PubMed · 5195331
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Chlorprothixene--Taractan.. https://pubmed.ncbi.nlm.nih.gov/5195331/
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Isocratic reversed-phase high-performance liquid chromatography with coulometric electrochemical detection was optimised to quantify the neuroleptic drugs chloroprothixene, levomepromazine, and promethazine in human serum. The method involves extraction of the neuroleptic drugs in n-heptane-isoamylalcohol from the alkalinized serum, followed by chromatographic separation on a Nucleosil CN column with acetonitrile-pyridine-sodium acetate buffer as the mobile phase. The extraction recovery was > 85% for each neuroleptic drug. The sensitivity and selectivity required for pharmacokinetic studies was obtained with a dual coulometric analytical cell operating in the oxidative screen mode. The lower limit of detection in human serum for chlorprothixene, levomepromazine, and promethazine, was 0.5, 0.2 and 0.1 ng/ml, respectively. A linear relationship (r2 > 0.99) was obtained between the concentrations of each neuroleptic drug and the detector signal. The accuracy of the quality control samples was +/- 7% for each neuroleptic drug with a precision within 9.5%, 8.1% and 13.5% for chlorprothixene, levomepromazine, and promethazine, respectively. The neuroleptic drugs were stable in acetonitrile and human serum for at least six months when stored at -20 degrees C. This method is applicable to analyze a large number of serum samples for pharmacokinetic studies of the neuroleptic drugs.
cis(Z)-Chlorprothixene has antidopaminergic potency, while trans(E)-chlorprothixene is virtually inactive. In order to reveal the structural features causing the difference in activity, the three-dimensional molecular and electronic structures of cis(Z)- and trans(E)-chlorprothixene were examined by computer graphics and molecular mechanical and quantum mechanical calculations. The internal molecular motions of the isomers were studied by molecular dynamics simulations in vacuo and in aqueous solution. The cis(Z)-isomer had lower potential molecular energy than the trans(E)-isomer, mainly due to electrostatic interactions within the side-chain and between the dimethylamino group and the chlorine atom. During molecular dynamics simulations in aqueous solution, the side-chain of the trans(E)-isomer stayed closer to the central S-C axis of the ring system than did the side-chain of the cis(Z)-isomer. The molecular electrostatic potentials were significantly lower in the vicinity of the chlorine atom in the trans(E)- than in the cis(Z)-isomer. Differences in molecular electrostatic potentials and in three-dimensional structure are suggested to be the main reasons for the difference in pharmacological activities of cis(Z)- and trans(E)-chlorprothixene.
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