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Biomedical subjects

J R Gillette

Publications and source records attributed to J R Gillette.

At least 73 records · Page 4Linked to original sources
PubMed1978

Theoretical relationships between area under the curve and route of administration of drugs and their precursors for evaluating sites and pathways of metabolism.

The bioavailability of a drug administered extrasystemically is a measure of the initial extraction of a compound by a series of eliminating events involving the intestinal mucosal enzymes, the gut bacterial microflora, the liver, and the lung. A theoretical analysis is presented to differentiate the process of gut wall elimination and hepatic removal of a drug during this first-pass effect. The area under the blood concentration--time curve (AUC) for a drug and its metabolite is shown to be useful in determining the presence of these processes when a drug and its metabolite are administered concomitantly by different routes of administration. Furthermore, the fraction of a precursor transformed to its metabolite also can be determined by pharmacokinetic analysis of the AUC of a drug and its metabolite after administration of both substances.

Biological Availability↗
PubMed1978

The effect of the administration of spironolactone on the concentration of plasma testosterone, estradiol and cortisol in male dogs (1).

The effect of the administration of spironolactone, deacetylspironolactone, aldadiene or soldactone on the concentration of plasma testosterone, estradiol, and cortisol was examined in male dogs. Decreases of 60 to 75% in plasma testosterone and estrodiol occur only at high doses (100 mg/kg) of spironolactone or deacetylspironolactone but not at low doses of spironolactone (5 to 10 mg/kg); they occur concomitantly with similar decreases of androgen formation by the testis. No decreases were detected with aldadiene or soldactone. Treatment of dogs with spironolactone (100 mg/kg) also lowered by 50 to 65% the concentration of cortisol in adrenal venous plasma.

Animals↗
PubMed1978

Kinetics of metabolite formation and elimination in the perfused rat liver preparation: differences between the elimination of preformed acetaminophen and acetaminophen formed from phenacetin.

Both [14C]phenacetin and [3H]acetaminophen in tracer concentrations were perfused simultaneously once through the rat liver preparation at a constant perfusate flow rate (10 ml/min), and the rates of appearance of [14C]acetaminophen and [3H]acetaminophen in the effluent were compared. The data indicated that the extraction ratio of [14C]acetaminophen derived from [14C]phenacetin was smaller than that of the preformed [3H]acetaminophen added to the input perfusate (exogenously), i.e., the availability of the metabolite formed in situ was higher than the availability obtained when the metabolite was presented in the input blood. The observed availability of the acetaminophen derived from phenacetin was usually greater than that predicted by a "well-stirred" model and less than that predicted by a "parallel tube" model of hepatic drug clearance; the former model describes the liver as a well-stirred compartment with the drug in liver in equilibrium with that in the hepatic venous blood, and the latter model describes the liver as a group of identical and parallel uints with enzymes distributed evenly in hepatocytes lining the tubes. We conclude that the liver may be viewed as an imperfectly mixed compartment with regard to the availability of the metabolite which is generated from a precursor.

Acetaminophen↗
PubMed1977

A prospective on covalent binding and toxicity.

In this paper are discussed (1) the three general mechanisms by which radioisotopes may be retained in animal tissues long after labeled drugs are administered, (2) ways of differentiating these mechanisms, and (3) possible relationships between the toxic effects of drugs and their metabolism. It is emphasized, however, that studies on the disposition of drugs should be coordinated with toxicity studies in order to make the results of bioavailability and pharmacokinetic studies more meaningful in setting limits for food residues.

Animals↗
PubMed1976

The role of biotransformation in chemical-induced liver injury.

The role of drug metabolism in chemical-induced liver injury is reviewed. Parameters for studying the formation of chemically reactive metabolites are discussed and the factors that alter the formation and covalent binding of reactive metabolites are selectively emphasized. Some of the experimental work that led to these concepts is discussed, especially the chemical toxicology of the hepatic injury produced by acetaminophen, bromobenzene, furosemide, isoniazid and iproniazid.

Acetaminophen↗
PubMed1976

Environmental factors in drug metabolism.

Although various kinds of environmental factors may alter the activity of cytochrome P-450 enzymes in liver micromes, their effects on the pharmacokinetics of drugs and other foreign compounds in living animals may not be as great as might be predicted from assays of these enzymes in vitro. Indeed, the effects will depend on the relative importance of excretory and metabolic mechanisms in the elimination of the drug, the relative importance of various metabolic reactions in different tissues, the extraction ratio of the drug by the liver, and in some instances on the route of administration of the drug. Moreover, the effect of the various environmental factors on the pharmacologic and the toxicologic actions of the drug will depend on whether these actions are caused by the parent foreign compounds or by one or more of their metabolites. It may also be important that the environmental factors may alter not only relative activiteis of the cytochrome P-450 in liver microsomes but also the activities of other drug-metabolizing enzymes and that the relative effects of the environmental factors of these enzymes may differ depending on the animal species or the animal strain. Indeed, a given factor may increase the pharmacologic effects of a drug metabolite in one animal species but decrease it in another. For these reasons, it frequently is not possible to predict the effects of environmental factors on drug action in living animals solely from in vitro rates of metabolism of model substrates.

Acetaminophen↗