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Biomedical subjects

J R Gillette

Publications and source records attributed to J R Gillette.

At least 55 records · Page 3Linked to original sources
PubMed1980

Pharmacokinetic factors governing the steady-state concentrations of foreign chemicals and their metabolites.

It is well known that various environmental chemicals can either increase or decrease the activities of enzymes that metabolize foreign compounds and their metabolites. In addition, changes in the activities of these enzymes can alter the concentration of the foreign compounds and metabolites in tissues. However, the theoretical basis by which we can quantitatively relate a change in the activity of a given enzyme to a change in the concentrations of these compounds remains in its infancy. In some instances, the change in concentration of a foreign compound or metabolite will be inversely proportional to the change in the enzyme activity. But in other instances, marked changes in enzyme activity may result in only trivial changes in the concentration of the compounds and their metabolites at sites of action. Pharmacokinetics provide a means for testing the validity of our concepts of how the concentrations of foreign compounds and their metabolites depend on enzyme activities, rates of excretion by the kidneys and lung, reversible binding to tissue components, rates of diffusion across cellular membranes, blood flow rates and the sites of administration. The present paper presents mathematical equations that show the effects of the route of administration on the steady-state concentrations of foreign compounds and their metabolites in tissues when the substances are metabolized by the liver and excreted by the kidney. These equations are especially relevant to studies of chemically reactive metabolites.

Animals↗
PubMed1980

Interindividual differences in amitriptyline demethylation.

Amitriptyline (AT) and its demethyl metabolite nortriptyline (NT) were given orally and intramuscularly to 6 normal subjects, and the areas under the blood concentration--time curves (AUC) were calculated. The mean unbound fraction of AT and NT in plasma was 5.4% and 8.3%, respectively. The blood-plasma ratio of NT was nearly double that of AT, which was close to unity. The mean systemic availability of oral relative to intramuscular AT and NT was 43% and 61%. The calculated mean oral blood clearance of AT as measured by dose (oral)/AUC was 1.6 1/min. The demethylation of orally administered AT varied considerably between the 6 individuals (from 25% to 89%) and correlated with oral drug clearance. Demethylation was estimated from the AUC applied to the NT metabolite. The estimated oral clearance of AT from demethylation ranged from 0.21 to 1.80 1/min.

Administration, Oral↗
PubMed1980

Kinetics of decomposition of chemically unstable metabolites in the presence of nucleophiles: derivation of equations used in graphical analyses.

The present paper provides a theoretical base for the development of various plots that may be used in studying the sequence of events that occur when the reaction of a chemically reactive intermediate with an exogenous nucleophile is pseudo first order, and all of the other reactions by which the initial reactive metabolite decomposes are either first order or pseudo first order. Several hypothetical models that should represent most of the decomposition mechanism of chemically reactive intermediates are discussed. Problems in assessing the kinetic characteristics of diffusional barriers of the intermediates and of enzymatic reactions in the inactivation of chemically reactive intermediates are raised and the possible solution of such problems are pointed out.

Biotransformation↗
PubMed1980

Effects of isoproterenol on the toxicity in rats of compounds eliminated by the kidneys.

In rats, l-isoproterenol (0.3 mg kg-1 s.c.) reduced the "average total body clearance" (as measured by dose/AUC) and the LD50 of various compounds that are eliminated almost entirely by the kidneys. These effects involve beta-adrenergic receptors since they are blocked by propranolol. Propranolol pretreatment prevented the isoproterenol-induced decreases in renal clearances of methoxy-inulin and tetraethylammonium bromide. Treatment with the alpha-adrenergic-blocking agent, phentolamine, potentiated the decreses in the renal clearances of these substances. The effects of isoproterenol were as marked in hypophysectomized as in intact rats. Peak plasma levels of isoproterenol after subcutaneous administration (0.3 mg kg-1) were about 42 ng ml-1.

Animals↗
PubMed1979

High-performance liquid chromatographic assay for acetaminophen and phenacetin in the presence of their metabolites in biological fluids.

