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With the intention of studying the fate of transplacentally transferred diphenylhydantoin (DPH, phenytoin) in the newborn infant, a mass fragmentographic analytic method has been developed, in which deuterium-labeled DPH is used as internal standard. The analytic procedure permits precise determinations of DPH in 100 µl plasma samples in concentrations down to 0.01 µg per milliliter. Seven newborn infants of epileptic mothers treated with DPH throughout the pregnancy were studied during the first 4 to 9 days of life. The rate of plasma disappearance of DPH in the newborn infants was of the same order of magnitude as previously reported in adults. The initial parts of the plasma concentration curves indicated zero-order disappearance of DPH. Nursing did not seem to affect the rapid plasma level decline in the babies until extremely low concentrations (0.1 p.g per milliliter) were reached. The arr,wunts of unchanged drug excreted in the urine were inSignificant. It is therefore concluded that babies born by mothers treated chronically with DPH are able to metabolize this drug effectively immediately after birth.

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.

After intravenous administration of desmethylimipramine and nortriptyline to dogs, the excretion of unchanged drug in urine or gastric juice was found to be of little quantitative importance. The renal excretion was pH dependent, indicating nonionic diffusion between blood and urine. The urinary excretion of desmethylimipramine or nortriptyline given in therapeutic doses to depressed patients was also shown to be pH dependent. At a steady-state plasma level of the antidepressant drugs, less than 5 per cent of the daily dose was excreted unchanged through the kidney. These data are discussed in relation to the treatment of tricyclic drug intoxications.

The inhibitory effect of nortriptyline (NT) on the neuronal uptake of radio labeled norepinephrine (NE) was studied with the use of the rat iris preparation in Krebs-Ringer solution or human plasma. When added to the incubation medium, NT inhibited the uptake of NE approximately ten times as effectively in buffer as in human plasma within the tested concentration range of NT (10−8 to 10−6M). This result is in good agreement with the 94 per cent binding (at NT concentration of 1.1 10−6M) obtained by the ultrafiltration method. Plasma from patients treated with NT also inhibited the uptake of NE. Correlation between the inhibitory effect and the “endogenous” plasma level of NT in the 14 patients studied was significant (p < 0.001). When NT was added in different concentrations to control plasma the inhibitory effect observed was close to that obtained with patient plasma containing the same “endogenous” concentration of NT.

A quantitative method has been developed for the determination of the tricyclic antidepressant drug nortriptyline in plasma, utilizing a combined technique of gas chromatography - mass spectrometry called mass fragmentography. A metabolite, desmethylnortriptyline, may be analyzed in the same run. The compounds are first converted to their heptafluorobutyranide derivatives. A complete chromatogram takes less than five minutes. Quantitive determinations under the present conditions are possible down to a few nanograms of nortriptyline per milliliter. There is a good correlation between the new method and that previously used which was based upon in vitro 3 11-acetylation labelling.

Wahrend der letzten Jahre versuchten wir an unserer Klinik immer mehr, die Patienten vom chemotherapeutischen Gesichtspunkt aus individuell zu behandeln. Wir halten uns nicht an das von den pharmazeutischen Firmen empfohlene standardisierte Dosierungsschema, das sich im allgemeinen auf umfangreiche klinische Untersuchungen stutzt, in denen der Patient aber als Durchschnitt „des untersuchten Krankengutes betrachtet wird“. Der einzelne Patient verhalt sich bezuglich Resorption, Verteilung, Metabolismus und Ausscheidung individuell.

5-(3,4-Dihydroxyphenyl)-5-phenylhydantoin, a diphenolic metabolite of diphenylhydantoin, has been identified by use of gas chromatography/mass spectrometry in urine from rats and man. The metabolite i

The binding of various tricyclic antidepressants to human plasma and the effects thereupon of other drugs were studied by an ultrafiltration technique utilizing labeled compounds. At a total concentration of 0·29 μ/ml the percentage of unbound desmethylimipramine(DMI) was found to be 9·5 ± 1·4 in 41 individuals. The unbound fraction of DMI in plasma increased only twofold when the total concentration of the drug was increased a thousand times. The degree of binding over the entire range of therapeutic plasma drug concentration was relatively constant. The binding of various tricyclic antidepressants was compared at a drug concentration of 1·1 μM. The percentage of unbound drug was for nortriptyline (NT) 5·5 ± 0·6, for amitriptyline (AT) 3·6 ± 0·8, for imipramine (I) 4·2 ± 0·8, for protriptyline (PT) 8·0 ± 0·6 (tested at a cone, of 7·7 μM) and for Leo 640, an imipramine analogue, 0·7 ± 0·7. The acetyl derivatives of DMI, NT and PT were much more bound than the parent compounds. The addition of NT, PT or AT in a “therapeutic” concentration of 0·2 μg/ml didnot displace DMI, nor did chlorpromazine in supratherapeutic concentration. Diphenylhydantoin was found to displace DMI, NT, PT, AT and particularly I.