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Biomedical subjects

K H Dudley

Publications and source records attributed to K H Dudley.

At least 19 recordsLinked to original sources
PubMed1980

Integrated method for the gas chromatographic determination of antiepileptic drugs in human plasma.

The principles of three independent extraction methods were utilized to develop an integrated extraction scheme for use in routine therapeutic monitoring of seven antiepileptic agents. The final method, in which the three extraction methods were interfaced, permitted routine monitoring in a single 1 ml volume of human plasma of any one or combination of the following drugs: phenytoin (PHT), phenobarbital (PB), primidone (PD), 5-ethyl-5-phenylhydantoin (EPH), ethosuximide (ES), carbamazepine (CBZ), and valproic acid (VPA). An on-column methylation technique was used for simultaneous determination of PHT, PB, PD, EPH, and ES. CBZ and VPA were determined by independent methods as the underivatized compounds. Six appropriate internal standards were employed in the integrated method for quantitation of the drugs.

Anticonvulsants↗
PubMed1980

Effects of drugs on behavior in pigeons tolerant to delta 9-tetrahydrocannabinol.

Schedule-controlled behavior was used to study how drug effects on behavior are modified by the development of tolerance to delta 9-tetrahydrocannabinol (delta 9-THC). Dose-effect curves were determined for pentobarbital, d-amphetamine and morphine on responding maintained by a multiple fixed-ratio fixed-interval schedule of food presentation in pigeons. The dose-effect curves were redetermined in combination with single injections of 1.0 mg/kg dose of delta 9-THC (which itself did not affect rates of responding) in birds made tolerant to delta 9-THC by multiple injections, and in combination with the 1.0 mg/kg delta 9-THC in birds tolerant to delta 9-THC. Acute doses of 1.0 mg/kg delta 9-THC potentiated the rate-decreasing effects of all three drugs. Pigeons tolerant to delta 9-THC were cross-tolerant to pentobarbital but not to d-amphetamine and morphine. Tolerance to delta 9-THC attenuated the potentiation of the effects of all three drugs by delta 9-THC. Determination of plasma pentobarbital levels in pigeons tolerant to delta 9-THC suggested that a drug dispositional mechanism played a role in the cross-tolerance from delta 9-THC to pentobarbital.

Amphetamine↗
PubMed1979

Determination of 5-(p-hydroxyphenyl)-5-phenylhydantoin and studies relating to the disposition of phenytoin in man.

A gas chromatographic on-column methylation technique was developed for the routine laboratory determination of 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), the principal urinary product of phenytoin )PHT) metabolism in man. 5-(p-Hydroxyphenyl)-5-(p-tolyl)hydantoin (HMPPH), a new internal standard, was synthesized and evaluated against 5-phenyl--5-(p-tolyl)hydantoin (MPPH), the compound normally used as the internal standard in p-HPPH assays. HMPPH withstood the challenges of intralaboratory quality control checks and tests of precision of p-HPPH values at times when MPPH provided erratic and unreliable values. Both an enzyme and acid treatment of urine were studied for the purpose of hydrolysis of p-HPPH-glucuronide, the form in which p-HPPH is excreted in urine. The use of both treatments in studies of three different patient urines pointed to the conclusion that acid-catalyzed decomposition of PHT dihydrodiol, a minor urinary metabolite of PHT in man, was unimportant from the analytical point of view, contributing little if anything to total urinary p-HPPH content. Some aspects of PHT disposition, as evidenced by studies of PHT plasma levels and p-HPPH urinary outputs in individual patients, are discussed.

Chemical Phenomena↗
PubMed1979

Gas chromatographic method for the determination of valproic acid in human plasma.

A gas chromatographic method has been developed for the routine monitoring of valproic acid (VPA) in human plasma samples. Two compounds, 2-ethylpentanoic acid (EPA) and 2-propylhexanoic acid (PHA), were synthesized and evaluated as internal standards together with cyclohexane carboxylic acid (CHCA), a commonly employed internal standard. Crystalline barium salts of VPA, EPA, and PHA were prepared, which enabled preparation of standard solutions of high accuracy for use in calibration experiments and in daily intra-laboratory quality control tests. The extraction scheme was designed on the basis of the solvent partitioning properties of VPA. Solvent transfers are required in the extraction scheme, but solvent evaporations are not. Studies were made of the performances of EPA, PHA, and CHCA as internal standards in the VPA assay at different lifetimes of the 10% SP-1000 chromatography column. As judged by these studies, EPA or CHCA is a better choice than PHA as an internal standard, provided that certain guidelines are followed in the use of CHCA.

Chromatography, Gas↗
PubMed1979

Determination of 5-(3,4-Dihydroxy-1,5-cyclohexadien-1-yl)-5-phenylhydantoin (Dihydrodiol) and quantitative studies of phenytoin metabolism in man.

