Maintaining steady state arterial alcohol levels in rats by using a physiologically based pharmacokinetic model
An intravenous method of alcohol administration that maintains arterial alcohol concentrations (AACs) in rats at a prescribed level for a prolonged period was previously described. This method produced steady state AACs between 30 and 180 min after the start of the infusion, but it resulted in substantial overshoots in AAC initially. The present study was designed to achieve target AACs close to steady state more quickly while minimizing any overshoot. A physiologically based pharmacokinetic (PBPK) model of alcohol distribution and elimination was developed for male Wistar rats. Body weight was used to compute individualized infusion rate profiles that would achieve steady state AACs of 75, 150, and 250 mg%. Rats were chronically implanted with cannulae in the jugular vein (for alcohol infusion) and carotid artery (for blood sampling). Alcohol was administered according to the individualized infusion rate profiles. Blood was collected at intervals for AAC determination. The PBPK model-based infusion profiles achieved target AACs 5 min after the start of the infusion and maintained the AACs for 2 h. The AACs deviated an average of 4.9%, 5.1%, and 5.9% from target at the 75, 150, and 250 mg% levels, respectively. Through the application of a PBPK model, it is possible to achieve target AACs close to steady state more quickly in male Wistar rats and to minimize any overshoot in AAC. The PBPK model-based method seems to be improved over the earlier method. Maintaining steady state AACs in rats is useful for studies in which fluctuating alcohol levels may confound experimental results. © 2002 Elsevier Science Inc. All rights reserved.
Morzorati, SL; Ramchandani, VA; Li, TK; O'Connor, S
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