Enantioselective pharmacokinetics of alpha-fluoromethylhistidine in rats and its comparison with histidine.

The enantiomer-specific pharmacokinetics of histidine and its analogue, alpha-fluoromethylhistidine (FMH), were investigated in rats. After bolus intravenous administration of each enantiomer of histidine or FMH at a dose of 40.3 mg kg-1 as free base equivalents, the plasma concentrations of L-histidine, D-histidine, (S)-FMH and (R)-FMH decreased biexponentially with half-lives of 39.2, 20.8, 32.8 and 25.0 min, respectively, in the elimination phase. Although the concentration of L-histidine in the plasma was lower than that of D-histidine, there was no large difference in plasma concentration-time curves of the enantiomers of FMH. The apparent total clearance of L-histidine from rat plasma was about 4 times that of D-histidine or the enantiomers of FMH. L-Histidine was quickly transferred to the peripheral tissues where the concentrations also decrease biphasically. L-Histidine penetrated more rapidly into the brain than either its D-enantiomer or a compound closely related in structure such as FMH. However, the disappearance of L-histidine from the various brain regions was very rapid. In contrast, brain/plasma ratios of D-histidine and (S)-FMH increased continuously after injection of these compounds, indicating that D-histidine or (S)-FMH partitioned into the brain and was very slowly removed from the brain; (R)-FMH was not distributed to the brain. These results suggested stereoselectivity in disposition of histidine and FMH enantiomers in rats.