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 (CL) parameters for unbound drug in the liver, and these are regulated by the liver-to-plasma partition coefficients (K). Both Poulin and Theil and Rodgers and Rowland have proposed in silico expressions for K for a variety of chemicals. In this study, two sets of in silico K values for 14 model substances were assessed using experimentally reported in vivo steady-state K data and time-dependent virtual internal exposures in the liver and plasma modeled by forward dosimetry in rats.

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.

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.