Design and Measurement of Drug Tissue Concentration Asymmetry and Tissue Exposure-Effect (Tissue PK-PD) Evaluation.
J Med Chem
; 65(13): 8713-8734, 2022 07 14.
Article
em En
| MEDLINE
| ID: mdl-35790118
ABSTRACT
The "free drug hypothesis" assumes that, in the absence of transporters, the steady state free plasma concentrations equal to that at the site of action that elicit pharmacologic effects. While it is important to utilize the free drug hypothesis, exceptions exist that the free plasma exposures, either at Cmax, Ctrough, and Caverage, or at other time points, cannot represent the corresponding free tissue concentrations. This "drug concentration asymmetry" in both total and free form can influence drug disposition and pharmacological effects. In this review, we first discuss options to assess total and free drug concentrations in tissues. Then various drug design strategies to achieve concentration asymmetry are presented. Last, the utilities of tissue concentrations in understanding exposure-effect relationships and translational projections to humans are discussed for several therapeutic areas and modalities. A thorough understanding in plasma and tissue exposures correlation with pharmacologic effects can provide insightful guidance to aid drug discovery.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Plasma
/
Descoberta de Drogas
Tipo de estudo:
Guideline
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2022
Tipo de documento:
Article