Pharmacokinetic-stereoselective differentiation of some isomeric analogues of ifosfamide

Three bromine-ifosfamide analogues: racemic chlorobromofosfamide (+/-)-(R,S)-1, its levorotatory enantiomer (-)-(S)-2 and racemic bromofosfamide (+/-)-(R,S)-3 showed considerable stereoselective differences in their pharmacokinetics and bioavailability depending on the route of administration and regimen of dosage studies in rats. Remarkable differences in the AUCi.p. parameters (212, 54, 89 mumol x min x ml-1, respectively) were demonstrated in comparison with a standard ifosfamide (158 mumol x min x ml-1). However, the AUCp.o. established for (+/-)-(R,S)-1 and (-)-(S)-2 were similar and different from the value measured for (+/-)-(R,S)-3. A wide variability in the determined parameters after i.p. injection and similarities after p.o. administration were finally confirmed by the AUCp.o./AUCi.p. mean ratio which equaled 0.24; 0.79;, 0.54, respectively, as well as by different bioavailability data. The results showed that the pharmacokinetic bioequivalance between i.v. and p.o. treatment is possible to approach by adjustment of fractionated oral dosage.