Combining radio telemetry and automated blood sampling: a novel approach for integrative pharmacology and toxicology studies.
BACKGROUND
A novel automated blood sampling and telemetry (ABST) system was developed to integrate pharmacokinetic (PK), pharmacodynamic (PD) and toxicology studies. The goals of this investigation were to determine: 1) optimal feeding conditions and minimal acclimation times for recording PD parameters (blood pressure, heart rate, and temperature) after animals arrived on-site; 2) stress hormone levels in ABST-housed rats; 3) the feasibility of simultaneously recording cardiovascular parameters with electroencephalogram (EEG); 4) the equivalence of renal endpoints from ABST-housed rats with those in the metabolic cage, and 5) the cardiovascular responses to baclofen.


METHODS
Body weight, blood pressure, temperature, stress biomarkers, urine chemistries, renal biomarkers and responses to vehicle or baclofen (10mg/kg) were compared in awake and freely moving rats housed in the ABST system, home cage (HC) or metabolic cage.


RESULTS
Fasted rats lost 5+/-1% and 7+/-1% body weight when housed in ABST and metabolic cages, respectively. Weight loss was reversed by supplementing regular diet with hydration and nutritional supplements. Based on PD parameters, the minimum acclimation time required for both ABST and HC rats was 3days. The feasibility of simultaneously measuring multiple parameters, such as EEG with cardiovascular parameters in ABST was demonstrated. Renal function and biomarkers in rats continuously housed in the ABST and metabolic cages were equivalent (p>0.05) on days 1, 3, and 7. Baclofen-induced quantitatively and qualitatively similar (p>0.05) PK, mean arterial pressure, heart rate and temperature in ABST- and HC-housed rats.


CONCLUSIONS
These studies demonstrate for the first time that drug-induced PD responses can be recorded simultaneously with time-matched pharmacokinetic, biochemical and metabolic parameters in the same animal. The ABST system has the added advantage of blood sampling without the need for satellite PK animals. ABST is a useful and novel tool for establishing efficacy and safety margins using an in vivo integrative pharmacology approach.
Kamendi
Harriet W
HW
Safety Assessment US, AstraZeneca R&D Wilmington, DE 19850, USA.
Brott
David A
DA
Chen
Yafei
Y
Litwin
Dennis C
DC
Lengel
David J
DJ
Fonck
Carlos
C
Bui
Khanh H
KH
Gorko
Mary Ann
MA
Bialecki
Russell A
RA
D000818:Animals; D001331:Automation; D001418:Baclofen / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D001794:Blood Pressure / Q000187:drug effects; D001800:Blood Specimen Collection; D001831:Body Temperature / Q000187:drug effects; D004567:Electrodes, Implanted / Q000662:veterinary; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006728:Hormones / Q000097:blood; D007668:Kidney / Q000737:chemistry; D008297:Male; D009125:Muscle Relaxants, Central / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D013686:Telemetry / Q000662:veterinary; D014556:Urine / Q000737:chemistry
D006728:Hormones; D009125:Muscle Relaxants, Central; D001418:Baclofen