Drug Interactions with Warfarin: Studies with Dichloralphenazone, Chloral Hydrate and Phenazone (Antipyrine)

1971 ◽  
Vol 40 (4) ◽  
pp. 351-364 ◽  
Author(s):  
A. Breckenridge ◽  
M. L'E. Orme ◽  
S. Thorgeirsson ◽  
D. S. Davies ◽  
R. V. Brooks
Keyword(s):  
Endoplasmic Reticulum ◽  
Steady State ◽  
Urinary Excretion ◽  
Binding Sites ◽  
Half Life ◽  
Chloral Hydrate ◽  
Maximal Velocity ◽  
Protein Binding Sites ◽  
Drug Oxidation ◽  
State Plasma

1. Administration of dichloralphenazone, a complex of chloral hydrate and phenazone (antipyrine) caused a fall in steady-state plasma warfarin concentration and loss of anticoagulant control in five subjects. 2. This effect of dichloralphenazone is due to stimulation of the drug-oxidizing enzymes of the liver endoplasmic reticulum by antipyrine, the non-hypnotic part of the complex. Administration of antipyrine caused a fall in steady-state plasma warfarin concentration in five subjects, a shortening of the plasma warfarin half-life, with increased urinary excretion of the metabolites of 14C-labelled warfarin in two subjects and increased urinary excretion of 6β-hydroxycortisol which is formed in the liver endoplasmic reticulum. 3. Administration of chloral hydrate, the hypnotic part of dichloralphenazone, caused no change in anticoagulant control but a fall in steady-state plasma warfarin concentration in five subjects. This is due to the accumulation of trichloroacetic acid which displaces warfarin from plasma protein binding sites. 4. Individual differences in the extent of enzyme induction have been shown to be related to the subjects' rates of drug oxidation. 5. In the rat administration of dichloralphenazone and antipyrine, but not chloral hydrate, caused shortening of pentobarbitone sleeping time and of the plasma [14C]pentobarbitone half-life, shortening of the zoxazolamine paralysis time and increase in the maximal velocity of N-demethylation of ethylmorphine.

scholarly journals Steady-State Plasma and Intrapulmonary Pharmacokinetics and Pharmacodynamics of Cethromycin

2004 ◽  
Vol 48 (9) ◽  
pp. 3508-3515 ◽  
Author(s):  
John E. Conte ◽  
Jeffrey A. Golden ◽  
Juliana Kipps ◽  
Elisabeth Zurlinden
Keyword(s):  
Steady State ◽  
Half Life ◽  
Dose Group ◽  
Drug Exposure ◽  
Pharmacokinetic Parameters ◽  
Multiple Time ◽  
Respiratory Pathogens ◽  
Once Daily ◽  
Standard Deviations ◽  
State Plasma

ABSTRACT The objective of this study was to determine the steady-state plasma and intrapulmonary pharmacokinetic parameters of orally administered cethromycin in healthy volunteers. The study design included administering 150 or 300 mg of cethromycin once daily to 25 or 35 healthy adult subjects, respectively, for a total of five doses. Standardized and timed bronchoalveolar lavage (BAL) was performed after the last dose. Blood was obtained for drug assay prior to the first and last dose, at multiple time points following the last dose, and at the time of BAL. Cethromycin was measured in plasma, BAL, and alveolar cell (AC) by using a combined high-performance liquid chromatography-mass spectrometric technique. Plasma, epithelial lining fluid (ELF), and AC pharmacokinetics were derived by noncompartmental methods. C max/90% minimum inhibitory concentration (MIC90) ratios, area under the concentration-time curve (AUC)/MIC90 ratios, intrapulmonary drug exposure ratios, and percent time above MIC90 during the dosing interval (%T > MIC90) were calculated for recently reported respiratory pathogens. The kinetics were nonlinear, i.e., not proportional to dose. In the 150-mg-dose group, the C max (mean ± standard deviations), AUC0-24, and half-life for plasma were 0.181 ± 0.084 μg/ml, 0.902 ± 0.469 μg · h/ml, and 4.85 ± 1.10 h, respectively; for ELF the values were 0.9 ± 0.2 μg/ml, 11.4 μg · h/ml, and 6.43 h, respectively; for AC the values were 12.7 ± 6.4 μg/ml, 160.8 μg · h/ml, and 10.0 h, respectively. In the 300-mg-dose group, the C max (mean ± standard deviations), AUC0-24, and half-life for plasma were 0.500 ± 0.168 μg/ml, 3.067 ± 1.205 μg · h/ml, and 4.94 ± 0.66 h, respectively; for ELF the values were 2.7 ± 2.0 μg/ml, 24.15 μg · h/ml, and 5.26 h, respectively; for AC the values were 55.4 ± 38.7 μg/ml, 636.2 μg · h/ml, and 11.6 h, respectively. We concluded that the C max/MIC90 ratios, AUC/MIC90 ratios, %T > MIC90 values, and extended plasma and intrapulmonary half-lives provide a pharmacokinetic rationale for once-daily administration and are favorable for the treatment of cethromycin-susceptible pulmonary infections.

