Plasma protein binding of diphenylhydantoin in man. Interaction with other drugs and the effect of temperature and plasma dilution.
01 Nov 1970-Clinical Pharmacology & Therapeutics (John Wiley & Sons, Ltd)-Vol. 11, Iss: 6, pp 846-855
TL;DR: Plasma protein binding of diphenylhydantoin (DPH) in normal plasma was investigated with an ultrafiltration technique (at room temperature) with the use of 14C‐labeled DPH with no marked difference between sexes or individuals.
Abstract: Plasma protein binding of diphenylhydantoin (DPH) in normal plasma was investigated with an ultrafiltration technique (at room temperature) with the use of 14C-labeled DPH. DPH was 92.6 per cent bound. There was no marked difference between sexes or individuals. In blood donor plasma the bound fraction was 93 per cent at a concentration of DPH of 16 μg per milliliter (therapeutic concentration). The binding was less at 37° C. than at wom temperature. The effect on DPH binding of some other drugs, including various anti-epileptics, was investigated. Of these only salicylic acid, sulfafurazole and phenylbutazone (in concentrations which may be obtained clinically) decreased DPH binding. The effects of plasma dilution and of dilution of both plasma and DPH were investigated. In the former case unbound concentrations increased but were fairly constant in the latter. The clinical significance of these findings is discussed.
Citations
More filters
TL;DR: Most drugs are carried from their sites of absorption to their Sites of action and elimination by the circulating blood, but many others are partly a part of serum water.
Abstract: Most drugs are carried from their sites of absorption to their sites of action and elimination by the circulating blood. Some drugs are simply dissolved in serum water, but many others are partly a...
417 citations
378 citations
327 citations
TL;DR: The binding of DPH by plasma proteins from azotemic patients appears to be decreased, probably owing to a change in the binding proteins.
Abstract: The protein binding of diphenylhydantoin (DPH) and desmethylimipramine (DMI) was measured in plasma from azotemic and uremic patients by an Ultrafiltration technic. DPH binding was decreased in uremic plasma. The impairment of binding was strongly correlated (p less than 0.001) to the degree of azotemia and degree of physical disability of the patients but weakly correlated (p less than 0.05) to their concentrations of serum proteins. DMI binding was almost normal. Dialysis of normal and uremic plasma in tap water or hemodialysis solution did not alter the DPH binding. The binding of DPH by plasma proteins from azotemic patients appears to be decreased, probably owing to a change in the binding proteins. The possibility of alteration of drug binding by pathologic states should be considered when total plasma concentrations of protein-bound drugs are measured and the values used to establish or modify drug-dosage regimens.
316 citations
TL;DR: Internal surface reversed-phase supports synthesized from commercially available porous silica particles with a variety of nominal pore diameters and specific surface areas are characterized with regard to physical and chromatographic properties.
Abstract: Internal surface reversed-phase (ISRP) supports synthesized from commercially available porous silica particles with a variety of nominal pore diameters and specific surface areas are characterized with regard to physical and chromatographic properties. Bonded phase coverage, pore size, capacity and efficiency measurements are made upon the various ISRP supports in order to evaluate the effect that the physical properties of silica have upon the chromatographic performance of ISRP packings. In addition, various models that describe the pore structure of silica supports are discussed.
293 citations
References
More filters
TL;DR: The correlation is described between the serum level of diphenylhydantoin and the anticonvulsant effect of the drug, the incidence of paroxysmal abnormalities in the electroencephalogram, and the occurrence of toxic side-effects.
Abstract: In a previous study 2 a method was described for determining diphenylhydantoin (5,5-diphenylhydantoin; phenytoin; Dilantin) concentrations in the serum when the drug was given in therapeutic amounts. With this method were determined the rate of rise of diphenylhydantoin in the serum after oral and after intravenous administration, the hourly and daily fluctuations, the ratio of dosage to serum level, and the rate of fall of serum diphenylhydantoin after withdrawal of the drug. In the study presented in this report the correlation is described between the serum level of diphenylhydantoin and the anticonvulsant effect of the drug, the incidence of paroxysmal abnormalities in the electroencephalogram, and the occurrence of toxic side-effects. Patients and Methods Patients. —1. Twelve patients, 19 to 58 years of age—six men and six women, hospitalized in the neuromedical, neurosurgical, or psychiatric department of the University Hospital. They had not taken diphenylhydantoin before admission to the hospital and
280 citations
"Plasma protein binding of diphenylh..." refers background in this paper
...There is an apparent correlation between total plasma concentration of diphenylhydantoin (DPH) and therapeutic effects.(6) The side effects associated with DPH also correlate with plasma concentration, thus representing the phenomenon of overdosage,5, 6, 12 but in none of these reports is the degree of plasma protein binding determined....
