Anthony J. Glazko

Metabolic disposition of diphenylhydantoin in normal human subiects following intravenous administration

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.

A Gas Chromatographic Assay for Ketamine in Human Plasma

A highly sensitive, quantitative assay procedure for ketamine and two of its metabolites, based upon gas–liquid chromatography of a heptafluorobutyryl derivative, has been developed. No appreciable interference occurred with procaine, atropine, meperidine or promethazine. Anesthetic doses in man (iv) produced ketamine plasma levels above 1 μg/ml, with a biological half-life of 17 min. The presence of the N-dealkylated metabolite of ketamine in human plasma was clearly demonstrated.

An evaluation of the absorption characteristics of different chloramphenicol preparations in normal human subjects.

The absorption characteristics of four different chloramphenicol preparations were compared in normal adult volunteers by means of blood level measurements and urinary excretion of chloramphenicol and its metabolites following administration of single 0.5 Gm. oral doses. Products of two manufacturers were compared in the first two studies, while a third study involved a compaTison of four commercial lots of chloramphenicol. Product A produced colorimetric and microbiologic plasma levels which were nearly double those of B; the area under the mean time‐concentration curve was nearly twice as great, and peak blood levels were reached earlier. Product C showed absorption characteristics similar to those of B. Product D showed a greatly extended period of absorption with maximum plasma levels about one quarter those of A. In vitro dissolution tests indicated that products B, C, and D went into solution more slowly than A. These observations emphasize the need for caution in assuming that absorption characteristics are the same for different chloramphenicol preparations containing identical amounts of drug.

Antiepileptic drugs: biotransformation, metabolism, and serum half-life.

1. Diphenylhydantoin ....................................................... 367 2. N-Alkylated Hydantoins .................................................. .373 3. Succinimides ........................................................... .373 4. Oxazolidinediones ........................................................ 376 5. Phenylureas ............................................................ .377 6. Barbiturates .............................................. ;: ............. 377

INHIBITION OF ADENOSINE DEAMINASE BY CO-VIDARABINE AND ITS EFFECT ON THE METABOLIC DISPOSITION OF ADENINE ARABINOSIDE (VIDARABINE)

The chemical structures of two adenosine dearninase inhibitors produced by bacterial fermentation have been established quite recently. Coformycin (co-F) was first isolated by Niida et al. * from cultures that produced forrnycin-A. It was found to be one of the most active adenosine deaminase inhibitors known a t that time, and it also inhibited deamination of formycin-A.2 The second deaminase inhibitor, co-vidarabine (co-V) was isolated recently as a fermentation product of Streptomyces an t ib io t i~us ,~ and it has also been found in the fermentation broth used for the production of vidarabine. The relationship between the chemical structures of the two inhibitors and the presence of a unique 7-membered ring in the aglycone portion of the molecule are shown below:

Species Differences in the Metabolism of Diphenhydramine (Benadryl)

Summary Tritium-labeled diphenhydramine given iv to rhesus monkeys produced a rapid drop in plasma levels of unchanged drug, but the total tritium activity rose slowly over a 4-hr period to levels severalfold greater than those observed 1 min after dosing. This was attributed to rapid removal of drug by the tissues, followed by a slow return of metabolites to the plasma. The major metabolite, strongly bound to plasma protein, was identified as diphenylmethoxyacetic acid. Similar observations were made in the dog, rabbit, guinea pig, and mouse; but not in the rat, which did not form diphenylmethoxyacetic acid. Species differences were noted in the conjugation of this metabolite with glutamine in the monkey, and with glycine in the dog.

Phenytoin Metabolism in Subjects with Long and Short Plasma Half-lives

Normal adult men with long and short phenytoin plasma half-lives were given 300-mg oral doses of phenytoin once daily for 15 days. Plasma levels of phenytoin (DPH) and its major metabolite (p-HPPH) were measured during the period of drug administration and for 5 days thereafter. Average steady-state plasma levels of DPH rose to 13.4 micrograms/ml in the long half-life group, compared with 3.6 micrograms/ml in the short half-life group. HPPH levels in the long half-life group were about one half of those observed in the short half-life group. The DPH/HPPH ratios in plasma specimens showed excellent correlation with the plasma half-lives of DPH and average steady-state levels, suggesting that this ratio could provide guidance in the selection of optimum dosage regimens for problem patients.

Determination of Ketamine in Blood Plasma

A novel assay procedure for ketamine, based upon the extraction of xylene red B into an organic solvent in direct proportion to the amount of ketamine present, is described. Dye concentration is measured by fluorescence, permitting assays in the 0–1 μg range. Some interference by the N-dealkylated metabolite of ketamine was encountered, and other basic drugs may interfere with the assay. With certain limitations, the fluorescent dye procedure appears suitable for clinical application.

Discovery of phenytoin.

Numerous letters and reports located in the Parke, Davis and Smithsonian files add to the story of Merritts and Putnams discovery of the anticonvulsant (AC) properties of phenytoin. The major events preceding this work were the fortuitous discovery of phenobarbital as an AC agent, structure/hypnotic activity studies with barbiturates and hydantoins in the early 1920s by A. W. Dox in the Parke, Davis laboratories, and the development of AC assay techniques in animals, by a number of laboratories. Phenytoin was the first item on the list of compounds sent to Putnam by Dox and W. G. Bywater in April 1936. It was found to have AC properties in animals late in 1936, but no public reports were issued until the following year. Clinical efficacy was established in 1937, but no public reports were issued until 1938. Dilantin sodium capsules were prepared by Parke, Davis & Co. and were ready for marketing the same year.

Bioavailability of Norethindrone in Human Subjects

SummaryA competitive protein binding assay for norethindrone was developed to measure plasma levels in human subjects. The plasma levels were considerably higher in women than in men, especially at low dose levels. The plasma levels were directly related to the dose in men; but greater variations in the plasma levels were observed in women. The plasma half-life was about 5 h in both sexes with single oral doses of 5 to 20 mg. A comparative bioavailability study with norethindrone from 2 different manufacturers, formulated in the same manner, showed no significant differences in absorption characteristics and provided sufficient data for pharmacokinetic analysis.