Ifosfamide pharmacokinetics and hepatobiliary uptake in vivo investigated using single- and double-resonance 31P MRS.

Abstract

MRS has considerable potential for the measurement of drug pharmacokinetics in vivo. In this study single- and double-resonance (31)P MRS was used to investigate the biodistribution, pharmacokinetics, and metabolism of ifosfamide following administration of 500 mg/kg ifosfamide in guinea pigs. (1)H-decoupling was found to nearly double the signal of detected peaks. However, in contrast to studies of ifosfamide in solution, the polarization transfer sequence gave no further signal enhancements. This was attributed to significantly reduced relaxation times in vivo. Chemical shift imaging (CSI) measurements showed that significant proportions of ifosfamide-related (31)P MRS signals arose from the liver, as expected, but also from the gall bladder, which was not predicted from the current literature. Signals were observed within 5 min of the end of administration. The halflife in liver was approximately 74 min, whereas in gall bladder there was no measurable signal decay during the 2.5-hr studies. High-resolution (31)P MRS of bile showed that the "ifosfamide" peak in vivo consists of at least two compounds. The lower-concentration peak is ifosfamide, and an investigation is under way to identify the higher-concentration peak. Other peaks observed in bile are tentatively assigned to carboxy-ifosfamide and dechloroethyl-ifosfamide. Overall, (1)H-decoupled (31)P MRS has proved to be a useful tool for investigating the metabolism of ifosfamide in vivo.