Monitoring local disposition kinetics of carboplatin in vivo after subcutaneous injection in rats by means of 195Pt NMR.
The anticancer drug carboplatin has been monitored in rats during treatment by means of in vivo 195Pt NMR spectroscopy at 2.0 T. The purpose of the study was to assess local disposition kinetics in intact tissue following subcutaneous injection of a platinum-containing drug. Serial 195Pt NMR measurements have been carried out in four animals after administration of carboplatin solutions with doses ranging from 37.1 to 59.4 mg per kg body weight. A surface coil of 2 cm diameter tuned to 18.3 MHz was placed over the injection site (back of the neck of the animals). To optimize measurement parameters of the single-pulse-acquire sequence and to determine chemical shifts and the detection threshold, in vitro 195Pt NMR experiments have been performed on model solutions of potassium tetrachloroplatinate(II), carboplatin, and cisplatin with different solvents such as H2O, DMSO, and DMF. Resonances of PtCl2-4, carboplatin, cisplatin, and cis-[Pt(NH2)Cl(DMSO)]+ were observed at chemical shift positions delta = -1623 ppm, -1705 ppm, -2060 ppm (cisplatin in DMSO), and -3120 ppm, respectively, relative to the reference signal of Na2PtCl6 at delta = 0 ppm. A spin-lattice relaxation time of carboplatin of T1 = (0.103 +/- 0.02) s was measured. The threshold for NMR detection of platinum-containing compounds estimated from the in vitro experiments was 10 micromol (corresponding to approximately 4.8 mM). In vivo 195Pt NMR spectra obtained in four rats after administration of carboplatin showed a broad resonance at delta = -(1715 +/- 8) ppm. The signal-to-noise ratio of this peak (starting 2 min after the injection) was approximately 9:1 for a measurement time of 6 min (TR= 13 ms, 28672 transients). The elimination rate constant of local disposition of carboplatin was kel = 0.017 (0.008-0.025) min-1 (median and range).
Becker
M
M
Department of Medical Physics and Biophysics, German Cancer Research Center (dkfz), Heidelberg, Germany.
Port
R E
RE
Zabel
H J
HJ
Zeller
W J
WJ
Bachert
P
P
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D016190:Carboplatin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D002712:Chlorides / Q000737:chemistry; D002945:Cisplatin / Q000737:chemistry; D004121:Dimethyl Sulfoxide; D004126:Dimethylformamide; D004578:Electron Spin Resonance Spectroscopy; D007279:Injections, Subcutaneous; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D009333:Neck; D010984:Platinum; D017671:Platinum Compounds / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D012815:Signal Processing, Computer-Assisted; D012867:Skin / Q000378:metabolism*; D012997:Solvents; D014867:Water
D000970:Antineoplastic Agents; D002712:Chlorides; D017671:Platinum Compounds; D012997:Solvents; D014867:Water; C036919:tetrachloroplatinate; D010984:Platinum; D004126:Dimethylformamide; D016190:Carboplatin; D002945:Cisplatin; D004121:Dimethyl Sulfoxide