Pharmacokinetics of intravenously injected [3H]tetrachloro(D,L-trans)1,2-diaminocyclohexane platinum (IV) (tetraplatin) in mice.
Platinum (Pt) complexes with diaminocyclohexane (DACH) carrier ligand are of interest because of their effectiveness against tumor cells resistant to cisplatin. We examined the pharmacokinetics and in vivo stability of Pt-N bond of tetraplatin using radiolabeled drug containing the 1,2-[4,5-3H]diaminocyclohexane ([3H]DACH) moiety and monitored the ratio 3H:Pt in biological samples. Following intravenous administration of [3H]tetraplatin (5 mg/kg and 163 microCi/kg) in mice, blood, urine, and tissue samples were collected and analyzed for both Pt level and radioactivity using flameless atomic absorption spectrophotometry and scintillation counting, respectively. In plasma, half-lives of 5 min (alpha-phase) and 1 hr (beta-phase) were generated for both "free" 3H and Pt. The 3H:Pt ratio of "free" levels did not change for at least 2 hr after intravenous administration. This indicated that the Pt-N bond was largely intact in the free drug fraction over this time period. In blood and plasma, however, there were decreases in "total" 3H:Pt ratios by 21 and 13% over 2 hr and 38 and 51% over 4 days, respectively, as a result of a greater rate of elimination of 3H than Pt. Urinary excretion in mice of 3H and Pt accounted for 55 and 43% of the administered dose, respectively, in 4 days, with 35 and 30% being excreted in the first 7 hr. The 3H:Pt ratio in urine increased 1.4-fold between 7 and 72 hr, and this was a further indication of dissociation of DACH ligand from Pt. Tissue distribution study revealed that the DACH moiety was also being removed more rapidly, and this was particularly evident in the liver and spleen than in other tissues.
Department of Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
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Kido
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Khokhar
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Siddik
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014316:Tritium
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D014316:Tritium; C049777:ormaplatin