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At least 19 recordsLinked to original sources
PubMed1979

Mephobarbital and phenobarbital plasma concentrations in epileptic patients treated with mephobarbital.

Plasma mephobarbital and phenobarbital concentrations were determined in 11 epileptic patients receiving mephobarbital alone or in combination with other antiepileptic drugs. The analysis was carried out by a selective ion monitoring (SIM) mass fragmentography technique following formation of N-propyl derivatives of both drugs. The plasma concentrations of phenobarbital ranged from 4 to 32 micrograms/ml and those of mephobarbital from 0.2 to 1.7 micrograms/ml. Differences in the metabolism rates of the drugs accounted for the plasma concentration differences; mephobarbital is metabolized more rapidly than phenobarbital. Phenobarbital concentrations obtained by SIM mass fragmentography were similar to those obtained by gas-liquid chromatographic on-column methylation, which quantitates only "total phenobarbital" (mephobarbital plus phenobarbital).

Chromatography, Gas↗
PubMed1985

Stereoselective mephobarbital hydroxylation cosegregates with mephenytoin hydroxylation.

The 8-hour urinary recovery of 4-hydroxy-mephobarbital has been measured after oral administration of racemic mephobarbital (90 mg) in 17 extensive (EM) and six poor (PM) metabolizer phenotypes of mephenytoin. The recovery of this metabolite was measurable in every EM and ranged from 2.5% to 48% (10.9% +/- 1.9% of dose), but was not detected in any PM (less than 1% of dose). In EMs, the 8-hour urine recovery of 4-OH-mephobarbital after mephobarbital was approximately half that of 4-OH-mephenytoin over the same time after mephenytoin administration. One EM received similar doses of R- and S-mephobarbital on separate occasions. Urinary recovery of 4-OH-mephobarbital was 33% and less than 1%, respectively. These results suggest that mephobarbital is stereoselectively hydroxylated by the same drug metabolizing enzyme that is responsible for the stereoselective aromatic hydroxylation of mephenytoin.

Administration, Oral↗
PubMed1992

Diminished mephobarbital anticonvulsant action following diphenhydramine pretreatment.

Diphenhydramine and other antihistamines produce biphasic effects on drug disposition and lower seizure threshold, thereby potentially diminishing the efficacy of anticonvulsants such as mephobarbital. Accordingly, the influence of diphenhydramine (50 mg/kg, IP) pretreatment on the anticonvulsant activity of mephobarbital (50 mg/kg, IP) was determined in adult female Swiss-Webster mice given pentylenetetrazol (SC). Diphenhydramine lowered the pentylenetetrazol convulsive dose (CD50) by 60%. Administration of diphenhydramine in combination with mephobarbital produced a 65% decrease in the CD50 of pentylenetetrazol in comparison with that of animals given mephobarbital plus pentylenetetrazol. Pharmacokinetic evaluation of mephobarbital blood level data indicates that the mechanism responsible for the observed interaction between diphenhydramine and mephobarbital involves a decrease in mephobarbital uptake from the administration site.

Animals↗
PubMed1990

The influence of age and gender on the stereoselective metabolism and pharmacokinetics of mephobarbital in humans.

In this clinical investigation, four groups of subjects (eight young women and eight young men [age range, 18 to 25 years], and eight elderly women and eight elderly men [greater than 60 years of age]) received single oral doses (400 mg) of racemic mephobarbital. The apparent total body clearance of R-mephobarbital was much greater and the elimination half-life was much shorter in the young men compared with the other three groups. This enantiomer displayed an age-dependent gender effect and a gender-dependent age effect in its metabolism. The apparent total body clearance of the S-enantiomer was much lower than that of the R-enantiomer in all subjects and did not differ between subject groups, although the elimination half-life was slightly but significantly shorter in young males. A consequence of these enantiomeric differences was an apparently enhanced stereoselectivity in the metabolism of mephobarbital in young men. These substantial influences of age and gender on the stereoselective disposition of mephobarbital are consistent with recent findings concerning the expression and regulation of cytochrome P450 enzymes.

