Liver and Plasma Concentrations of Food Chemicals after Virtual Oral Doses Extrapolated Using in Silico Estimated Input Pharmacokinetic Parameters to Confirm Reported Liver Toxicity in Rats.

The estimation of health risks of chemical substances was historically investigated using animal studies; however, current research focuses on reducing the number of animal experiments. The toxicity of chemicals in fish screening systems is reportedly correlated with their hydrophobicity. The inverse relationship between absorption rates (intestinal cell permeability) and virtual hepatic/plasma pharmacokinetics of diverse chemicals has been previously evaluated by modeling oral administration in rats. In the current study, internal exposures, i.e., virtual maximum plasma concentrations (Cmax) and areas under the concentration-time curves (AUC), of 56 food chemicals with reported hepatic lowest-observed-effect levels (LOELs) of ≤1000 mg/kg/d in rats were pharmacokinetically modeled using in silico estimated input pharmacokinetic parameters. After a virtual single oral dose of 1.0 mg/kg of 56 food chemicals, the output Cmax and AUC values in rat plasma generated by modeling using the corresponding in silico estimated input parameters were not significantly correlated with the reported hepatic LOEL values. However, significant inverse relationships between hepatic/plasma concentrations of selected lipophilic food chemicals (i.e., octanol-water partition coefficient log P > 1) using forward dosimetry and reported LOEL values (≤300 mg/kg/d) were observed (n = 14, r=-0.52-0.66, p ≤ 0.05). This simple modeling approach, which uses no experimental pharmacokinetic data, has the potential to play a significant role in reducing the use of animals to estimate toxicokinetics or internal exposures of lipophilic food components after oral doses. Therefore, these methods are valuable for estimating hepatic toxicity by using forward dosimetry in animal toxicity experiments.

Modeled Rat Hepatic and Plasma Concentrations of Chemicals after Virtual Administrations Using Two Sets of in Silico Liver-to-Plasma Partition Coefficients.

The hepatic elimination of chemical substances in pharmacokinetic models requires hepatic intrinsic clearance (CLh,int) parameters for unbound drug in the liver, and these are regulated by the liver-to-plasma partition coefficients (Kp,h). Both Poulin and Theil and Rodgers and Rowland have proposed in silico expressions for Kp,h for a variety of chemicals. In this study, two sets of in silico Kp,h values for 14 model substances were assessed using experimentally reported in vivo steady-state Kp,h data and time-dependent virtual internal exposures in the liver and plasma modeled by forward dosimetry in rats. The Kp,h values for 14 chemicals independently calculated using the primary Poulin and Theil method in this study were significantly correlated with those obtained using the updated Rodgers and Rowland method and with reported in vivo steady-state Kp,h data in rats. When pharmacokinetic parameters were derived based on individual in vivo time-dependent data for diazepam, phenytoin, and nicotine in rats, the modeled liver and plasma concentrations after intravenous administration of the selected substrates in rats using two sets of in silico Kp,h values were mostly similar to the reported time-dependent in vivo internal exposures. Similar results for modeled liver and plasma concentrations were observed with input parameters estimated by machine-learning systems for hexobarbital, fingolimod, and pentazocine, with no reference to experimental pharmacokinetic data. These results suggest that the output values from rat pharmacokinetic models based on in silico Kp,h values derived from the primary Poulin and Theil model would be applicable for estimating toxicokinetics or internal exposure to substances.

Plasma and Hepatic Exposures of Celecoxib and Diclofenac Prescribed Alone in Patients with Cytochrome P450 2C9*3 Modeled after Virtual Oral Administrations and Likely Associated with Adverse Drug Events Reported in a Japanese Database.

The impacts of polymorphic cytochrome P450 (P450 or CYP) 2C9 on drug interactions and the pharmacokinetics of cyclooxygenase inhibitors have attracted considerable attention. In this survey, the prescribed dosage was reduced or discontinued in 150 and 56 patients, respectively, receiving celecoxib and diclofenac prescribed alone, as recorded in a Japanese database of adverse drug events. Among the factors underlying adverse events, intrinsic drug clearance rates may be a contributing factor. The pharmacokinetically modeled plasma concentrations of celecoxib after an oral 200-mg dose increased in CYP2C9*3 homozygotes: the area under the plasma concentration curve was 4.7-fold higher than that in CYP2C9*1 homozygotes. In patients with CYP2C9*3/*3, the virtual hepatic concentrations of diclofenac after three daily 25-mg doses for a week were 11-fold higher than the plasma concentrations in subjects with CYP2C9*1/*1. The in vivo and in vitro fractions of the victim drug metabolized by a specific polymorphic P450 form is an important determining factor for estimating drug-drug interactions. Virtual hepatic and plasma exposures estimated by pharmacokinetic modeling in patients harboring the impaired CYP2C9*3 allele could represent a causal factor for adverse events induced by celecoxib or diclofenac in a manner similar to that for drug interactions.