Characterization of molecular associations involving L-ornithine and α-ketoglutaric acid: crystal structure of L-ornithinium α-ketoglutarate.

The crystal structure of L-ornithinium α-ketoglutarate (C5H13N2O2, C5H5O5) has been solved by direct methods using single crystal X-ray diffraction data. It crystallizes in the monoclinic system, space group P21, unit cell parameters a=15.4326(3), b=5.2015(1), c=16.2067(3) Å and ß=91.986(1)°, containing two independent pairs of molecular ions in the asymmetric unit. An extensive hydrogen-bond network and electrostatic charges due to proton transfer provide an important part of the cohesive energy of the crystal. The conformational versatility of L-ornithine and α-ketoglutaric acid is illustrated by the present results and crystal structures available from the Cambridge Structural Database.

Metabolic chiral inversion of stiripentol in the rat. I. Mechanistic studies.

To study enantioselective aspects of the disposition of stiripentol (STP), a chiral allylic alcohol undergoing development as an antiepileptic drug, a stereoselective synthesis was developed and the configuration of the two enantiomers determined to be (R)-(+) and (S)-(-). Following a single oral dose (300 mg kg-1) of the individual enantiomers to adult male Sprague-Dawley rats, it was found that (R)-STP was transformed extensively to its antipode, whereas little inversion was detected when (S)-STP was administered. Studies on the mechanism of this apparently unidirectional chiral inversion revealed that the phenomenon was dependent on the presence of the side-chain C==C double bond, because the enantiomers of the corresponding saturated alcohol (D2602) did not interconvert in vivo. Experiments with analogs of STP labeled with deuterium or oxygen-18 at the chiral center showed that, whereas the deuterium was retained in vivo, partial loss of the 18O occurred from both enantiomers of the drug. Pretreatment of rats with pentachlorophenol (40 mumol kg-1 i.p.), an inhibitor of sulfation (and possibly other conjugation reactions), led to a marked decrease in the rate of conversion of (R)-STP to its antipode, suggesting that the chiral inversion phenomenon may be mediated, at least in part, by an enantioselective conjugation process.

Comparative anticonvulsant potency and pharmacokinetics of (+)-and (-)-enantiomers of stiripentol.

The anticonvulsant potency and pharmacokinetics of the enantiomers of stiripentol were compared using the intravenous pentylenetetrazol infusion seizure model in the rat. Enantioselectivity was observed with respect to both the anticonvulsant activity and elimination kinetics of this compound. (+)-Stiripentol was 2.4 times more potent than its antipode against pentylenetetrazol-induced clonic seizure (brain EC50 of 15.2 micrograms/ml versus 36.1 micrograms/ml). The (+)-enantiomer was eliminated more rapidly than the (-)-enantiomer, as reflected in a higher plasma clearance (1.64 l/h/kg versus 0.557 l/h/kg) and a shorter half-life (2.83 h versus 6.50 h). Parallel studies with the racemate of stiripentol indicated that the anticonvulsant potency of the racemate was between the potency of the two enantiomers, suggesting that the combined activity reflects the additive action of (+)- and (-)-stiripentol. However, a marked metabolic interaction between enantiomers was evident after racemate administration. These results point to the need for information on the differential pharmacokinetics of stiripentol enantiomers following racemic drug administration.

In vitro and in vivo investigations of dihydropyridine-based chemical delivery systems for anticonvulsants.

A dihydropyridine-based chemical delivery system (CDS), intended to improve drug delivery to the brain, was investigated with a series of analogues of the anticonvulsant striripentol. In vitro experiments demonstrated that the rates of hydrolysis of the corresponding pyridinium conjugates were influenced markedly by small changes in the structure of the drug moiety to be released. Thus, allylic esters were hydrolyzed rapidly to drug in all aqueous media, while the analogous saturated esters and an allylic amide derivative were almost totally stable. The mechanism of hydrolysis, which is particular to this series of CDS conjugates, appeared to occur via ionization to a resonance-stabilized carbocation intermediate. The same CDS compounds were investigated in vivo and compared to the corresponding drugs after intravenous administration. Only those CDS compounds that were found to hydrolyze in vitro released appreciable amounts of drug in vivo. Prolonged release of the drug from the CDS in the brain could be demonstrated for these compounds, but the gain in the ratio of brain-to-plasma AUC when the CDS was administered depended on the innate distribution characteristics of the drug. Thus, the drug D3, which had a high brain-to-plasma AUC ratio, did not show an improvement in this ratio when administered as CDS3. In contrast, stiripentol with a poor brain-to-plasma AUC ratio showed a two- to threefold increase in this ratio when administered as a CDS. These investigations highlight the need for a thorough understanding of the mechanism of drug release and the importance of the pharmacokinetic properties of the drug in designing a carrier system for delivery of drugs to the brain.

The metabolic fate of stiripentol in man.

The metabolism of stiripentol (I), a new antiepileptic drug, was studied in healthy human subjects. Following a single 1200-mg oral dose to one subject, 13 metabolites of I were detected in urine and were identified by GC/MS techniques. The structures of 9 of these metabolites were confirmed subsequently by synthesis of the corresponding reference compounds. The nature of the urinary metabolites of I revealed the operation of five distinct metabolic pathways for this drug, viz. conjugation with glucuronic acid, oxidative cleavage of the methylenedioxy ring system, O-methylation of catechol metabolites, hydroxylation of the t-butyl group, and conversion of the allylic alcohol side-chain to the isomeric 3-pentanone structure. Metabolites of I excreted into urine over 12 hr accounted for the majority (73%) of an acute dose, whereas a further 18% was recovered in feces as the unchanged drug. These findings suggested that the search for additional metabolites would yield only trace amounts. From a quantitative standpoint, the most important pathway of biotransformation of I following both acute and chronic dosing involved opening of the methylenedioxy ring to generate catechol derivatives. This finding probably accounts for the known inhibitory effects of I on the oxidative metabolism of other antiepileptic agents and for the clinically significant drug interactions involving stiripentol.