph.D. Of these, the most critically needed at the present time are Ph.D. pharmacists qualified for positions in drug discovery, formulation, pharmacokinetics and pharmacodynamics, and in the development and evaluation of new drug delivery systems.

Education, Pharmacy↗

PubMed1984

Absorption and metabolism of acetaminophen shortly before parturition.

The absorption and metabolism of acetaminophen 1 g po (as tablets) by a healthy 27-year-old woman was determined one day before parturition and again 38 days after parturition. Based on the urinary excretion data, acetaminophen was absorbed much more slowly and incompletely, and the metabolic conversion of acetaminophen to the sulfate conjugate was less pronounced on the last day of pregnancy than 38 days after parturition. These results are consistent with reports of decreased gastric emptying rate in late human pregnancy and with decreased acetaminophen sulfation by rats during the last days of gestation.

Acetaminophen↗

PubMed1984

Evaluation of activated charcoal-sodium sulfate combination for inhibition of acetaminophen absorption and repletion of inorganic sulfate.

Activated charcoal is an effective inhibitor of acetaminophen absorption while sodium sulfate can prevent the depletion of endogenous inorganic sulfate associated with the formation of acetaminophen sulfate. Administration of activated charcoal plus sodium sulfate soon after acetaminophen overdose may reduce acetaminophen absorption and facilitate the elimination of absorbed acetaminophen by providing sufficient sulfate ion for rapid sulfation of the drug. This investigation was designed to determine if sodium sulfate modifies the inhibitory effect of activated charcoal on acetaminophen absorption or if activated charcoal affects the absorption of sodium sulfate. Eight normal adults received, on separate occasions, 1 g acetaminophen, 1 g acetaminophen and 18 g sodium sulfate (decahydrate), 1 g acetaminophen with 10 g activated charcoal and 1 g acetaminophen, with 10 g activated charcoal and 18 g sodium sulfate, in random order. Urine was collected for 48 hours and assayed for acetaminophen and its major metabolites and for inorganic sulfate. The results confirm that activated charcoal can reduce acetaminophen absorption and show that oral administration of activated charcoal with sodium sulfate does not alter the inhibitory effect of activated charcoal on acetaminophen absorption or the bioavailability of the sulfate. A combination of activated charcoal and sodium sulfate may therefore be useful for the initial management of acetaminophen overdose.

Absorption↗

PubMed1984

Kinetics of drug action in disease states. II. Effect of experimental renal dysfunction on phenobarbital concentrations in rats at onset of loss of righting reflect.

The purpose of this investigation was to determine if renal dysfunction is associated with an alteration in the concentration-pharmacologic activity relationship of phenobarbital (PB). Adult female rats (congruent to 200 g) were pretreated with uranyl nitate or subjected to bilateral ureteral ligation to produce renal dysfunction. Saline-injected and sham-operated rats, respectively, served as controls. PB (0.824 mg/min) was infused i.v. until the animals lost their righting reflex (LRR). Renal dysfunction reduced the total dose of PB required to produce LRR, the concentrations of total and free (unbound) PB in serum and the concentrations of PB in brain and cerebrospinal fluid at onset of LRR. Results were quantitatively similar in both experimental models of impaired renal function. Concomitant infusion of p-hydroxyphenobarbital (the major metabolite of PB) and PB in rats with uranyl nitrate-induced renal dysfunction had no effect on the PB concentrations at onset of LRR. When PB was infused at different rates (either 0.412, 0.824, 2.04 or 4.12 mg/min), rats with renal dysfunction had increasing concentrations of PB at onset of LRR with increasing infusion rate, not only in serum and brain but also (unlike normal rats) in cerebrospinal fluid. Thus, renal dysfunction is associated with increased sensitivity to PB and with a change in the kinetic relationship between PB in cerebrospinal fluid and in the biophase.

Acute Kidney Injury↗

PubMed1984

Pharmacokinetic and pharmacodynamic studies of acute interaction between warfarin enantiomers and metronidazole in rats.

This investigation was designed to determine if the reported stereoselectivity of the pharmacokinetic interaction between warfarin and metronidazole in humans occurs also in rats and if the potentiation of the anticoagulant effect of warfarin can be ascribed solely to inhibition of warfarin metabolism by metronidazole. Metronidazole had no effect on the serum protein binding of racemic warfarin in vitro over a wide concentration range but decreased the protein binding of R-(+)-warfarin and S-(-)-warfarin in vivo, perhaps indirectly through metabolite(s). Treatment with i.p. metronidazole, 100 mg/kg every 6 hr, decreased the plasma clearance of free warfarin ("intrinsic clearance"). This inhibitory effect was more pronounced with S-(-)-warfarin than with R-(+)-warfarin (congruent to 60 and congruent to 30%, respectively). Metronidazole did not affect plasma prothrombin complex activity in vitro but reduced it in vivo. Metronidazole treatment increased the elimination rate constant for endogenous prothrombin complex activity and decreased the plasma concentration of free R-(+)-warfarin required to decrease prothrombin complex activity synthesis rate to one-half of normal (there were insufficient data to determine the effect of metronidazole on the activity of the other enantiomer). It is concluded that metronidazole preferentially inhibits the metabolism of S-(-)-warfarin in rats as in humans but that (at least in rats) the stereoselectivity is not absolute. Moreover, metronidazole has an indirect inhibitory effect on warfarin protein binding in vivo and also affects the pharmacodynamics of warfarin as well as the blood clotting process per se.

