Metabolism of dimetindene in rats.
The preparative separation of dimetindene (CAS 5636-83-9) enantiomers was achieved by fractionated crystallization of the diastereomeric tartrate salts. HPLC on alpha-AGP (alpha 1-acid glycoprotein) was used for confirmation of the enantiomeric purity. After administration of the enantiomers to rats the AUC and Cmax of S(+) dimetindene and (-)N-demethyldimetindene were slightly increased. In agreement with the serum concentration data significantly more (-)N-demethyldimethindene was excreted into urine after administration of the individual enantiomers. S(+) dimetindene was metabolised to a lesser extent in vivo (see above) as well as in vitro in rat liver homogenate. After prior enzyme induction conversion of the enantioselectivity with respect to unmetabolised dimetindene occurred. 6-Methoxydimetindene, 6-hydroxydimetindene and 6-hydroxy-N-demethyldimetindene were synthesized. 6-Methoxydimetindene is likely to be a metabolite since the retention times of synthetic compound and the substance extracted from serum and urine are identical. The formation of 6-hydroxy-N-demethyldimetindene was proved for the first time by comparison of the mass spectra of metabolite isolated from in vitro incubations and synthetic compound after derivatisation with acetic anhydride.
Radler
S
S
Institut für Pharmazeutische Chemie, Universität Münster, Germany.
Wermeille
M
M
Blaschke
G
G
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004115:Dimethindene / Q000378:metabolism* / Q000493:pharmacokinetics; D006634:Histamine H1 Antagonists / Q000378:metabolism* / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D006634:Histamine H1 Antagonists; D004115:Dimethindene