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AAPS PharmSci (1)
Journal of Clinical Investigation (1)
Balant, Luc (2)
Burr, Ian M. (1)
Peck, Carl (1)
Renold, Albert E. (1)
Rowland, Malcolm (1)
Stauffacher, Werner (1)
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Physiologically based pharmacokinetics in Drug Development and Regulatory Science: A workshop report (Georgetown University, Washington, DC, May 29–30, 2002)
A 2-day workshop on “Physiologically Based Pharmacokinetics (PBPK) in Drug Development and Regulatory Science” came to a successful conclusion on May 30, 2002, in Washington, DC. More than 120 international participants from the environmental and predominantly pharmaceutical industries, Food and Drug Administration (FDA), and universities attended this workshop, organized by the Center for Drug Development Science, Georgetown University, Washington, DC. The first of its kind specifically devoted to the subject, this intensive workshop, comprising 7 plenary presentations and 10 breakout sessions addressed 2 major objectives: (1) to “define demonstrated and potential contributions of PBPK in drug development and regulatory science,” and (2) to “assess current PBPK methodologies with the identification of their limitations and outstanding issues.” This report summarizes the presentations and recommendations that emerged from the workshop, while providing key references, software, and PBPK data sources in the appendices. The first day was initially devoted to presentations setting the stage and providing demonstrated applications to date. This was followed by breakout sessions that considered further opportunities and limitations, and which extended into Day 2 to deal with developments in methodologies and tools. Although the primary emphasis was on pharmacokinetics, consideration was also given to its integration specifically with mechanism-based pharmacodynamics.
Perifusion of rat pancreatic tissue in vitro: substrate modification of theophylline-induced biphasic insulin release
Burr, Ian M.
Renold, Albert E.
Journal of Clinical Investigation
The immunoreactive insulin (IRI) release patterns produced by continuous theophylline stimulation of rat pancreas have been defined, using an in vitro perfusion system. In the presence of glucose, citrate, and pyruvate at concentrations which were nonstimulatory by themselves, continuous stimulation with theophylline produced a biphasic IRI release profile. In the absence of substrate, continuous theophylline stimulation produced only an abrupt and limited primary response. Of the substrates tested, only glucose significantly enhanced this primary response. With increasing theophylline concentrations, whether in the presence or absence of substrate, significant increases were noted in the primary response as estimated by either the maximum rate of IRI release attained or by the total amount of IRI released during this time. Similarly, the secondary responses to theophylline increased with theophylline concentration in the presence of either citrate or pyruvate. With glucose as substrate, however, increasing theophylline concentrations from 2.5 to 5, then 10 mM produced a progressive reduction in both indices of the secondary response, which was inversely related to the primary response. These findings suggest that cyclic AMP not only mediates IRI release in quantitative terms but is also implicated in the qualitative nature of the response pattern. They also indicate a possible metabolic basis for biphasic IRI release, the acute or primary response being dependent upon the basal state of the cell and the availability of endogenous energy sources, the secondary response upon the availability of exogenous substrate.
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