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Biomedical subjects

J T Slattery

Publications and source records attributed to J T Slattery.

At least 109 records · Page 6Linked to original sources
PubMed1979

Accumulation kinetics of drugs with nonlinear plasma protein and tissue binding characteristics.

The purpose of this investigation was to study, by digital computer stimulation, the accumulation kinetics of drugs which exhibit concentration-dependent binding to tissues and either linear (constant free fraction) or concentration-dependent (increasing free action with increasing drug concentration) binding to plasma proteins. It was assumed that elimination rate is proportional to free drug concentration in plasma and that there occurs instantaneous equilibration of drug between vascular and nonvascular spaces. Nonlinear binding can yield, under certain conditions, apparently biexponential plasma concentration-time curves which may be misinterpreted as being representative of a linear and biexponential system. Such misinterpretation would cause the following errors in the prediction of drug accumulation and elimination kinetics during and after constant-rate infusion: (a) the time required to reach steady state may be overestimated, and (b) the prominence of the apparent distribution phase after cessation of infusion may be underestimated. Drugs with linear and nonlinear plasma protein binding characteristics differ with respect to the relaionship between infusion rate and steady-state concentration. This relationship is linear when plasma protein binding is linear. Steady-state concentration increases less than proportionally with increasing infusion rate if plasma protein binding is drug concentration dependent.

Blood Proteins↗
PubMed1979

Determination of naproxen and its desmethyl metabolite in human plasma or serum by high performance liquid chromatography.

1. A liquid chromatographic method has been developed for the simultaneous determination of the anti-inflammatory agent naproxen and its metabolite, 6-0-desmethyl-naproxen, in human plasma or serum. 2. After addition of p-chlorowarfarin as the internal stardard, plasma is acidified and extracted with either chloroform (for assay of naproxen only) or ethyl acetate (for assay of naproxen and desmethyl-naproxen), the organic solvent is evaporated, the residue is dissolved in acetonitrile and injected onto a reverse phase column coupled with an ultra-violet absorbance detector. 3. Drug and metabolite can be detected readily in concentrations above 2 micrograms per ml in 0.5 ml samples. Salicylic acid and its metabolites and a number of other durgs were found not to interfere with the assay.

Chromatography, High Pressure Liquid↗
PubMed1979

Single point clearance estimation.

Linear relationships were observed between the log of total body clearance (C1B) and simulated serum concentrations (Cmin) six hours after a test dose of chloramphenicol, as well as between C1B and the reciprocal of Cmin. Correlation coefficients for these relationships were 0.988 and 0.977, respectively. Clearance estimates obtained from a single serum sample following a test dose of a drug may prove to be a useful method of predicting dosage requirements for individual patients.

Chloramphenicol↗
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↗
PubMedDate not supplied

Metabolic activation of (R)-(+)-pulegone to a reactive enonal that covalently binds to mouse liver proteins.

Pulegone, a naturally occurring hepatotoxin, is metabolically activated to chemically reactive intermediates that are capable of covalent binding to cellular protein. Studies in vivo and in vitro with inhibitors and inducers of cytochrome P-450 demonstrated an association among the hepatocellular toxicity of pulegone and its metabolic activation and covalent binding to protein. The exocyclic double bond of pulegone apparently is an important structural feature in the activation mechanism and binding to protein inasmuch as the reduced analogue, menthone, is neither hepatotoxic nor does it bind extensively to tissue proteins. Preliminary studies using semicarbazide as a trapping agent indicate that an unsaturated gamma-ketoaldehyde is the ultimate chemically reactive metabolite of pulegone.

Alkylation↗
PubMedDate not supplied

Reactive intermediates in the oxidation of menthofuran by cytochromes P-450.

