RT Journal Article
SR Electronic
T1 A physiologically based pharmacokinetic model for (-)-quinuclidinyl benzylate using nonlinear irreversible tissue binding parameters in rats.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 485
OP 489
VO 20
IS 4
A1 J Ishizaki
A1 E Nakashima
A1 K Yokogawa
A1 T Nagano
A1 T Takayasu
A1 F Ichimura
YR 1992
UL http://dmd.aspetjournals.org/content/20/4/485.abstract
AB The disposition characteristics of (-)-quinuclidinyl benzylate (QNB) were investigated in rats, and a physiologically based pharmacokinetic model was established using its linear and nonlinear tissue binding parameters. The steady-state distribution volume (Vdss) and systemic clearance (CLtot) were comparable after iv administration of 325 ng/kg and 3.2 mg/kg, suggesting that QNB pharmacokinetics based on plasma concentrations is linear. However, tissue accumulation was observed in the heart, lung, muscle, and brain. This accumulation persisted for over 12 hr after the iv administration of 325 ng/kg [3H]QNB. Tissue binding parameters were determined after continuous infusion of QNB. Irreversible and nonlinear binding parameters were obtained in various regions of the brain and other tissues. Reversible equilibrium concentration ratios between tissue and plasma were determined after high-dose infusion. QNB concentrations in the plasma, heart, lung, muscle, and brain were predicted after the administration of 325 ng/kg or 3.2 mg/kg. There was reasonable agreement between the model predictions and the observed data.