Comparative Pharmacokinetics\nand Tissue Distribution\nof Hexahydrocurcumin Following Intraperitoneal vs Oral Administration\nin Mice Using LC-MS/MS

A liquid chromatography-tandem mass spectrometry (LC-MS/MS)\nmethod\nwas developed and validated to determine hexahydrocurcumin (HHC) levels\nin mouse plasma, brain, liver, and kidneys using a negative ion mode\nelectrospray ionization (ESI) source. Demonstrating a lower limit\nof quantification (LLOQ) of 5 ng/mL, the method showed excellent linearity\nacross a concentration range of 5–500 ng/mL in all tested matrices.\nPrecision evaluations reported a coefficient of variation (CV%) of\nless than 13.19% for both intraday and interday measurements, while\naccuracy ranged from 95.13 to 105.07% across all quality control levels.\nHHC extraction recovery was consistently observed between 70.18 and\n93.28%, with a CV% deviation of less than 15%. In the pharmacokinetic\nevaluation of HHC in mice following a single intraperitoneal (IP)\nor oral administration, a noncompartment analysis was utilized. After\nIP administration (40 mg/kg), the <i>C</i><sub>max</sub> value was 47.90 times higher than that achieved via oral administration.\nPeak plasma concentrations were observed approximately 5 min post-IP\nand 15 min post-oral dosing. The observed half-lives after these administrations\nwere approximately 1.52 and 2.17 h for IP and oral routes, respectively.\nOral administration revealed a relative bioavailability of only 12.28%\ncompared with the IP route. Furthermore, following IP administration,\nthe half-life values in brain, liver, and kidney were not significantly\ndifferent but more than the half-life value found in plasma. The liver\nand kidney exhibited the highest concentrations of HHC, while the\nbrain showed the least, suggesting that the hydrophobic nature of\nHHC impedes its passage through the blood–brain barrier. This\nstudy is the first to provide detailed insights into the pharmacokinetics\nand tissue distribution characteristics of HHC following oral and\nIP administration in mice, setting the stage for further focus on\nHHC as a potential new drug candidate.