Preparative HPLC separation of bambuterol enantiomers and stereoselective inhibition of human cholinesterases.

Ivana Gazić, Anita Bosak, Goran Sinko, Vladimir Vinković, Zrinka Kovarik

Analytical and bioanalytical chemistry 2006 Aug

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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.

Citation

Ivana Gazić, Anita Bosak, Goran Sinko, Vladimir Vinković, Zrinka Kovarik. Preparative HPLC separation of bambuterol enantiomers and stereoselective inhibition of human cholinesterases. Analytical and bioanalytical chemistry. 2006 Aug;385(8):1513-9