[Pharmacokinetics and Metabolic Activations of Drugs in Pharmacology and Toxicology].

Authors

Hiroshi Yamazaki

Published in

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. Volume 146. Issue 10. Pages 843-864.

Abstract

The parameters for the absorption, distribution, and metabolic clearance of a wide array of chemicals can be calculated and integrated into a physiologically based pharmacokinetic (PBPK) model that simulates plasma drug concentration over time. Typically, pharmacological and toxicological assessments of chemicals involve estimating human clearance through allometric extrapolation from in vivo rat profiles using empirical compartmental and PBPK models. For patients with genetically impaired cytochrome P450 (P450 or CYP) enzymes who are prescribed only certain drugs, moderate plasma exposure should be noted as a precaution on drug labels, as genetic variants can cause changes in blood concentrations similar to those caused by drug-drug interactions. Many drug oxidations are facilitated by species-specific and polymorphic P450 enzymes and flavin-containing monooxygenases (FMOs). Although interaction study alerts are triggered by a 1.25-fold increase in the clearance of the object drug or the metabolite/parent concentration ratio, such increases may fall within the range of intrinsic baseline variation in vivo of cytochrome CYP3A-dependent phenotypes. The metabolic capacity of polymorphic FMO3 was assessed through urine testing for the levels of food-derived trimethylamine N-oxide. Human PBPK model input parameters for various compounds have been effectively estimated using in silico-generated chemical descriptors and machine learning tools to assess internal exposure in humans without relying on experimental data. This pharmacokinetic modeling approach, which incorporates polymorphic drug-metabolizing enzyme information, can be applied in clinical settings and during computational data-driven evaluations of the potential risks associated with a broad spectrum of chemicals.

PMID:
42816351
Bibliographic data and abstract were imported from PubMed on 01 Oct 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.