Adolescent↗
PubMed1995

Synthesis of N-beta-D-glucopyranosyluronate derivatives of barbital, phenobarbital, metharbital, and mephobarbital.

The synthesis and characterization of barbital, phenobarbital, metharbital, and mephobarbital glucuronides is reported. The condensation of per(trimethylsilyl)-barbital and -phenobarbital with methyl 1,2,3,4-tetra-O-acetyl-beta-D-glucopyranuronate in the presence of trimethylsilyl trifluoromethanesulfonate gave moderate yields of the N1-(beta-D-glucopyranosyluronate) barbiturate derivatives. The diastereomers of the phenobarbital derivatives were resolved by use of C18 reversed-phase HPLC. The homologous N3-methyl barbiturate N1-glucuronates were prepared by reaction of the barbital and phenobarbital N1-glucuronate derivatives with diazomethane. The absolute configuration of the phenobarbital N1-beta-D-glucopyranuronate epimers was determined by oxidative removal of the glycon from the mephobarbital N1-beta-D-glucopyranuronate epimers to give the optical isomers of mephobarbital. The spectroscopic data for this series of compounds will facilitate the characterization of N-glycosylated imide xenobiotics that may be detected as mammalian metabolites in biodisposition studies.

Barbital↗
PubMed1986

Polymorphic metabolism of mephenytoin in man: pharmacokinetic interaction with a co-regulated substrate, mephobarbital.

The simultaneous dosing of two drugs with co-regulated genetic polymorphisms determined by a single cytochrome P-450 isozyme could result in competitive inhibition of metabolism. We investigated this hypothesis in vivo by studying the interaction of mephobarbital and mephenytoin in eight normal subjects with wide variability in S-mephenytoin 4-hydroxylation. Each received oral racemic mephenytoin (100 mg) alone and, on a separate occasion, 1 hour after oral racemic mephobarbital (200 mg). After mephenytoin dosing alone, the 8-hour urinary enantiomeric (R/S) ratio indicated one poor (PM), one intermediate (IM), and six extensive (EM) metabolizers. Total intrinsic clearance of S-mephenytoin varied more than 100-fold, whereas the range for R-mephenytoin was only twofold. The urinary R/S ratio correlated (r = 0.92) with the enantiomeric ratio of the plasma AUCs over the same period, indicating no stereoselectivity in renal clearance. When mephenytoin was taken in the presence of mephobarbital, peak levels and AUC of S-mephenytoin increased while those of the R-enantiomer remained unchanged. Accordingly, the R/S ratios in both plasma and urine were reduced, with the change rank order-related to the control value of the total intrinsic clearance of S-mephenytoin (i.e., greatest in the most extensive EM). Thus the urinary R/S ratio can be used as a measure of the enantiomeric ratio of the plasma concentrations over the same time period of collection. Moreover, this ratio may be used to detect drug interactions that involve the cytochrome P-450 isozyme(s) responsible for the polymorphic 4-hydroxylation of mephenytoin.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1986

A randomized, double-blind, crossover study of phenobarbital and mephobarbital.

Some pediatric neurologists maintain that mephobarbital (Mebaral) causes fewer behavioral side effects than phenobarbital. Because this hypothesis has not been previously tested, we conducted a prospective, double-blind, randomized, crossover study of these two anticonvulsants. Both drugs were equally effective in reducing the frequency of seizure, although serum phenobarbital levels were significantly higher when the patients were taking phenobarbital compared to mephobarbital. As measured by the Abbott Parent Questionnaire, there was no significant deterioration of behavior with either phenobarbital or mephobarbital, regardless of which drug was administered first.

Child↗
PubMed1989

Synthesis of N-beta-D-glucopyranosyl derivatives of barbital, phenobarbital, metharbital, and mephobarbital.

