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  • 1
    ISSN: 1573-8744
    Keywords: in vitro/in vivo correlation ; ethoxybenzamide ; physiological pharmacokinetics ; tissue distribution ; drug binding ; animal scale-up ; tissue-to-blood partition coefficient
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Ethoxybenzamide (EB) concentrations in plasma and various tissues were simulated using a physiological pharmacokinetic model. The biochemical parameters, such as plasma and tissue binding constants and Michaelis-Menten constants for EB deethylation, which were needed for these simulations, were, however, obtained from in vitro data. The simulations predicted well the observed data in plasma and various tissues of the rat. Furthermore, animal scale-up predicted reasonably well the concentrations of EB in plasma and various tissues of the rabbit from data gathered in rats.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1573-8744
    Keywords: quinidine disposition ; tissue distribution ; nonlinear tissue binding ; physiological pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The nonlinear tissue distribution of quinidine in rats was investigated by a physiologically based pharmacokinetic model. Serum protein binding of quinidine showed a nonlinearity over thein vivo plasma concentration range. The blood-to-plasma concentration ratio (C b/C p) of quinidine also showed a concentration dependence. The steady-state volume of distribution (V ss) determined over the plasma concentration range from 0.5 to 10 μg/ml was 6.0 ±0.45 L/kg. The tissue-to-plasma partition coefficient (Kp) of muscle, skin, liver, lung, and gastrointestinal tract (GI) showed a nonlinearity over thein vivo plasma concentration range of quinidine, suggesting saturable tissue binding. The concentration of quinidine in several tissues and plasma was predicted by a physiologically based pharmacokinetic model usingin vitro plasma protein binding and theC b/C p of quinidine. The tissue binding parameters were estimated fromin vivo Kp values. The predicted concentration curves of quinidine in each tissue and in plasma showed good agreement with the observed values.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1573-904X
    Keywords: cardiac glycosides ; ouabain ; Na,K-ATPase ; guinea pig ; tissue distribution ; tissue-to-plasma concentration ratio ; kinetic modeling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The significance of the binding to Na,K-ATPase in the tissue distribution of ouabain was previously documented (Harashima et al., Pharm. Res. 9:474-479, 1992). The purpose of this study was to obtain a kinetic model of ouabain tissue distribution. In most tissues, the ouabain concentration continued to rise after the termination of infusion (5 min), with the peak tissue concentration at approximately 20 min. This delay could not be explained by the rapid equilibrium model (RE model), nor could the kinetics of ouabain be explained by an RE model modified for saturable binding. Since ouabain binding to Na,K-ATPase is slow, the association and dissociation processes were incorporated into a model that can accurately fit the observed time courses of ouabain. The obtained binding parameters corresponded well with the observed values in the in vitro binding experiments, except for muscle. These results quantitatively support the role of the slow and saturable binding of ouabain to Na,K-ATPase in its tissue distribution.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1573-904X
    Keywords: cardiac glycosides ; ouabain ; Na,K-ATPase ; guinea pig ; tissue distribution ; tissue-to-plasma concentration ratio
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Ouabain binds specifically to Na,K-ATPase on the plasma membrane and therefore serves to measure the tissue concentration of Na,K-ATPase. We examined the role of ouabain binding to Na,K-ATPase in its overall tissue distribution. The tissue-to-plasma concentration ratio (K p,vivo) was defined in each tissue after intravenous administration of 3H-ouabain in guinea pigs, and specific binding of ouabain to Na,K-ATPase was measured in tissue homogenate to obtain the dissociation constant and binding capacity in each tissue. A predicted tissue-to-plasma concentration ratio (K p,vitro) was calculated using the obtained binding parameters and the volume of extracellular space in each tissue. The absolute values of K p,vitro were comparable to those of K p vivo, except in brain. Regression analysis showed that the specific binding capacity of Na,K-ATPase in each tissue is the main factor in the tissue variation of K p,vivo. Therefore, the binding of ouabain to Na,K-ATPase plays a significant role in the tissue distribution of ouabain.
    Type of Medium: Electronic Resource
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