We propose a method in which tracer amounts of a radiolabeled compound are used as the internal standard for the same unlabeled compound in high-performance liquid chromatography. The approach is valuable when a response from the internal standard becomes undesirable due to the presence of interference by the metabolites. We tested our approach with phenacetin and its metabolites, acetaminophen, 2-hydroxyphenacetin, N-hydroxyphenacetin, phenetidine, acetaminophen sulfate conjugate and acetaminophen glucuronide conjugate in biological fluids with the use of [14C]phenacetin and [3H]acetaminophen as the internal standards, and were able to quantitate both phenacetin and acetaminophen simultaneously. We also tested the alternative approach in which the unlabeled drug was used as internal standard for tracer amounts of the same radiolabeled compound, with phenacetin and acetaminophen as the internal standards for tracer amounts of [14C]phenacetin and [3H]acetaminophen. Again, we were able to quantitate the two tracer radiolabeled compounds simultaneously.

Acetaminophen↗
PubMed1979

Sequential first-pass elimination of a metabolite derived from a precursor.

We examined data from our previous studies in which we not only delivered perfusate containing tracer concentrations of [14C]phenacetin and its metabolite [3H]acetaminophen under constant perfusate flow (10 ml/min/liver) into the rat liver preparation just once, but also recirculated fresh reservoir perfusate containing a tracer dose of [14C]phenacetin through the same rat liver preparation. From the single-pass studies, estimates of fm, the fractional rate of conversion for [14C]phenacetin to form [14C]acetaminophen, and F(M.P), the apparent availability of [14C]acetaminophen, were obtained by determining the concentrations of [14C]acetaminophen in the perfusate before and after incubation with Glusulase. These estimates were fm = 0.871 +/- 0.16 and F(M.P) = 0.43 +/- 0.10. These and the steady-state clearance values of phenacetin (9.1 +/- 0.8 ml/min) and acetaminophen (6.7 +/- 0.7 ml/min) from the single-pass studies were used to predict the concentrations of [14C]acetaminophen in the reservoir perfusate on recirculation of [14C]phenacetin. We found that the sequential first-pass elimination of the metabolite must be considered when the metabolite is highly extracted by the liver. If we had neglected to take this into account, the fractional rate of conversion of a precursor to form a metabolite and the rate of formation of the metabolite would have been underestimated by the factor F(M.P).

Acetaminophen↗
PubMed1979

Kinetic evidence for multiple chemically reactive intermediates in the breakdown of phenacetin N-O-glucuronide.

N-hydroxyphenacetin glucuronide has been previously shown to be an unstable compound (half-life 8.7 h) that breaks down to phenacetin, 2-hydroxyphenacetin glucuronide, acetaminophen, acetamide, and a deethylated metabolite that covalently binds to protein. Evidence was presented that the acetamide, acetaminophen and a compound that binds covalently were formed from a common intermediate which was postulated to be N-acetylimidoquinone. In the presence of phosphate buffer, 3-hydroxyphenacetin phosphate is formed at the expense of acetaminophen, acetamide and covalent binding. Phosphate buffer, however, only partially blocks covalent binding to protein suggesting that two deethylated reactive metabolites are formed that can covalently bind to protein. These metabolites also may be converted to acetaminophen but only one of them leads to acetamide. Since the phosphate conjugate contains the ethyl group apparently a third reactive intermediate, which can react with phosphate but not with protein, serves as a precursor of one of the metabolites.

Animals↗
PubMed1979

Effects of induction of cytochrome P-450 enzymes on the concentration of foreign compounds and their metabolites and on the toxicological effects of these compounds.

Most foreign compounds, including nonnutrients in foods and vapors in air, undergo extensive metabolism before they are eliminated from the body. Included in this paper are discussions of the urinary clearance of various kinds of foreign compounds, the nonspecific enzymes that catalyze the formation of many metabolites of foreign compounds, the mechanisms by which the activities of these enzymes are altered, and the pharmacokinetics of the accumulation and elimination of the metabolites after single dose administration and during constant exposure of animals to foreign compounds. The formation of toxic reactive metabolites of foreign compounds and their role in toxic reactions are discussed.

Animals↗
PubMed1979

Biotransformation of drugs during aging.

Although the biological half-lives of many drugs appear to be longer in the elderly than in the young, the reasons for these longer half-lives are seldom clear, because the pharmacokinetic data obtained in humans are seldom sufficient to make a proper pharmacokinetic analysis. In the present paper are outlined the kinds of data required, the reasons they are required, and the possible consequences resulting from misinterpretation of inadequate data.

Aging↗