Physiologically based pharmacokinetics of zearalenone.
The objectives of this study were to (1) develop physiologically based pharmacokinetic (PBPK) models for zearalenone following intravenous (i.v.) and oral (p.o.) dosing in rats and (2) predict concentrations in humans via interspecies scaling. The model for i.v. dosing consisted of vein, artery, lung, liver, spleen, kidneys, heart, testes, brain, muscle, adipose tissue, stomach, and small intestine. To describe the secondary peak phenomenon observed after p.o. administration, the absorption model was constructed to reflect glucuronidation, biliary excretion, enterohepatic recirculation, and fast and slow absorption processes from the lumenal compartment. The developed models adequately described observed concentration-time data in rats after i.v. or p.o. administration. Upon model validation in rats, steady-state zearalenone concentrations in blood and tissues were simulated for rats after once daily p.o. exposures (0.1 mg/kg/d). The average steady-state blood zearalenone concentration predicted in rat was 0.014 ng/ml. Subsequently, a daily human p.o. dose needed to achieve the same steady-state blood concentration found in rats (0.014 ng/ml) was determined to be 0.0312 mg/kg/d or 2.18 mg/70 kg/d. The steady-state zearalenone concentration-time profiles in blood and tissues were also simulated for human after multiple p.o. administrations (dose 0.0312 mg/kg/d). The developed PBPK models adequately described the pharmacokinetics in rats and may be useful in predicting human blood and tissue concentrations for zearalenone under different p,o, exposure conditions.
Shin
Beom Soo
BS
College of Pharmacy, Catholic University of Daegu, Gyeongsan-si, Gyeongbuk, Korea.
Hong
Seok Hyun
SH
Bulitta
Jürgen B
JB
Lee
Jong Bong
JB
Hwang
Sang Wook
SW
Kim
Hyoung Jun
HJ
Yang
Seung Du
SD
Yoon
Hae-Seong
HS
Kim
Do Jung
DJ
Lee
Byung Mu
BM
Yoo
Sun Dong
SD
D000273:Adipose Tissue / Q000737:chemistry / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000737:chemistry / Q000378:metabolism; D008168:Lung / Q000737:chemistry / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013737:Testis / Q000737:chemistry / Q000378:metabolism; D014018:Tissue Distribution; D015025:Zearalenone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D015025:Zearalenone