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Rapid CommunicationSpecial Section on Pediatric Drug Disposition and Pharmacokinetics—Short Communication

Effect of Age on The Hepatocellularity Number for Wistar rats

Sarinj Fattah, Patrick Augustijns and Pieter Annaert
Drug Metabolism and Disposition July 2016, 44 (7) 944-947; DOI: https://doi.org/10.1124/dmd.115.066381
Sarinj Fattah
Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium
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Patrick Augustijns
Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium
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Pieter Annaert
Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium
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Abstract

Recently there has been a substantial increase in the number of juvenile animal toxicity studies that are conducted to support pediatric 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) modeling 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 (relative standard deviation 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 compared with 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.

Footnotes

    • Received July 19, 2015.
    • Accepted December 21, 2015.
  • This work is partly supported by internal funds from the KU Leuven Drug Delivery and Disposition Laboratory.

  • dx.doi.org/10.1124/dmd.115.066381.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (7)
Drug Metabolism and Disposition
Vol. 44, Issue 7
1 Jul 2016
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Rapid CommunicationSpecial Section on Pediatric Drug Disposition and Pharmacokinetics—Short Communication

Age-Dependent Hepatocellularity in Rat

Sarinj Fattah, Patrick Augustijns and Pieter Annaert
Drug Metabolism and Disposition July 1, 2016, 44 (7) 944-947; DOI: https://doi.org/10.1124/dmd.115.066381

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Rapid CommunicationSpecial Section on Pediatric Drug Disposition and Pharmacokinetics—Short Communication

Age-Dependent Hepatocellularity in Rat

Sarinj Fattah, Patrick Augustijns and Pieter Annaert
Drug Metabolism and Disposition July 1, 2016, 44 (7) 944-947; DOI: https://doi.org/10.1124/dmd.115.066381
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