title: Preparative HPLC separation of bambuterol enantiomers and stereoselective inhibition of human cholinesterases.
abstract: We separated and characterized the enantiomers of bambuterol (5-[-(tert-butylamino)-1-hydroxyethyl]-m-phenylene-bis(dimethylcarbamate) hydrochloride), which is used in racemic form as a prodrug of terbutaline, a beta(2)-adrenoceptor agonist. The enantioseparation was attempted on several chiral HPLC columns, and the most effective separation was achieved on the amylose-based Chiralpak AD column. Since in vivo conversion of bambuterol into terbutaline involves hydrolysis by butyrylcholinesterase (EC 3.1.1.8), we studied the reaction of enantiomers with eight human BChE variants. Both enantiomers inhibited all studied BChE variants; however, the rate of inhibition with the (R)-enantiomer was about five times faster than with the (S)-enantiomer. (R)-bambuterol inhibition rate constants for homozygous usual (UU), fluoride-resistant (FF) or atypical (AA) variant ranged from 6.4 to 0.11 min(-1)microM(-1). The inhibition rates for heterozygotes were between the respective constants for the corresponding homozygotes.
authors.affiliation: Ruder Bosković Institute, Bijenicka cesta 54, 10002, Zagreb, Croatia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Gazić
authors.forename: Anita
authors.initials: A
authors.lastname: Bosak
authors.forename: Goran
authors.initials: G
authors.lastname: Sinko
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vinković
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Kovarik
mesh_terms: D002802:Cholinesterases / Q000187:drug effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D006801:Humans; D013237:Stereoisomerism; D013726:Terbutaline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology
chemical_list: D002802:Cholinesterases; D013726:Terbutaline; C047766:bambuterol