期刊
JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS
卷 28, 期 6, 页码 507-532出版社
KLUWER ACADEMIC/PLENUM PUBL
DOI: 10.1023/A:1014414520282
关键词
target-mediated drug disposition; nonlinear pharmacokinetics; imirestat; bosentan; interferon-beta; receptor binding; receptor-mediated endocytosis; mathematical modeling; human
资金
- NIGMS NIH HHS [GM57980] Funding Source: Medline
Drugs that bind with high affinity and to a significant extent (relative to dose) to a pharmacologic target such as an enzyme, receptor, or transporter may exhibit nonlinear pharmacokinetic (PK) behavior. Processes such as receptor-mediated endocytosis may result in drug elimination. A general PK model for characterizing such behavior is described and explored through computer simulations and applications to several therapeutic agents. Simulations show that model predicted plasma concentration vs. time profiles are expected to be polyexponential with steeper distribution phases for lower doses and similar terminal disposition phases. Noncompartmental parameters always show apparent V-ss and CLD decreasing with dose, but apparent clearance decreases only when the binding process produces drug elimination. The proposed model well captured the time-course of drug concentrations for the aldose reductase inhibitor imirestat, the endothelin receptor antagonist bosentan, and recombinant human interferon-beta 1a. This type of model has a mechanistic basis and considerable utility for fully describing the kinetics for various doses of relevant drugs.
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