Multivariate analysis of experimental and computational descriptors of molecular lipophilicity.

Two experimental (log P, R(Mw)) and 17 calculation descriptors for molecular lipophilicity (fragmental, atom-based or based on molecular properties) were investigated by multvariate analysis for a database of 159 compounds including both simple structures as well as more complex drug molecules. Principal component analysis (PCA) of the entire database exhibits a clustering of chemical groups; preciseness of clustering corresponds to chemical similarity. Thus, diversity searching in databases might effectively be performed by PCA on the basis of calculated log P. The comparative validity check of experimental and computational procedures by regression analysis and PCA was performed with a chemically balanced, reduced data set (n = 55) representing 11 chemical groups with 5 members each. Regression of experimental descriptors (log Poct versus RMW) proves that chromatographic data, obtained under well-defined experimental conditions, can be used as valid substitutes for log P. Regression of calculated versus experimental lipophilicity data shows a superiority of fragmental over atom-based methods and approaches based on molecular properties, as indicated by correlation coefficients, slopes and intercepts. In addition, PCA revealed that fragmental methods (Rekker-type, KOWWIN, KLOGP) sense the compound ranking in log P data to almost the same extent as experimental approaches. For atom-based procedures and CLOGP, both the comparability of absolute values and the sensing of the compound ranking in the database are slightly less. This trend is more pronounced for the methods based on molecular properties, with the exception of BLOGP.

Comparative evaluation of the predictive power of calculation procedures for molecular lipophilicity.

The predictive power of four calculation procedures for molecular lipophilicity is checked by comparing with experimental data (log P and chromatographical RMw) taken from the literature. Two sets of test compounds are used: the first comprises simple organic molecules and the second consists of more complicated drug molecules. Our comparative evaluation leads us to conclude that the predictive power is significantly better for not too complicated organic molecules than for drugs with complicated structural pattern. The four investigated calculation procedures should be arranged in two groups with significantly differing predictive power: (a) Rekker and Hansch/Leo and (b) Ghose/Crippen and Suzuki/Kudo. This conclusion is based on a statistical control using log P and RMw as the independent parameters. Correlations have in common: (1) slopes in correlations with calculated data based on fragmental methods are not significantly different from 1; calculations with data from atom-based procedures show up in most cases with slopes below 1. (2) The accompanying overall statistics underline the superiority of the fragmental methods. We think that all four tested calculation procedures have their own restrictions; for future development we would advise a thorough reconsideration of structural effects not fully (or even not at all) incorporated in the data sets. Special attention will have to be paid to the conformational aspects of lipophilic behavior.

Absorption, metabolism and excretion of 14C-sultopride in the rat.

Rats received (14C)-Sultopride (St) in doses of 20 mg/kg by ip. and oral route. After ip.-administration, urinary elimination was 62% of administered dose in 72 hours, fecal excretion, 25% in 96 hours. Conversely, at 120 hours after oral administration, renal elimination was 46% and fecal elimination 34%. From these data 75% absorption of St in rat intestine may be deduced. From total excreted radioactivity (feces plus urine; ip. route) 35% is due to unchanged St. Seven metabolites were isolated from the urine. By comparison of isolated compounds with chemically synthesized putative metabolites using spectrophotometric and radiometric TLC scanning procedures 5 metabolites were identified: O-desmethylated St (DMSt; 20% of total radioactivity excreted), sulfon-desethylated St (SDESt; 13%), 5-pyrrolidine-oxo St (OSt; 3%), the product of hydrolysis of the central amide bond (MESS; 4%) and the secondary metabolite O-desmethyl-oxo St (ODMST; less than 1%). Two metabolites both minor (1% or less), remained unidentified. In guinea-pigs, metabolism of St leads almost exclusively to OSt while in mice, to DMSt.

Studies on the distribution of 14C-sulpiride and its metabolites in the rat and guinea pig.

After ip. injection of 14C-labelled sulpiride in rats, about one third is metabolized while the other two thirds are excreted unchanged in feces and urine. The highest level of its metabolites was found in the liver (about 65% of total radioactivity). In the brain, 90% of the radioactivity consisted of unchanged sulpiride, which seems to be responsible for the central effects of the drug. The highest concentrations within the brain were found in the median eminence, circumventricular organs, plexus, and pineal body.

The metabolites of 14C-sulpiride in the rat.

The elimination of total radioactivity after i.p. application of carbonyl-14C-labelled sulpiride (SP) was estimated in urine and feces. An average of 30% of administered radioactivity was found in feces, 50% in urine. By preparative thin-layer chromatography of urine SP and five metabolites were isolated. On the basis of chromatographic-spectrophotometric comparisons to synthesized standards four metabolites were identified: O-desmethyl-SP, 5-oxo-pyrrolidine-SP, N-desethyl-SP and O-desmethyl-5-oxo-pyrrolidine-SP. The chemical structure of one metabolite could not be established.

[The relevance of anticholinesterase properties to toxicity and neuromuscular effects of sulpiride (author's transl)]. / Die Bedeutung der cholinesterasehemmendren Eigenschaften für Toxizität und neuromuskuläre Wirkungen von Sulpirid

N-[(1-Ethyl-pyrrolidin-2-yl)-methyl]-2-methoxy-5-sulf-amoyl-benzamide (sulpiride, Dogmatil) inhibits acetylcholinesterase of rat brain in a mixed-type manner (Ki 0.3 mM; Ki 1.8 mM) as well as serum cholinesterase of the rat competitively (Ki 0.37 mM). Using acetylthiocholine in concentrations below 0.1 mM and purified enzyme from Electrophorus, reaction becomes first-order kinetics. At 35 micronM sulpiride doubles half-life and is without effects below 3.5 micronM. Hydrolysis of acetylthiocholine in homogenates of stomach muscle from rats is not affected by sulpiride up to 20 micronM. Pretreatment of mice with 5 mg atropine/kg i.p. decreases i.p. LD50 of sulpiride to 67% of controls. The conclusion is drawn that neither toxicity nor hypermotility of stomach seen after sulpiride by other authors is due to the cholinesterase inhibiting properties of sulpiride.