Simultaneous sustained release of fludarabine monophosphate and Gd-DTPA from an interstitial liposome depot in rats: potential for indirect monitoring of drug release by magnetic resonance imaging.
BACKGROUND
Cytostatic depot preparations are interstitially administered for local chemotherapy and prevention of tumor recurrence. It would be of interest to monitor in patients as to when, to what extent, and exactly where, the drug is actually released. Liposomes containing a hydrophilic cytostatic and a hydrophilic contrast agent might be expected to release both agents simultaneously. If so, then drug release could be indirectly followed by monitoring contrast enhancement at the injection site.


METHODS
Multivesicular liposomes containing the antimetabolite fludarabine monophosphate and the magnetic resonance imaging (MRI) contrast agent Gd-DTPA were subcutaneously injected in rats and both agents were monitored at the injection site for 6 weeks by 19F nuclear magnetic resonance spectroscopy (MRS) in vivo and contrast-enhanced 1H MRI (T1w 3D FLASH), respectively, in a 1.5-T whole-body tomograph. The MRS and MRI data were analyzed simultaneously by pharmacokinetic modeling using NONMEM.


RESULTS
During an initial lag time, the amount of drug at the injection site stayed constant while the contrast-enhanced depot volume expanded beyond the volume injected. Drug amount and depot volume then decreased in parallel. Lag time and elimination half-life were 9 and 6 days, respectively, in three animals, and were about 50% shorter in another animal where the depot split into sub-depots.


CONCLUSIONS
The preliminary data in rats suggest that simultaneous release of a hydrophilic cytostatic and a hydrophilic contrast agent from an interstitial depot can be achieved by encapsulation in liposomes. Thus, there seems to be a potential for indirect drug monitoring through imaging.
Port
Ruediger E
RE
Unit Pharmacology of Cancer Treatment, Department of Medical Physics in Radiology, German Cancer Research Center, 69009, Heidelberg, Germany.
Schuster
Christian
C
Port
Christa R
CR
Bachert
Peter
P
D000465:Algorithms; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics; D001682:Biological Availability; D003287:Contrast Media / Q000008:administration & dosage / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods; D016903:Drug Monitoring / Q000379:methods; D005461:Fluorine; D019786:Gadolinium DTPA / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006859:Hydrogen; D007279:Injections, Subcutaneous; D008081:Liposomes; D008279:Magnetic Resonance Imaging / Q000379:methods; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D001084:Vidarabine Phosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D000964:Antimetabolites, Antineoplastic; D003287:Contrast Media; D003692:Delayed-Action Preparations; D008081:Liposomes; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate; D005461:Fluorine; D006859:Hydrogen; D019786:Gadolinium DTPA