Animals↗

PubMed1984

Pharmacokinetic and pharmacodynamic studies of acute interaction between warfarin enantiomers and chloramphenicol in rats.

The purpose of this investigation was to explore the mechanisms and possible stereoselectivity of the interaction between warfarin and chloramphenicol in rats. Chloramphenicol had no apparent effect on the serum protein binding of R-(+)-warfarin or S-(-)-warfarin in vitro or in vivo. Treatment with i.p. chloramphenicol, 50 mg/kg every 4 hr or 30 mg/kg every 6 hr, decreased the plasma clearance of free warfarin by one-half or more, with no apparent stereoselectivity. The volume of distribution was not significantly affected; the half-life of each warfarin enantiomer was appreciably increased by chloramphenicol. Treatment with chloramphenicol had no apparent effect on relative liver size and on serum aspartate aminotransferase activity. Prothrombin complex activity in plasma was not affected by in vitro addition or in vivo administration of chloramphenicol alone. Chloramphenicol treatment did not affect significantly the elimination kinetics of endogenous prothrombin complex activity and the plasma concentration of free R-(+)-warfarin or S-(-)-warfarin required to decrease prothrombin complex activity synthesis rate to one-half of normal. It appears that the pronounced potentiation of the anticoagulant effect of warfarin by chloramphenicol is due only to inhibition of warfarin metabolism and that this effect is not stereoselective.

Animals↗

PubMed1984

Assessment of biotransformation during transfer of propoxyphene and acetaminophen across the isolated perfused human placenta.

The purpose of this investigation was to assess the extent of biotransformation of drugs by the human placenta during their transfer from the maternal to the fetal circulation. Propoxyphene was used to determine N-demethylation, and acetaminophen served as a substrate for glucuronide and sulfate conjugation. Human full-term placentae were dually perfused in vitro, with one or the other drug being added to the maternal circulation. Propoxyphene and acetaminophen concentrations reached an essentially constant fetal/maternal ratio within 1 hour, with a half-time of about 20 minutes. The concentrations of both drugs in the placental tissues were higher than in the perfusion fluids; this accumulation was particularly pronounced in the case of propoxyphene. No metabolites of either drug were found in the maternal or fetal circulations, but norporpoxyphene, the N-demethylated metabolite of propoxyphene, was detected in placental tissue.

Acetaminophen↗

PubMed1984

Kinetics of drug action in disease states. I. Effect of infusion rate on phenobarbital concentrations in serum, brain and cerebrospinal fluid of normal rats at onset of loss of righting reflex.

The purpose of this investigation was to develop a method to determine the effect of various diseases on the concentration-pharmacologic activity relationship of phenobarbital (PB) in a manner that excludes or accounts for pharmacokinetic variables affecting drug disposition. Adult female rats (congruent to 180 g) received an i.v. infusion of PB at one of five different rates (0.412-4.12 mg/min) until the animals lost their righting reflex (after 8.0 +/- 0.4 to 62 +/- 10 min of infusion). The total dose, the serum concentration (both total and unbound drug) and the brain concentration of PB at onset of loss of righting reflex (LRR) increased with increasing infusion rate. The PB concentration in cerebrospinal fluid at onset of LRR (mean +/- S.D.: 108 +/- 19 micrograms/ml, n = 29) was not affected by the infusion rate. Concomitant infusion of PB and its p-hydroxy metabolite had no apparent effect on the concentrations of PB at onset of LRR even though the serum concentration of p-hydroxy PB was higher than upon infusion of PB only. The results of this investigation indicate that cerebrospinal fluid, unlike some regions of the brain, equilibrates very rapidly with the biophase of the receptors for PB-induced LRR. Determination of PB concentrations in the cerebrospinal fluid at the onset (rather than offset) of action facilitates assessment of the effect of diseases on the PB concentration-pharmacologic activity relationship by avoiding development of acute tolerance and excluding or minimizing effects due to disease-associated pharmacokinetic variables such as altered plasma protein binding and body distribution of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Effect of pregnancy on the pharmacokinetics of phenytoin in rats.

Phenytoin, in single doses of 10 or 30 mg/kg, was administered by i.v. injection to nonpregnant (congruent to 200-300 g) and 20 days pregnant inbred Lewis rats. The plasma protein binding of phenytoin was determined under conditions which minimized in vitro lipolysis and consequent artifactual results. The absolute (milliliters per minute) plasma clearance of total (free plus bound) phenytoin by the pregnant rats was increased (10-mg/kg dose) or not significantly different (30-mg/kg dose) compared to concurrent nonpregnant controls. The relative (milliliters per minute per kilogram) plasma clearance of total phenytoin was not significantly changed (10-mg/kg dose) or was decreased (30-mg/kg dose) in pregnancy. The relative apparent volume of distribution of free drug (but not of total drug) was essentially the same in the pregnant and nonpregnant animals and was independent of dose. The plasma clearance of free (unbound) phenytoin decreased with dose and was decreased during pregnancy, at both doses studied (more so at the larger dose). The elimination kinetics of p- hydroxyphenytoin , the major metabolite of phenytoin which inhibits phenytoin metabolism in rats, were similar in pregnant and nonpregnant rats and so were the plasma concentrations of this metabolite after phenytoin administration. The relatively more pronounced effect of pregnancy on the elimination of the larger dose of phenytoin may reflect a greater inhibitory effect of p- hydroxyphenytoin during pregnancy. This does not occur in humans (due to much lower plasma concentrations of the metabolite) and that may account for possible differences in the effect of pregnancy on phenytoin pharmacokinetics in rats and humans.

Animals↗

PubMed1984