Title:Plasma Concentration Profiles for Hepatotoxic Pyrrolizidine Alkaloid
Senkirkine in Humans Extrapolated from Rat Data Sets Using a Simplified
Physiologically Based Pharmacokinetic Model
Volume: 15
Issue: 1
Author(s): Yusuke Kamiya, Tomonori Miura, Airi Kato, Norie Murayama, Makiko Shimizu and Hiroshi Yamazaki*
Affiliation:
- Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo
194-8543, Japan
Keywords:
PBPK modeling, allometric scaling, hepatotoxin, HepaRG, P. japonicus, toxins.
Abstract:
Aim: The main aim of the current study was to obtain forward dosimetry assessments of
pyrrolizidine alkaloid senkirkine plasma and liver concentrations by setting up a human physiologically
based pharmacokinetic (PBPK) model based on the limited information available.
Background: The risks associated with plant-derived pyrrolizidine alkaloids as natural toxins have
been assessed.
Objective: The pyrrolizidine alkaloid senkirkine was investigated because it was analyzed in a European
transcriptomics study of natural hepatotoxins and in a study of the alkaloidal constituents of
traditional Japanese food plants Petasites japonicus. The in silico human plasma and liver concentrations
of senkirkine were modeled using doses reported for acute-term toxicity in humans.
Methods: Using a simplified PBPK model established using rat pharmacokinetic data, forward
dosimetry was conducted. Since in vitro rat and human intrinsic hepatic clearances were similar; an
allometric scaling approach was applied to rat parameters to create a human PBPK model.
Results: After oral administration of 1.0 mg/kg in rats in vivo, water-soluble senkirkine was absorbed
and cleared from plasma to two orders of magnitude below the maximum concentration in 8
h. Human in silico senkirkine plasma concentration curves were generated after virtual daily oral
administrations of 3.0 mg/kg senkirkine (the dose involved in an acute fatal hepatotoxicity case). A
high concentration of senkirkine in the culture medium caused in vitro hepatotoxicity as evidenced
by lactate dehydrogenase leakage from human hepatocyte-like HepaRG cells.
Conclusion: Higher virtual concentrations of senkirkine in human liver and plasma than those in
rat plasma were estimated using the current rat and human PBPK models. Current simulations
suggest that if P. japonicus (a water-soluble pyrrolizidine alkaloid-producing plant) is ingested daily
as food, hepatotoxic senkirkine could be continuously present in human plasma and liver.
