Stereoselectivity of the carbonyl reduction of dolasetron in rats, dogs, and humans

Abstract

The initial step in the metabolism of dolasetron or MDL 73,147EF [(2 alpha, 6 alpha, 8 alpha, 9a beta)-octahydro-3-oxo-2,6-methano-2H- quinolizin-8-yl 1H-indol-3-carboxylate, monomethanesulfonate] is the reduction of the prochiral carbonyl group to give a chiral secondary alcohol "reduced dolasetron." An HPLC method, using a chiral column to separate reduced dolasetron enantiomers, has been developed and used to measure enantiomers in urine of rats, dogs, and humans after dolasetron administration. In all cases, the reduction was enantioselective for the (+)-(R)-enantiomer, although the dog showed lower stereoselectivity, especially after iv administration. An approximate enantiomeric ratio (+/-) 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 alcohols 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 human whole blood. The enantiomeric composition of reduced dolasetron formed in human whole blood was the same as that found in human urine after administration of dolasetron. Enantioselectivity 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 same enantiomeric composition as the dose administered. it is fortuitous that the (+)-(R)-enantiomer is predominantly formed by carbonyl reductase, as it is the more active compound.

Human Carbonyl Reduction Pathways and a Strategy for Their Study In Vitro

“…This raises the issue of stereochemical metabolic coverage across species in the drug development process. Differences in the stereochemistry of reduction have been noted between human and animal metabolism for some compounds (Benedetti et al, 1991(Benedetti et al, , 1993Dow and Berg, 1995;Vickers et al, 1993;Weil et al, 1989;Wsól et al, 1998a). Thus, the occurrence of this metabolic pathway requires that a decision be made about the timing for development of a chiral assay for the metabolite.…”

“…The outcome of pharmacokinetic studies with this derivative of benfluron has not yet been reported. In a different example, carbonyl reduction was the mode of activation of the prodrug dolasteron (Anzemet) to the antiemetic, hydrodolasetron (Dow and Berg, 1995). When administered orally, only the reduced dolasetron was quantifiable in plasma; when administered intravenously, the parent drug was rapidly cleared from plasma and could be measured for only 2 to 4 hr after dosing (Boxenbaum et al, 1992(Boxenbaum et al, , 1993Shah et al, 1995).…”

“…The stereochemistry of ketone reduction has been reported for a number of xenobiotics (Asami et al, 1996;Benedetti et al, 1991Benedetti et al, , 1993Breyer-Pfaff and Nill, 1995;Dow and Berg, 1995;Eyles and Pond, 1992;Hermans and Thijssen, 1989;Kume et al, 2000;Lawrence et al, 1990;McMahon et al, 1965;Nagata et al, 1992;Nicklasson et al, 2002;Rush et al, 1990;Skálová et al, 2003;Takasaki and Tanaka, 1992;Vickers et al, 1993;Volosov et al, 1999;Weil et al, 1989;Wsól et al, 1998a). However, the absolute configuration has not been determined in all cases.…”

Intravenous pharmacokinetics and absolute oral bioavailability of dolasetron in healthy volunteers: part 1

“…The reduced alcohol formed by this conversion, hydrodolasetron, contains a chiral carbon center. In a study that measured the enantiomers of hydrodolasetron in urine of rats, dogs, and humans following intravenous and oral administration of dolasetron, the conversion of achiral dolasetron to chiral hydrodolasetron was found to be stereoselective, with the R(+ ) enantiomer accounting for the majority (\ 90%) of hydrodolasetron excreted in human urine [11]. Therefore, a final objective was to determine the pharmacokinetic profiles of R(+ ) and S(− )-hydrodolasetron following both intravenous and oral administration of dolasetron based on plasma concentration determinations, as well as urinary excretion profiles.…”

Chiral aspects of metabolism of antiinflammatory drug flobufen in human hepatocytes

“…4 Both stereoselectivity and stereospecificity of reduction has been observed with warfarin and its analogs, 5 ketotifen, oxonortriptyline, 6 and dolasetron. 7 Monitoring the stereospecificity of reduction enabled the detection of the participation of two different enzyme systems in the reduction of 4-phenyl-3-butyn-2-one 8 and haloperidol. 9 Many nonsteroidal antiinflammatory drugs (NSAID) belong to important groups of chiral drugs.…”