Measurement of glomerular filtration rate in the conscious rat.
BACKGROUND
Glomerular filtration rate (GFR) is an important parameter for studying drug-induced impairments on renal function in rats. The GFR is calculated from the concentration of creatinine and blood urea nitrogen (BUN) in serum and in urine, respectively. Following current protocols serum and urine samples must be taken from the same animal. Thus, in order to determine time-dependent effects it is necessary to use for each time point one separated group of animals. We developed a statistical test which allows analyzing the GFR from two different groups of animals: one used for repeated serum and the other one used for repeated urine analysis.


METHODS
Serum and urine samples were taken from two different sets of rats which were otherwise treated identically, i.e. drug doses, routes of administration (per os or per inhalation) and tap water loading. For each dose group GFR mean, standard deviation and statistical analysis to identify differences between the dose groups were determined.


RESULTS
After determination of the optimal time points for measurements, the effect on GFR of the three reference compounds, furosemide, hydrochlorothiazide and formoterol, was calculated. The results showed that the diuretic drugs furosemide and hydrochlorothiazide decreased the GFR and the antidiuretic drug formoterol increased the GFR, as counter regulation on urine loss or urine retention, respectively.


CONCLUSIONS
A mathematical model and the corresponding algorithm were developed, which can be used to calculate the GFR, and to test for differences between groups from two separated sets of rats, one used for urine, and the other one for serum analysis. This new method has the potential to reduce the number of animals needed and to improve the quality of data generated from various groups of animals in renal function studies.
Pestel
Sabine
S
Group General Pharmacology, Drug Discovery Support, Boehringer-Ingelheim Pharma GmbH & Co. KG, D-88397 Biberach an der Riss, Germany. S.Pestel@bc.boehringer-ingelheim.com
Krzykalla
Volker
V
Weckesser
Gerhard
G
D000280:Administration, Inhalation; D000284:Administration, Oral; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D000465:Algorithms; D000818:Animals; D003243:Consciousness; D004232:Diuretics / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005260:Female; D000068759:Formoterol Fumarate; D005665:Furosemide / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005919:Glomerular Filtration Rate; D006852:Hydrochlorothiazide / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000318:Adrenergic beta-Agonists; D004232:Diuretics; D004983:Ethanolamines; D006852:Hydrochlorothiazide; D005665:Furosemide; D000068759:Formoterol Fumarate