Enantioselective biotransformation of the chiral antihistaminic drug dimethindene in humans and rats.
The biotransformation of dimethindene (CAS 5636-83-9, dimethindene maleate, CAS 3614-69-5) after oral administration was determined in urine using an HPLC gradient method. Besides the phase I metabolites the conjugates of the hydroxylated metabolites with glucuronic and/or sulfuric acid were quantitatively determined after enzymatic deconjugation. The cumulative excretion of 6-hydroxydimethindene and 6-hydroxy-N-demethyldimethindene in human urine after hydrolysis of the conjugates ranged from 18 to 23% of the administered dose, independent of the amount of the dose applied. The results indicate that conjugated 6-hydroxydimethindene is the main metabolite of dimethindene. Increasing doses of 5 to 20 mg dimethindene maleate did not affect the relative amount of the excreted metabolites but changed the ratio of 6-hydroxydimethindene to 6-hydroxy-N-demethyldimethindene from 3:1 to 1:1. In rats about 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 metabolites was 2 to 3 fold higher compared to the administration of the S-(+)-enantiomer. By chiral HPLC, in 10 human volunteers a stereoselective elimination of N-demethyl-dimethindene after oral administration of racemic dimethindene with the predominant excretion of the R-(-)-enantiomer was observed.
Prien
D
D
Institute of Pharmaceutical Chemistry, University of Münster, Germany.
Rehn
D
D
Blaschke
G
G
D000328:Adult; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004115:Dimethindene / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D013237:Stereoisomerism
D006634:Histamine H1 Antagonists; D004115:Dimethindene