Abstract：
: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 Vss and CL(D) 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.
journal_name
J Pharmacokinet Pharmacodynjournal_title
Journal of pharmacokinetics and pharmacodynamicsauthors
Mager DE,Jusko WJdoi
10.1023/a:1014414520282keywords:
subject
Has Abstractpub_date
2001-12-01 00:00:00pages
507-32issue
6eissn
1567-567Xissn
1573-8744journal_volume
28pub_type
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