Metabolic profiles for the pyrrolizidine alkaloid neopetasitenine and its metabolite petasitenine in humans extrapolated from rat <i>in vivo</i> and <i>in vitro</i> data sets using a simplified physiologically based pharmacokinetic model

Abstract

Naturally occurring food substances may constitute safety hazards. The risks associated with plant-derived pyrrolizidine alkaloids have been extensively evaluated. Petasites japonicus (common Japanese name, fuki) is a widely consumed water-soluble pyrrolizidine alkaloid-producing plant. In this study, neopetasitenine (acetylfukinotoxin) was selected as a model food substrate (for which human pharmacokinetics were estimated) because of its high concentration in fuki, along with petasitenine (fukinotoxin), its carcinogenic deacetylated metabolite. Although neopetasitenine was rapidly absorbed and converted to petasitenine after oral administration of 1.0 mg/kg in rats, petasitenine was slowly cleared from plasma. Forward dosimetry was conducted using in silico simplified physiologically based pharmacokinetic (PBPK) modeling formulated on experimental pharmacokinetic rat data. From ~2 hr after the oral administration of neopetasitenine in rats, the plasma concentrations of petasitenine were higher than those of neopetasitenine under the present conditions. A human PBPK model was established following an allometric scaling approach applied to rat parameters (without considering interspecies factors) to estimate human intrinsic hepatic clearances from empirical rat values. Human in silico neopetasitenine and petasitenine plasma concentration curves were simulated after daily oral administrations of 3.0 and 1.3 mg/kg neopetasitenine. These doses were taken from reported acute/short-term cases of pyrrolizidine alkaloid toxicity. In vitro hepatotoxicity of neopetasitenine and petasitenine was caused by their high concentrations in the medium for human hepatocyte-like cell line HepaRG cells as an index of lactate dehydrogenase leakage. Neopetasitenine was estimated to be rapidly absorbed and converted to deacetylated carcinogenic petasitenine, even after hepatotoxic doses of 1.0 mg/kg in humans. If the water-soluble pyrrolizidine alkaloid-producing plant P. japonicus were daily consumed as food, current simulation results suggest that dangerous amounts of deacetylated petasitenine could be continuously present in human plasma.

Updated <i>in Silico</i> Prediction Methods for Fractions Absorbed and Key Input Parameters of 355 Disparate Chemicals for Physiologically Based Pharmacokinetic Models for Time-Dependent Plasma Concentrations after Virtual Oral Doses in Humans

“…In the past, human metabolic profiles for substances such as food-derived pyrrolizidine alkaloids (e.g., neopetasitenine, its metabolite petasitenine, and senkirkine) were allometrically extrapolated from rat in vivo and in vitro datasets. 28,29) If human internal exposures of a diverse range of compounds could be generated without any reference to experimental pharmacokinetic data by using PBPK models with in silico-generated input parameters (based on in silico chemical descriptors), it would greatly facilitate and simplify forward dosimetry after virtual oral administrations for application in fields such as risk assessment and drug development. In the current study, simplified PBPK models using three sets of input parameters (in vivo-derived values 13,30) and in silico-derived values based on our previous 25) and herein updated systems) were used to estimate three sets of human plasma (and tissue) concentrations after virtual oral administrations for an enlarged panel of 355 chemicals and 10 secondary medicines.…”

“…Traditionally, the human metabolic profiles for substances such as food-derived toxic compounds were allometrically extrapolated from rat concentration profiles determined in vivo. 28,29) We previously used the current approach to PBPK modeling with in silico estimation of input parameters to generate virtual concentrations in plasma (and in tissues) after oral doses of 323 chemicals in rats. We could successfully generate PBPK model input parameters for rat models calculated from a small number of chemical properties by machine-learning prediction tools.…”

Revisiting Migraine: The Evolving Pathophysiology and the Expanding Management Armamentarium

“…It is reported to cause reversible fetal or neonatal bradycardia [79][80][81][82][83][84][85][86][87][88][89].…”

“…It is also well tolerated and effective in children and teenagers at lower doses [ 82 ]. Further monitoring of the liver profile is important due to its metabolic effect on the liver when taken for a longer duration at a higher dose [ 83 ]. Feverfew ( Tanacetum parthenium ) has shown better results than a placebo in a few studies when given thrice daily in a patient with mild migraine at a dose of 6.25 mg [ 84 , 85 ].…”