The condensation of per(trimethyl)silylbarbital and -phenobarbital with 1,2,3,4,6-penta-O-acetyl-beta-D-glucopyranose in the presence of stannic chloride in dichloroethane gave moderate yields of the beta-coupled barbiturate N-D-glucopyranosyl derivatives. Reaction of metharbital and mephobarbital under the same conditions was unsuccessful. The homologous N-methylglucosides were prepared by reaction of the barbital and phenobarbital N-glucosyl derivatives with diazomethane. The diastereomers of the phenobarbital and mephobarbital derivatives were resolved by use of C-18 reverse-phase h.p.l.c. 1H- and 13C-n.m.r. spectroscopy, and thermospray 1.c.-m.s. proved to be the most useful methods for characterizing the barbiturate glucosides.

Barbital↗
PubMed1990

Enantioselective binding of mephobarbital to plasma proteins.

The enantioselective protein binding of mephobarbital (MPB) was investigated in human plasma and human serum albumin solutions by equilibrium dialysis. A small but statistically significant difference was observed in the in vitro plasma protein binding of the enantiomers; (S)-MPB was approximately 59% bound and (R)-MPB approximately 67% bound. The binding to albumin [(S)-MPB: approximately 29% bound, and (R)-MPB: approximately 41% bound] was less than to plasma proteins but showed somewhat greater enantioselectivity, suggesting that albumin binding is a major source of the enantioselectivity in plasma. The effects of MPB concentration, of varying enantiomeric concentration ratio, and of phenobarbital on the enantioselective binding of MPB were studied. The effect of age was also investigated by measuring the binding in plasma from 8 young (18-25 yr) and 8 elderly (greater than 60 yr) male subjects who took single doses of MPB. The results were in close agreement with the in vitro binding data, and the binding of both enantiomers was marginally but significantly lower in the young compared with the elderly subjects. These differences in binding were consistent with previously observed pharmacokinetic differences between the two subject groups.

Adult↗
PubMed1978

Simultaneous determination of diphenylhydantoin, mephobarbital, carbamazepine, phenobarbital and primidone in serum using direct chemical ionization mass spectrometry.

A quantitative method for the simultaneous determination of five anticonvulsants in serum has been developed using chemical ionization mass spectrometry without prior chromatographic separation. The technique was shown to be rapid, simple and sensitive, allowing the routine analysis of 50 microliter of serum with good within-day and day-to-day precision.

Anticonvulsants↗
PubMed1985

Induction of a cytochrome P-450-dependent fatty acid monooxygenase in Bacillus megaterium by a barbiturate analog, 1-[2-phenylbutyryl]-3-methylurea.

In previous publications from our laboratory, we reported that a soluble, cytochrome P-450-dependent fatty acid monooxygenase from Bacillus megaterium ATCC 14581 can be induced by phenobarbital and a variety of other barbiturates. The tested barbiturates showed an excellent correlation between increasing lipophilicity and increasing inducer potency (Kim BH, Fulco AJ; Biochem Biophys Res Commun 116: 843-850, 1983). The only exception proved to be mephobarbital (N-methylphenobarbital) which, although more lipophilic than phenobarbital, is not an inducer of fatty acid monooxygenase activity. We have now found that 1-[2-phenylbutyryl]-3-methylurea (PBMU), an acylurea that can be derived from mephobarbital by hydrolytic cleavage of the barbiturate ring, is an excellent inducer of this activity. Paradoxically, the addition of mephobarbital to the bacterial growth medium containing PBMU significantly enhances the apparent potency of the acylurea to induce fatty acid monooxygenase activity as measured in cell-free extracts. When cell-free extracts of cells grown separately in PBMU or mephobarbital are mixed no enhancement of activity is seen. This finding suggests that the effect of mephobarbital is to somehow increase the efficiency of PBMU as an inducer of the P-450-dependent fatty acid monooxygenase rather than to induce an activator of this enzyme or a rate-limiting component of the monooxygenase system. Finally, both mephobarbital and PBMU induce the synthesis of total cytochrome P-450 in B. megaterium although PBMU is a much more potent P-450 inducer. For cytochrome P-450 induction, however, there is no synergistic or even additive effect when mephobarbital and PBMU are used together in the bacterial growth medium.

Bacillus megaterium↗