RT Journal Article
SR Electronic
T1 Effect of Age on the Hepatocellularity Number for Wistar Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.115.066381
DO 10.1124/dmd.115.066381
A1 Sarinj Fattah
A1 Patrick Augustijns
A1 Pieter P Annaert
YR 2015
UL http://dmd.aspetjournals.org/content/early/2015/12/23/dmd.115.066381.abstract
AB Recently there has been a substantial increase in the number of juvenile animal toxicity studies that are conducted to support paediatric drug safety evaluation. Adequate design of juvenile toxicity studies in rats, for instance with respect to dose levels per age group, requires an understanding of age-dependent pharmacokinetics. In vitro-in vivo extrapolation (IVIVE) and physiologically-based pharmacokinetic (PBPK) modelling can help to anticipate age-dependent drug exposure in juvenile toxicity studies provided age-dependent profiles for animal physiology and scaling factors are available. For instance, when hepatocytes are used to predict hepatic drug clearance, the hepatocellularity (number of hepatocytes per gram liver, HPGL) is required as one of the scaling factors. Although HPGL is known for adult rats, information on the influence of age on HPGL is missing. The present work profiles the hepatocellularity number in male Wistar rats as a function of age. Using the NADPH-cytochrome P450 reductase (NCR) activity method, the mean HPGL for the adult rat (8 weeks) was 104 × 106 cells/gram liver (RSD 17%). This value was calculated as a ratio between NRC activities in liver homogenates and suspended hepatocytes. The HPGL values were significantly higher (p = < 0.001) for rat pups until 3 weeks of age as compared to adults. Our results revealed that the HPGL value showed a rapid decrease after 3 weeks (end of weaning) essentially reaching adult values by 4 weeks. This age-dependent HPGL profile will be instrumental for hepatic drug clearance prediction when designing juvenile toxicity studies in Wistar rats.