STEREOSELECTIVITY OF THE CARBONYL REDUCTION OF DOLASETRON IN RATS, DOGS, AND HUMANS

The initial step in the metabolism of dolasetron or MDL 73,147EF [(2 a lpha, 6 alpha, 8 alpha, 9a beta)-octahydro-3-oxo-2, 6-methano-2H-quino lizin-8-yl 1H-indol-3-carboxylate, monomethanesulfonate] is the reduct ion of the prochiral carbonyl group to give a chiral secondary alcohol ''reduced dolasetron.'' An HPLC method, using a chiral column to sepa rate reduced dolasetron enantiomers, has been developed and used to me asure enantiomers in urine of rats, dogs, and humans after dolasetron administration, In all cases, the reduction was enantioselective for t he (+)-(R)-enantiomer, although the dog showed lower stereoselectivity , especially after iv administration. An approximate enantiomeric rati o (+/-) of 90:10 was found in rat and human urine, The contribution of further metabolism to this enantiomeric ratio was considered small as preliminary studies showed that oxidation of the enantiomeric alcohol s by human liver microsomes demonstrated only minor stereoselectivity, Further evidence for the role of stereoselective reduction in man was obtained from in vitro studies, where dolasetron was incubated with h uman whole blood. The enantiomeric composition of reduced dolasetron f ormed in human whole blood was the same as that found in human urine a fter administration of dolasetron. Enanitioselectivity was not due to differences in the absorption, distribution, metabolism, or excretion of enantiomers, as iv or oral administration of rac-reduced dolasetron to rats and dogs lead to the recovery, in urine, of essentially the s ame enantiomeric composition as the dose administered, It is fortuitou s that the (+)-(R)enantiomer is predominantly formed by carbonyl reduc tase, as it is the more active compound. (C) 1995 Wiley-Liss, Inc.