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Dear PharmPK group:
I would like to get your opinions on our findings in a rat PK study.
Rats were dosed a test article at 3 different dose levels, 25, 50 or
75 mg/kg either via IV bolus or 30 min infusion.
The test article was dissolved in D5W, pH adjusted with HCl to 4.5.
When plasma samples were analyzed, it was found that although AUC
values were similar between bolus and infusion groups, the plasma
concentrations at later timepoints (4 hours or later) in the infusion
groups were much (5-10 fold) higher and the half life was longer than
in the bolus groups at all 3 dose levels.
The plasma concentration - time profiles for bolus and infusion groups
cross at ~2 hour timepoint (< 2 hours, higher conc. in bolus; > 2
hours, higher conc. in infusion).
I do not know how to explain this phenomenon, and would greatly
appreciate your thoughts on this.
Thank you very much in advance.
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If I have understood your problem, what you have described is normal
behaviour for drugs displaying multi-compartment kinetics. It is more
evident for drugs with large peripheral compartments (e.g. fentanyl).
The anaesthetic literature covers this area well, where is is called
"context sensitive half-life". You should be able to find some more
information by searching on that topic.
Dr Richard Upton
Principal Medical Scientist/Senior Lecturer
Discipline of Anesthesia and Intensive Care
Royal Adelaide Hospital/University of Adelaide
North Tce, SA 5000, Australia
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