ENANTIOSELECTIVE BIOTRANSFORMATION OF THE CHIRAL ANTIHISTAMINIC DRUG DIMETHINDENE IN HUMANS AND RATS

The biotransformation of dimethindene (CAS 5636-83-9, dimethindene mal eate, CAS 3614-69-5) after oral administration was determined in urine using an HPLC gradient method. Besides the phase I metabolites the co njugates of the hydroxylated metabolites with glucuronic and/or sulfur ic acid were quantitatively determined after enzymatic deconjugation. The cumulative excretion of 6-hydroxydimethindene and 6-hydroxy-N-deme thyldimethindene in human urine after hydrolysis of the conjugates ran ged from 18 to 23 % of the administered dose, independent of the amoun t of the dose applied. The results indicate that conjugated 6-hydroxyd imethindene is the main metabolite of dimethindene. Increasing doses o f 5 to 20 mg dimethindene maleate did not affect the relative amount o f the excreted metabolites but changed the ratio of 6-hydroxydimethind ene to 6-hydroxy-N-demethyldimethindene from 3 : 1 to 1 : 1. In rats a bout 4 to 8 % of the administered dose of dimethindene was excreted as dimethindene-N-oxide which is the main metabolite in rat urine. After administration of R-(-)-dimethindene the elimination of all metabolit es was 2 to 3 fold higher compared to the administration of the S-(+)- enantiomer. By chiral HPLC, in 10 human volunteers a stereoselective e limination of N-demethyl-dimethindene after oral administration of rac emic dimethindene with the predominant excretion of the R-(-)-enantiom er was observed.