MONITORING LOCAL DISPOSITION KINETICS OF CARBOPLATIN IN-VIVO AFTER SUBCUTANEOUS INJECTION IN RATS BY MEANS OF PT-195 NMR

The anticancer drug carboplatin has been monitored in rats during trea tment by means of in vivo Pt-195 NMR spectroscopy at 2.0 T. The purpos e of the study was to assess local disposition kinetics in intact tiss ue following subcutaneous injection of a platinum-containing drug. Ser ial Pt-195 NMR measurements have been carried out in four animals afte r 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 th e animals). To optimize measurement parameters of the single-pulse-acq uire sequence and to determine chemical shifts and the detection thres hold, in vitro Pt-195 NMR experiments have been performed on model sol utions of potassium tetrachloroplatinate(II), carboplatin, and cisplat in with different solvents such as H2O, DMSO, and DMF. Resonances of P tCI42-, carboplatin, cisplatin, and cis[Pt(NH2)Cl(DMSO)](+) were obser ved at chemical shift positions delta - 1623 ppm, - 1705 ppm, - 2060 p pm (cisplatin in DMSO), and -3120 ppm, respectively, relative to the r eference signal of Na2PtCl6 at delta = 0 ppm. A spin-lattice relaxatio n time of carboplatin of T-1 = (0.103 +/- 0.02) s was measured. The th reshold for NMR detection of platinum-containing compounds estimated f rom the in vitro experiments was 10 mu mol (corresponding to similar t o 4.8 mM). In vivo Pt-195 NMR spectra obtained in four rats after admi nistration of carboplatin showed a broad resonance at delta = -(1715 /- 8) ppm. The signal-to-noise ratio of this peak (starting 2 min afte r the injection) was similar to 9:1 for a measurement time of 6 min (T -R = 13 ms, 28672 transients). The elimination rate constant of local disposition of carboplatin was k(el) = 0.017 (0.008-0.025) min(-1) (me dian and range). (C) 1998 Academic Press.