EVALUATION OF TISSUE STEROID BINDING IN VITRO

1971 ◽  
Vol 68 (1_Suppl) ◽  
pp. S223-S246 ◽  
Author(s):  
C. R. Wira ◽  
H. Rochefort ◽  
E. E. Baulieu
Keyword(s):  
Protein Binding ◽  
Binding Sites ◽  
Experimental System ◽  
Specific Protein ◽  
Coupling Mechanism ◽  
Target Tissue ◽  
Protein Binding Sites ◽  
Definition Of ◽  
Hormone Specificity

ABSTRACT The definition of a RECEPTOR* in terms of a receptive site, an executive site and a coupling mechanism, is followed by a general consideration of four binding criteria, which include hormone specificity, tissue specificity, high affinity and saturation, essential for distinguishing between specific and nonspecific binding. Experimental approaches are proposed for choosing an experimental system (either organized or soluble) and detecting the presence of protein binding sites. Techniques are then presented for evaluating the specific protein binding sites (receptors) in terms of the four criteria. This is followed by a brief consideration of how receptors may be located in cells and characterized when extracted. Finally various examples of oestrogen, androgen, progestagen, glucocorticoid and mineralocorticoid binding to their respective target tissues are presented, to illustrate how researchers have identified specific corticoid and mineralocorticoid binding in their respective target tissue receptors.

Predicting the Strength of Stacking Interactions Between Heterocycles and Aromatic Amino Acid Side Chains

2019 ◽  
Author(s):  
Andrea N. Bootsma ◽  
Analise C. Doney ◽  
Steven Wheeler
Keyword(s):  
Amino Acid ◽  
Binding Sites ◽  
Aromatic Amino Acid ◽  
Aromatic Amino Acids ◽  
Biologically Active ◽  
Side Chains ◽  
Stacking Interactions ◽  
Inhibitor Binding ◽  
Protein Binding Sites ◽  
Amino Acid Side Chains

<p>Despite the ubiquity of stacking interactions between heterocycles and aromatic amino acids in biological systems, our ability to predict their strength, even qualitatively, is limited. Based on rigorous <i>ab initio</i> data, we have devised a simple predictive model of the strength of stacking interactions between heterocycles commonly found in biologically active molecules and the amino acid side chains Phe, Tyr, and Trp. This model provides rapid predictions of the stacking ability of a given heterocycle based on readily-computed heterocycle descriptors. We show that the values of these descriptors, and therefore the strength of stacking interactions with aromatic amino acid side chains, follow simple predictable trends and can be modulated by changing the number and distribution of heteroatoms within the heterocycle. This provides a simple conceptual model for understanding stacking interactions in protein binding sites and optimizing inhibitor binding in drug design.</p>

Placental Transfer of Calcium and Strontium in the Rat and Rabbit

1957 ◽  
Vol 189 (1) ◽  
pp. 91-97 ◽  
Author(s):  
R. H. Wasserman ◽  
C. L. Comar ◽  
M. M. Nold ◽  
F. W. Lengemann
Keyword(s):  
Steady State ◽  
Urinary Excretion ◽  
Fetal Development ◽  
Placental Transfer ◽  
Maternal Diet ◽  
Late Pregnancy ◽  
Placental Barrier ◽  
Tracer Techniques ◽  
Comparative Metabolism ◽  
Differential Movement

The comparative metabolism of calcium and strontium during fetal development was investigated in rats and rabbits using double tracer techniques. In general, the placental transfer from dam to fetus of strontium was about one-half that of calcium; the site of discrimination was the placental barrier. The major discrimination occurred in movement of Ca* and Sr* from dam to fetus, with little or no differential movement from fetus to dam. Under steady state conditions in the rat the relative Sr*/Ca* ratios in the fetus, maternal skeleton and diet were 0.17, 0.28 and 1, respectively. The over-all discrimination of 0.17 between fetus and diet resulted from absorption (0.42), urinary excretion (0.63) and placental transfer (0.65). In the rat it was estimated that 92% of the fetal calcium had originated from the maternal diet. In the rabbit during late pregnancy, it was determined that about 24 mg of calcium/fetus/day moved across the placenta as compared with a need of about 13 mg for fetal development.

scholarly journals Transcription signals and protein binding sites for sericin gene transcription in vitro

1989 ◽  
Vol 264 (31) ◽  
pp. 18707-18713 ◽  
Author(s):  
K Matsuno ◽  
C C Hui ◽  
S Takiya ◽  
T Suzuki ◽  
K Ueno ◽  
...  
Keyword(s):  
Protein Binding ◽  
Gene Transcription ◽  
Binding Sites ◽  
Protein Binding Sites ◽  
Transcription In Vitro ◽  
Transcription Signals
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