The Synthesis and Pharmacokinetics of a Novel Liver-Targeting Cholic Acid-Conjugated Carboplatin in Rats.

A novel cholic acid-conjugated carboplatin (CP-CA) is developed as a liver-targeting prodrug of carboplatin (CP) for liver cancer. Instead of using CP as a raw material, CP-CA was synthesized simultaneously. This paper is focused on the comparison of CP-CA and CP with respect to their pharmacokinetic (PK) and tissue distribution profiles in rats after their intravenous administration. Additionally, their uptake by human liver tumor cell Huh7 and normal human liver cell HL7702 are investigated. The inductively coupled plasma mass spectrometry (ICP-MS) method is applied for the determination of platinum in plasma, tissues, and cells. The PK results show that both the AUC_0–t and AUC_0–∞ data on Pt for CP-CA are significantly higher than those for CP (p < 0.01), indicating that the plasma exposure of CP-CA is significantly higher than that of CP. The CL₁, Vd₁, and Vd₂ data on Pt for CP-CA are significantly lower than those for CP (p < 0.01), while the MRT_0–t is significantly higher (p < 0.01), which is possibly related to a higher PPBR, and can strongly support the higher AUC_0–t and AUC_0–∞ of Pt for CP-CA compared to for CP. The tissue distribution results show that CP-CA is mainly distributed and accumulated in the liver after its intravenous administration to rats, revealing its liver-targeting profile. Compared to CP, CP-CA is more easily taken up by human liver cancer cells and normal human liver cells. The results suggest that CP-CA has a potential for further development as a new prodrug specific to liver cancer. [ABSTRACT FROM AUTHOR]