Prediction of Drug Distribution in Distribution Dialysis and In Vivo from Binding to Tissues and Blood

Clausen, Johan S.R.; Bickel, Marcel H.

doi:10.1002/jps.2600820402

Cited by 44 publications

(36 citation statements)

References 15 publications

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“…The techniques used in the present study combined a published method for distribution dialysis (Bickel et al, 1987;Clausen and Bickel, 1993) and a 96-well equilibrium dialysis apparatus (Banker et al, 2003). These techniques have been used extensively to determine drugs binding to plasma protein, tissue protein, or any macromolecules (Pacifici and Viani, 1992;Cory Kalvass and Maurer, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…These techniques have been used extensively to determine drugs binding to plasma protein, tissue protein, or any macromolecules (Pacifici and Viani, 1992;Cory Kalvass and Maurer, 2002). Many of the drug-binding studies were aimed at predicting drug distribution in vivo (Khalafallah and Jusko, 1984;Barre et al, 1988;Clausen and Bickel, 1993) or to understand pharmacokinetic consequences (Wilkinson, 1983;Fichtl et al, 1991). Similar studies were conducted to understand pharmacokinetics/ pharmacodynamics and to predict drug effect based on receptor binding at the target (Proost et al, 1996) or to determine free drug concentration at the target site (Cory Kalvass and Maurer, 2002).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Establishment of Correlation between in Vitro Enzyme Binding Potency and in Vivo Pharmacological Activity: Application to Liver Glycogen Phosphorylase a Inhibitors

Yu¹,

Chen²,

Treadway³

et al. 2006

J Pharmacol Exp Ther

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In drug discovery, establishing a correlation between in vitro potency and in vivo activity is critical for the validation of the selected target and for developing confidence in the in vitro screening strategy. The present study developed a competition equilibrium dialysis assay using a 96-well dialysis technique to determine the intrinsic K d for 13 inhibitors of human liver glycogen phosphorylase a (GPa) in the presence of liver homogenate to mimic the physiological environment. The results provided evidence that binding of an inhibitor to GPa was affected by extra cofactors present in the liver homogenate. A good correlation was demonstrated between the in vitro K d determined under liver homogenate environment and free liver concentration of an inhibitor at the minimum efficacious dose in diabetic ob/ob mice. This study revealed important elements (such as endogenous cofactors missing from the in vitro assay and free concentration at the target tissue) that contributed to a better understanding of the linkage between in vitro and in vivo activity. The approach developed here may be applied to many drugs in pharmacology studies in which the correlation between in vitro and in vivo activities for the target tissue (such as solid tumors, brain, and liver) is critical.In the drug discovery process within the pharmaceutical industry, initial lead compounds are usually identified from high-throughput in vitro biological screens, for example, an inhibition assay against a target enzyme. It is often hoped that the in vitro potency (such as IC 50 ) can be used to predict the in vivo pharmacological activity (such as EC 50 ). However, discovery scientists often face a question: why doesn't an in vitro potent inhibitor work in vivo or only work at a much higher in vivo concentration? Establishment of a correlation between in vitro potency and in vivo activity is crucial for validation of the target enzyme and for achieving confidence in an in vitro screening strategy.According to the fundamental free ligand hypothesis, the average free efficacious concentration at the steady-state in vivo should correlate with the intrinsic (unbound) potency determined from an in vitro assay. This hypothesis has been supported by many researchers (Wagner et al., 1965;Wagner, 1976;DeGuchi et al., 1992;Wright et al., 1996). In practice, however, this relationship is often obscured or confounded because of a variety of factors. For example, nonphysiological conditions, involvement of nonspecific binding within in vitro systems, or a combination may yield an inaccurate estimate of the true intrinsic potency. In addition, complex pharmacokinetic/pharmacodynamic relationships arising from indirect effects or target site disequilibrium may result in the inappropriate determination of in vivo potency.Several of the variables stated above confounded the initial establishment of a correlation between in vitro potency and This work was supported by Pfizer Inc. Article, publication date, and citation information can be found at http://jpe...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Establishment of Correlation between in Vitro Enzyme Binding Potency and in Vivo Pharmacological Activity: Application to Liver Glycogen Phosphorylase a Inhibitors

Yu¹,

Chen²,

Treadway³

et al. 2006

J Pharmacol Exp Ther

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“…Following this expectation, attempts have been made to predict tissue partitioning from in vitro estimates of unbound plasma fraction and unbound tissue fraction with mixed success (Bickel and Gerny, 1980;Bickel et al, 1987;Schuhmann et al, 1987;Clausen and Bickel, 1993). Previous reports suggest that the dilution, homogenization, and incubation process necessary to determine unbound tissue fraction by equilibrium dialysis may disrupt or destroy intracellular components that contribute to distribution in vivo.…”

mentioning

confidence: 99%

“…Previous reports suggest that the dilution, homogenization, and incubation process necessary to determine unbound tissue fraction by equilibrium dialysis may disrupt or destroy intracellular components that contribute to distribution in vivo. For example, it has been suggested that disruption of the postnuclear fractions containing the acidic organelles (e.g., lysosomes) may explain reported under-predictions in the distribution of the basic lipophilic drugs imipramine, desipramine, chlorpromazine, and methadone from liver, lung, and kidney homogenates (Clausen and Bickel, 1993). Further supporting this hypothesis, accurate predictions have been reported for acidic and neutral drugs in these same tissues and also for the same basic lipophilic drugs in tissues with less abundant lysosomes (e.g., brain, muscle, and adipose tissue).…”

mentioning

confidence: 99%

Relationship Between Exposure and Nonspecific Binding of Thirty-Three Central Nervous System Drugs in Mice