A routine gas chromatographic assay for urinary 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), the major metabolite of phenytoin (PHT) in man, was adapted to allow quantitation of 5-(3,4-dihydroxy-1,5-cyclohexadien-1-yl)-5-phenylhydantoin (Dihydrodiol, DHD) is based on the observation that acid-catalyzed dehydration of DHD quantitatively yields a mixture of p-HPPH and m-HPPH in a reproducible molar ratio of 56:44p-HPPH: m-HPPH and on the assumption that all m-HPPH found in urine after heating with acid has been derived from DHD. The urinary DHD content was verified by a "specific" method in which urine was incubated with beta-glucuronidase and the released phenolic metabolites completely removed by extraction. Subsequent acid-catalyzed dehydration of the remaining DHD yielded p-HPPH and m-HPPH, from the sum of which the original DHD concentration in urine could be calculated. In all of the urine samples from PHT patients examined to date, there was close agreement between the DHD values obtained by the "specific" method and those calculated from m-HPPH, in the simple acid-hydrolysis method. It can be inferred that much the greater part (greater than 90%) of m-HPPH found in human urine after acid treatment has been derived from DHD. All samples of urine after acid treatment has been derived from DHD. All samples of urine from PHT patients examined have shown detectable quantities of DHD. The methods described here may be useful in a survey of PHT patients to reveal unusual patterns of PHT metabolism and to permit recognition of possible associations between such unusual patterns and the occurrence of adverse reactions.

Chromatography, Gas↗
PubMed1978

Absolute configuration of (+)-5-(o-hydroxyphenyl)-5-phenylhydantoin, the major metabolite of 5,5-diphenylhydantoin in the dog.

5-(3-Hydroxyphenyl)-5-phenylhydantoin (m-HPPH) has been resolved by crystallization of the brucine salts. The (+) enantiomer has been converted to (-)-5-cyclohexyl-5-phenylhydantoin, a compound previously demonstrated to have the R configuration. The R configuration can accordingly be assigned to (+)-m-HPPH, the principal metabolite of 5,5-diphenylhydantoin (phenytoin) in the dog.

Crystallization↗
PubMed1977

Gas chromatographic on-column methylation technique for the simulataneous determination of antiepileptic drugs in blood.

An on-column methylation technique (OCMT) is described for the simultaneous, gas chromatographic determination in blood of ethosuximide (ES), phenobarbital (PB), primidone (PD), phenytoin (DPH), and 5-ethyl-5-phenylhydantoin (EPH). Multiple internal standards are employed in the OCMT, in order to eliminate or to minimize greatly error sources common to the technology of gas chromatography and to compensate for the different chemical dispositions of the antiepileptic drugs in an OCMT. The internal standards used in the OCMT were as follows: alpha,alpha,beta-trimethylsuccinimide (TMS) was used for the determination of ES; 5-ethyl-5-para-tolylbarbituric acid (MPB), for PB; 5-ethyl-5-(para-tolyl) hexahydropyrimidine-4,6-dione (MPD), for PD; and 5-(para-tolyl)-5-phenylhydantoin (MPPH), for EPH and DPH. The use of ether, the buffering of the plasma sample at pH 7.6, and the use of dilute (0.30-0.35 M) trimethyl-phenylammonium hydroxide (TMPAH) contributed to the specificity of the extraction scheme of the OCMT. The precision and accuracy of the OCMT was attributed to the use of appropriate, multiple internal standards. A method is described for the preparation of standard solutions of drugs in blank plasma (biological matrix) and for the use of the standards in calibration and daily intra-laboratory control of the OCMT.

Anticonvulsants↗
PubMed1977

Hydroxylation of 5,5-diphenylhydantoin (phenytoin) by dog liver microsomes.

Chang and Glazko in 1972 had reported failure to demonstrate any production from 5-5-diphenylhydantoin (phenytoin, DPH) by dog liver microsomes of either 5-(m-hydroxyphenyl-5-phenylhydantoin (m-HPPH) or 5-(P-hydroxyphenyl-5-phenylhydantoin (p-HPPH), metabolites of DPH produced by the dog in vivo. We have incubated DPH with 9,000 X g supermatants of dog liver homogenates and with suspensions of separated microsomes with added NADPH generating system, Mg(2+), and nicotinamide and have demonstrated the production of both m-HPPH and p-HPPH. Both metabolities were detected by thin-layer chromatography of extracts of the incubation mixtures. Detection and roughly quantitative measurement of m-HPPH were also accomplished with gas chromatography.

Animals↗
PubMed1976

Studies of the metabolism of 5,5-diphenylhydantoin relating principally to the stereoselectivity of the hydroxylation reactions in man and the dog.

The hydroxylated metabolites of 5,5-diphenylhydantoin (DPH) in dog and human urine, after release by beta-glucuronidase, have been isolated and purified by procedures entailing only solvent partitioning without crystallization or any other procedure that could change the proportions of optical isomers. Dogs produced both the meta- and para-5-hydroxyphenyl-5-phenylhydantoins (m-HPPH and p-HPPH) from DPH, the former in approximately 6 times the amount of the latter. The m-HPPH from dog urine was dextrorotatory and had the properties of a pure optical isomer. The p-HPPH from dog urine was a mixture of optical isomers with approximately a 2:1 preponderance of the levorotatory isomer. When dog urine was heated with acid rather than treated with beta-glucuronidase, the isolated p-HPPH contained a small preponderance of the dextrorotatory isomer, probably owing to production of d-p-HPPH from the dihydrodiol metabolite. No o-HPPH was found in dog urine. When racemic p-HPPH and m-HPPH were administered to dogs, there was little if any preponderance of either optical isomer in the materials isolated from urine. Enzymatically released p-HPPH isolated from urine of human patients receiving DPH was a mixture of optical isomers with approximarely a 10:1 preponderance of the levorotatory isomer. Crystallization of this material readily yields pure l-p-HPPH. Human urine contained only very small amounts of m-HPPH, which was detectable by gas chromatography but insufficient in amount to permit isolation. Hypotheses are discussed that could account for the differences in the metabolism of DPH in man and dog. Small amounts of 2,2-diphenylhydantoic acid were found in urine of dogs but not of human patients receiving DPH.

Animals↗