Search

The urinary excretion of secbutobarbitone (I) and its metabolites has been studied quantitatively using combined gas chromatographymass spectrometry. After a single oral dose was given to healthy male volunteers, unchanged drug (5–9%), 2′-hydroxysecbutobarbitone (II, 1·7–3·2%), 2′-oxosecbutobarbitone (III, less than 1%), and the carboxylic acid (IV, 24–34%) were found. The kinetics of the excretion process were studied.

The human metabolism of 5-allyl-5-neopentylbarbituric acid (nealbarbitone, Censedal), taken orally, has been studied. Comparison of the gas chromatography—mass spectra of extracts from urine with the spectra of model compounds showed nealbarbitone diol (III) to be the only urinary metabolite present in significant amount (about 30–40% of dose); the rate of excretion of diol reached a maximum about 36 h after ingestion of a single 300 mg dose. Treatment of nealbarbitone with a model oxidase of the Udenfriend type resulted only in oxidation of the allyl side-chain to the 2-oxopropyl derivative, in low yield.

Experimentally determined concentrations of butobarbitone, and three or its metabolites, in the urine of two volunteers, have been studied using a computer technique, which tests the data for limited capacity or first order kinetics. In both volunteers, the 3′-hydroxy and the 3′-oxo metabolites follow limited capacity kinetics for the first few days of excretion, and unchanged butobarbitone follows first order kinetics. Differing results were found for the two persons with the 3′-carboxylic acid metabolite. An additional calculation is proposed when applying the Levy method for interpreting limited capacity kinetics to data where drug recovery is incomplete.

The metabolism of pentobarbitone has been investigated in two healthy volunteers, and the urinary excretion of unchanged drug, and the products of omega- and (omega-1)-oxidation, quantified for four days after each of three doses to each volunteer. The rates of excretion are discussed in terms which include enzyme induction effects.

The proportions of the main components present in gentamicin sulphate complex, gentamicins C1, C1a and C2, can be monitored by 1H nuclear magnetic resonance (nmr) spectrometry. The method depends on measurement of the peak heights of signals for N-methyl and C-methyl groups present in all three components and of those present in C1 and C2 only, followed by calculation of peak height ratios to control composition within acceptable limits. The precision and reproducibility of the method have been established through two collaborative studies each involving seven laboratories. In the second study, with an improved procedure, the mean variance between laboratories with 10 samples was 3·4 × 10−4 for the N-methyl ratio of the peak at δ 2·75 to that at δ 2·95, and 1·25 × 10−3 for the C-methyl ratio of the peak at δ 1·25 to that at δ 1·35. Within laboratories the mean variance for triplicate determinations was 7·4 × 10−5 and 8·9 × 10−5 respectively. The data presented here form the experimental basis for the test controlling the composition of gentamicin sulphate in the British Pharmacopoeia 1973: Addendum 1975, and for the introduction into the British Pharmacopoeia of nmr spectrometry as an analytical technique. The reference standards and all batches of gentamicin sulphate intended for therapeutic use in the United Kingdom examined by this procedure comply with the limits laid down.

The mass spectra of twenty-six commercially available medicinal phenothiazines have been determined at high resolution. In each compound, the side chain attached to the 10-position of the phenothiazine ring contains nitrogen and fission of the CC bond α to this nitrogen gives in most cases the base peak. Some of the compounds are also substituted at the 2-position and this substituent generally remains intact, though some substituents such as acetyl, propionyl, methoxyl and methylthio can undergo fragmentation. Fragmentations fall into three groups; those which give ions representing a part of the side chain; those which give ions representing the intact phenothiazine ring with part of the side chain attached; those which give ions representing a partially fragmented ring system.

The human metabolism of 5-ethyl-5-cycloheptenylbarbituric acid, heptabarbitone, Medomin, taken orally, has been studied. Comparison of g.c., and g.c.-m.s. data, from derivatized urine extracts, with data from authentic synthetic samples, has shown that 5-(3î-oxocycloheptenyl)-5-ethylbarbituric acid (II) and 5-(3î-hydroxycycloheptenyl)-5-ethylbarbituric acid (III) are major metabolites of heptabarbitone. In addition, similar data have been obtained for a third metabolite. There was no evidence for the presence of the parent drug in the urine of the two volunteers. The rate of urinary excretion of the three metabolites is briefly discussed.

The urinary excretion of butobarbitone and its metabolites has been studied quantitatively using combined gas chromatography-mass fragmentography, tuned to ions at m/e 169 and 184. After a single oral dose (200 mg) to healthy male volunteers, unchanged drug (7 to 9%), 3′-hydroxybutobarbitone (22 to 27%), 3′-oxobutobarbitone (14 to 18%) and the 3′-carboxylic acid (4 to 8%), were found. In all cases, the maximum rate of excretion was in or near the third 12 hour urine.

The human metabolism of (±)-5-allyl-5-(1′-methylbutyl) barbituric acid (I), quinalbarbitone, taken orally, has been studied. Comparison of g.c. and g.c.-m.s. data from derivatized extracts of urine with similar data from synthetic samples confirmed the presence of the two diastereoisomeric forms of 5-allyl-5-(3′-hydroxy-1′-methylbutyl) barbituric acid (II), 5-allyl-5-(3′-oxo-1′-methylbutyl) barbituric acid (III), 5-allyl-5-(1′-methyl-3′-carboxypropyl) barbituric acid (IV), and 5-(2′,3′-dihydroxypropyl)-5-(1′-methylbutyl) barbituric acid (V) in the urine. There was no evidence for the urinary excretion of unchanged drug. The rate of excretion of these metabolites has been examined in some detail, and rate-limited kinetics shown to apply for excretion of the acid (IV) and the diol (V).

N-Hydroxyaprobarbitone (I) has been synthesized by oxidation of aprobarbitone, characterized, and a method developed for its estimation in urine. It has shown to be no more than a minor metabolite (

Combined gas-liquid chromatography-mass spectrometry is shown to be a useful technique for the identification of barbiturates and their metabolites, when applied to NN’-dimethyl derivatives.

Book reviewed in this article: POWDERED VEGETABLE DRUGS. By Betty P. Jackson and Derek W. Snowdon. PRACTICAL PHARMACEUTICAL CHEMISTRY. Second Edition, Part I. By A. H. Beckett and J. B. Stenlake.

The substances named in the title have been synthesised. They are the racemates of the corresponding optically active compounds derived from ring C of rosenonolactone.