Maurer

DeBartolo²,

Tess³

et al. 2004

Drug Metab Dispos

205

171

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ABSTRACT:Unbound fractions in mouse brain and plasma were determined for 31 structurally diverse central nervous system (CNS) drugs and two active metabolites. Three comparisons were made between in vitro binding and in vivo exposure data, namely: 1) mouse brainto-plasma exposure versus unbound plasma-to-unbound brain fraction ratio (fu plasma /fu brain ), 2) cerebrospinal fluid-to-brain exposure versus unbound brain fraction (fu brain ), and 3) cerebrospinal fluid-to-plasma exposure versus unbound plasma fraction (fu plasma ). Unbound fraction data were within 3-fold of in vivo exposure ratios for the majority of the drugs examined (i.e., 22 of 33), indicating a predominately free equilibrium across the blood-brain and blood-CSF barriers. Some degree of distributional impairment at either the blood-CSF or the blood-brain barrier was indicated for 8 of the 11 remaining drugs (i.e., carbamazepine, midazolam, phenytoin, sulpiride, thiopental, risperidone, 9-hydroxyrisperidone, and zolpidem). In several cases, the indicated distributional impairment is consistent with other independent literature reports for these drugs. Through the use of this approach, it appears that most CNS-active agents freely equilibrate across the blood-brain and blood-CSF barriers such that unbound drug concentrations in brain approximate those in the plasma. However, these results also support the intuitive concept that distributional impairment does not necessarily preclude CNS activity.

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“…8,9) Heart Tissue Homogenates: Homogenates were prepared from rabbit hearts at a concentration of 50 mg/ml in phosphate buffer (1/15 M, pH 7.4) to study the binding of digoxin to heart tissue. Untreated homogenates and homogenates previously treated with a solution of acenocoumarol (1 mg/ml) over 4 h before the dialysis experiments were compared.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic Study of the Digoxin-acenocoumarol Interaction in Rabbits

Martín-Suárez

Atencio

López

et al. 2003

Biological & Pharmaceutical Bulletin

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Digoxin remains among the most frequently administered cardiac drugs. Its narrow therapeutic range, together with the existence of many factors that modify the pharmacological response to digoxin, make routine monitoring of its plasma levels crucial. Among such factors, one of the most important is the large number of interactions shown by the drug, most of them with a pharmacokinetic basis. 1,2) Acenocoumarol is the oral anticoagulant most widely used in continental Europe. Despite its widespread use, the literature contains few references to this drug, particularly in comparison with the large body of information on warfarin, the most widely used anticoagulant in other areas of the world. The important pharmacokinetic differences shown by acenocoumarol mean that the results obtained with other anticoagulants cannot be extrapolated to this drug. [3][4][5] Treatments with digoxin and acenocoumarol are usually chronic and often simultaneous. At two hospitals in our region it was observed that patients receiving treatment with acenocoumarol required higher doses of digoxin to control their conditions and for digoxin levels within the therapeutic range to be obtained.6) The literature contains no references to this possible interaction. Indeed, in a review paper on the interactions of anticoagulants Harder and Thürmann 7) specifically cite the absence of references to interactions between cardiotonic glucosides and coumarin derivatives, and they highlight the need for controlled studies of these drugs. Accordingly, the aim of the present work was to evaluate the potential pharmacokinetic interaction between digoxin and acenocoumarol in rabbits both in vitro and in vivo. MATERIALS AND METHODSThe interaction between digoxin and acenocoumarol was studied in in vitro and in vivo experiments. In the in vitro studies, the binding of digoxin to cardiac tissue homogenates was assessed in the presence and absence of acenocoumarol, using the equilibrium dialysis technique. In the in vivo experiments, the kinetics of digoxin administered in single-and multiple-dose regimens were compared in a group of control rabbits and in another group treated with both drugs simultaneously. The levels of digoxin in heart tissue at the end of the dosage regimen were also studied.In Vitro Study The in vitro studies of the binding of digoxin to heart homogenates were carried out using the equilibrium dialysis technique. 8,9) Heart Tissue Homogenates: Homogenates were prepared from rabbit hearts at a concentration of 50 mg/ml in phosphate buffer (1/15 M, pH 7.4) to study the binding of digoxin to heart tissue. Untreated homogenates and homogenates previously treated with a solution of acenocoumarol (1 mg/ml) over 4 h before the dialysis experiments were compared.Prior to the study, experiments had been conducted that showed that digoxin is not adsorbed onto the dialysis membrane. Neither was any significant shift across the membrane observed. The process was carried out at physiological temperature (37°C). Using this technique, two types of ex...

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Prediction of Drug Distribution in Distribution Dialysis and In Vivo from Binding to Tissues and Blood

Cited by 44 publications

References 15 publications

Establishment of Correlation between in Vitro Enzyme Binding Potency and in Vivo Pharmacological Activity: Application to Liver Glycogen Phosphorylase a Inhibitors

Establishment of Correlation between in Vitro Enzyme Binding Potency and in Vivo Pharmacological Activity: Application to Liver Glycogen Phosphorylase a Inhibitors

Relationship Between Exposure and Nonspecific Binding of Thirty-Three Central Nervous System Drugs in Mice

Pharmacokinetic Study of the Digoxin-acenocoumarol Interaction in Rabbits

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