Menthofuran, a naturally occurring hepatotoxin, is metabolically activated to chemically reactive intermediates that are capable of covalent binding to cellular proteins. Studies in vivo and in vitro with inhibitors and inducers of hepatic cytochromes P-450 demonstrated an association between hepatocellular damage caused by menthofuran and its metabolic activation and covalent binding to target organ proteins. The same gamma-ketoenal formed from the metabolic precursor of menthofuran, pulegone, is the major electrophilic metabolite of menthofuran as well. Diastereomeric mintlactones also are formed, and studies with H218O and 18O2 indicate that the gamma-ketoenal is a precursor to the mintlactones, as well as other reactive intermediates in the cytochrome P-450 mediated oxidation of menthofuran.

Acetaminophen↗
PubMedDate not supplied

Haemoperfusion in the management of digoxin toxicity: is it warranted?

Several recent publications have encouraged the use of hemoperfusion to remove digoxin from the body of overdosed patients. The usefulness of haemoperfusion in removing digoxin from the body has therefore been examined using pharmacokinetic simulation techniques and published data. Haemoperfusion for a period of 4 hours with a clearance of 100 ml/min removes less than 7% of the amount of digoxin in the body (including that in the gastrointestinal tract at the beginning of haemoperfusion), regardless of the time after the dose that haemoperfusion is started. Dramatic therapeutic benefit in digoxin intoxication is unlikely to be a consequence of the amount of digoxin removed from the body by haemoperfusion. If therapeutic benefit is derived from a transient decline of digoxin concentration in plasma, it may be expected to be negated as the drug redistributes from tissues.

Digoxin↗
PubMedDate not supplied

Prediction of maintenance dose required to attain a desired drug concentration at steady-state from a single determination of concentration after an initial dose.

Strong correlations have been reported between drug concentrations at steady-state and a single drug concentration determined sometime after an initial dose for lithium, nortriptyline, imipramine, desipramine, choramphenicol and theophylline. The mathematical basis of these relationships suggests that a one point method for predicting steady-state drug concentrations and individual dosing requirements should be widely applicable to most drugs and should be valid for patients having a wide range of drug half-lives. A method is presented for evaluating the optimum time of blood sampling to determine a drug concentration in serum of plasma that best correlates with steady-state levels and for defining the range of drug half-lives beyond which the predictive approach is likely to give poor results.

Antidepressive Agents, Tricyclic↗
PubMedDate not supplied

Inhibition and activation of acetaminophen reactive metabolite formation by caffeine. Roles of cytochromes P-450IA1 and IIIA2.

Caffeine has previously been shown to diminish or potentiate acetaminophen (APAP) hepatotoxicity in rats, depending on induction state. To elucidate the P-450 forms involved in these divergent effects, rat liver microsomes, prepared after pretreatment with various inducers, were used to examine the effect of caffeine on N-acetyl-p-benzoquinone imine (NAPQI) formation. The addition of caffeine to incubations with 3-methylcholanthrene (MC)-induced microsomes resulted in a biphasic effect on the formation of NAPQI. A 43% decrease in NAPQI formation was observed as caffeine concentration was increased from 0 to 0.5 mM; however, NAPQI formation was accelerated as caffeine concentration increased, exceeding the control (no caffeine) value, at caffeine concentrations greater than 2.5 mM. Incubations with purified P-450IA1 showed that as caffeine concentration increased from 0 to 5 mM, a 50% inhibition was observed with no evidence of acceleration. In contrast to MC microsomes, the addition of caffeine to incubations with uninduced and phenobarbital-induced adult rat microsomes resulted in a marked (3- to 4-fold) acceleration of NAPQI formation with no evidence of inhibition. Caffeine (5 mM) also accelerated NAPQI formation in microsomes isolated from diabetic rats, but to a substantially lesser extent (120%), suggesting a modest (if any) effect on P-450IIE1, a form previously shown to form NAPQI from APAP. Interestingly, caffeine caused a 3- to 4-fold increase in NAPQI formation by juvenile male and female rat microsomes, but no activation was observed with adult female rat microsomes. These results suggested that caffeine activated a member of the cytochrome P-450IIIA subfamily.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