[...]
TL;DR: Detailed data have been obtained relating symptoms and signs of toxicity to blood levels of diphenylhydantoin relating to the common signs of dose-related toxicity and defects in the metabolism of DiphenylHydantoin.
Abstract: Introduction Diphenylhydantoin is one of the most frequently used anticonvulsants, and it has a relatively low incidence of serious side reactions. The common signs of dose-related toxicity are nystagmus, ataxia, dysarthria, and drowsiness. Diphenylhydantoin must usually be given to adults in amounts of 500 mg or more a day1to produce clinical evidence of intoxication. Buchthal et al2reported that mild toxic symptoms and signs were observed with blood levels of 15μg/ml, and severe symptoms and signs have been noted with diphenylhydantoin blood levels of 30μg/ml or more. However, this report does not give a detailed account of the relationship of the specific symptoms and signs of toxicity to diphenylhydantoin blood levels. Along with our studies of toxicity and defects in the metabolism of diphenylhydantoin, detailed data have been obtained relating symptoms and signs of toxicity to blood levels of diphenylhydantoin. The first part of this paper deals
276 citations
TL;DR: In vitro studies comparing minimal inhibitory and bactericidal activity of these penicillins in 100 per cent human serum and trypticase soy broth revealed a close relation of inhibition of antimicrobial action to the extent of binding to serum.
Abstract: The effect of human serum binding on free and total concentrations and urinary excretion of penicillins G, V, and ampicillin, oxacillin, cloxacillin, dicloxacillin, and methicillin achieved after administration in man is reported. In vitro studies comparing minimal inhibitory and bactericidal activity of these penicillins in 100 per cent human serum and trypticase soy broth revealed a close relation of inhibition of antimicrobial action to the extent of binding to serum. Quantitative data were obtained by use of arithmetic linear dilutions, in small steps, rather than the usual twofold dilution method. Extensive binding to serum proteins was demonstrated by equilibrium dialysis and ultrafiltration methods utilizing serum obtained from human volunteers receiving therapeutic doses of each penicillin analogue. Dicloxacillin, cloxacillin, oxacillin, and nafcillin were most highly bound in descending order. Penicillin G and V were intermediate, while methicillin and ampiCillin were least bound. Serum binding appears to be an important determinant of the high serum concentrations achieved with some of the new orally absorbed penicillinase-resistant compounds. The uncritical use of the term “absorption curve” to describe concentrations of drugs which differ in distribution, metabolism, and excretion, after oral administration is deplored since the term implies that serum concentrations are the resultant of efficiency of gastrointestinal absorption alone. Alternate methods to assess absorption are illustrated. The customary twofold dilution broth assay of serum antibacterial activity may be misleading when employed with highly bound antibiotics. It is proposed that reports of studies of serum concentrations achieved with highly bound antimicrobial agents include data not only on total drug levels, but of free as well. This approach permits a more realistic correlation of serum concentration with minimum effective levels determined in the usual broth assays.
149 citations
TL;DR: The maximum excretion rate of HPPH was found to occur about 6 to 8 hours after the intravenous dose, presumably due to an initial delay in the enzymatic processes of hydroxylation or conjugation prior to excretion of the metabolite.
Abstract: Plasma levels of diphenylhydantoin and the urinary excretion of its hydroxylated metabolite were studied in 6 normal adults following single intravenous doses of 0.25 Gm. DPH‐sodium. The high initial plasma levels dropped rapidly to a mean value of 6.3 µg per milliliter 20 minutes after dosing and 5.2 µg per milliliter in one hour; the plasma half‐life in later time periods was about 15 hours (range 11 to 29 hours). Urinary excretion of free and conjugated HPPH in 5 of the 6 subjects, measured by a new gas‐chromatography procedure, accounted for 76 per cent of the dose (range 65 to 81 per cent) over a period of 5 days. Approximately one third of the administered dose was accounted for by urinary excretion in the first 24 hours, with diminishing amounts being excreted thereafter over periods of 4 to 5 days or more. The maximum excretion rate of HPPH was found to occur about 6 to 8 hours after the intravenous dose, presumably due to an initial delay in the enzymatic processes of hydroxylation or conjugation prior to excretion of the metabolite.
118 citations
TL;DR: The plasma protein binding of diphenylhydantoin (DPH) in heparinized plasma from normal and hyperbilirubinemic newborn infants was investigated by means of an ultrafiltration technique utilizing 14 C-DPH.
105 citations