Mechanisms of cellular distribution of psychotropic drugs. Significance for drug action and interactions

Daniel, W.A.

doi:10.1016/s0278-5846(02)00317-2

Cited by 89 publications

(61 citation statements)

References 60 publications

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“…But these studies constitute a first step toward delineation of potential ligand binding sites within transmembrane spans. Second, it is expected that ligands binding to the transmembrane domains would be highly hydrophobic, but this would also increase the risk of off-target effects considerably (Daniel, 2003).…”

Section: Discussionmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

Dessauer¹,

Watts²,

Ostrom³

et al. 2017

Pharmacol Rev

175

198

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Section: Discussionmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

Dessauer¹,

Watts²,

Ostrom³

et al. 2017

Pharmacol Rev

175

198

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“…Lysosomes represent 1% of the hepatocyte volume; therefore, trapping is an important distribution process for weak bases, which can accumulate within this compartment due to the pH gradient between the acidic lysosome compartment (pH 5), the hepatic cytosol (pH 7.2), and the plasma (pH 7.4) (Daniel, 2003). Drug accumulation resulting from this process or from intracellular binding to cytosolic proteins will not result in a drug concentration within the hepatic cytosol that differs from the unbound concentration in the external incubation medium.…”

mentioning

confidence: 99%

Use of Isolated Hepatocyte Preparations for Cytochrome P450 Inhibition Studies: Comparison with Microsomes forK_iDetermination

Brown

Chadwick²,

Houston

2007

Drug Metab Dispos

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ABSTRACT:Predicting drug-drug interactions requires an assessment of the drug concentration available to the enzyme active site, both in vivo, and within an in vitro incubation. These predictions are confounded when the inhibitor accumulates within the liver, either as a result of active transport processes or intracellular binding (including lysosomal trapping). In theory, hepatocytes should provide a more accurate estimation of inhibitory potency compared with microsomes for those compounds that undergo hepatic accumulation. However, they are not routinely used for K i determination and there is limited comparative information available. Therefore, the aims of this study were to compare K i values determined in rat microsomes and freshly isolated hepatocytes using six cytochrome P450 inhibitors (miconazole, fluconazole, ketoconazole, quinine, fluoxetine, and fluvoxamine) with a range of uptake properties (cell-to-medium concentration ratios 4.2-6000). Inhibition studies were performed using four probe substrates for CYP2C, CYP2D, and CYP3A enzymes (tolbutamide and phenytoin, dextromethorphan and midazolam, respectively). Comparison of unbound K i values (range 0.05-30 M) showed good agreement between microsomes and hepatocytes for inhibition of 18 pathways of metabolism. In addition to this, there was no relationship between the cell-to-medium concentration ratios (covering over 3 orders of magnitude) and the microsomal to hepatocyte K i ratio of these inhibitors. These data suggest that the hepatic accumulation of these inhibitors results from intracellular binding rather than the involvement of uptake transporters and indicate that microsomes and hepatocytes appear to be equivalent for determining the inhibitory potency of the six inhibitors investigated in the present study.Quantitative prediction of drug-drug interactions (DDIs) requires an accurate estimation of drug concentration at the enzyme active site, both in vivo within the liver and within an in vitro incubation. Since it is impossible to directly measure this liver concentration in humans, plasma concentrations have been used as an in vivo surrogate, but with varying degrees of success (Ito et al., 2002(Ito et al., , 2004. Although the use of plasma inhibitor concentration has accurately predicted the degree of in vivo DDIs for several compounds (Brown et al., 2005(Brown et al., , 2006Obach et al., 2006), even the use of total plasma concentrations may underestimate hepatocellular concentrations for inhibitors that are accumulated within the liver.Drug can be sequestered within the hepatocyte via several mechanisms; for example, lysosomal uptake, intracellular protein binding, or the involvement of hepatic uptake transporters. Lysosomes represent 1% of the hepatocyte volume; therefore, trapping is an important distribution process for weak bases, which can accumulate within this compartment due to the pH gradient between the acidic lysosome compartment (pH 5), the hepatic cytosol (pH 7.2), and the plasma (pH 7.4) (Daniel, 2003). Drug accumulation...

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“…ADs are supposedly acting at an intracellular site not likely to be mediated by actions at noradrenaline/serotonin transporters. As basic lipophilic compounds (Daniel, 2003) ADs can cross the plasma membrane and therefore could have direct intracellular actions such as the effects presented in this study on ␤-arrestin2. It is known that ␤-arrestin2 forms complexes with individual members of a particular MAP kinase cassette, retaining the activated MAP kinase in the cytoplasm, thereby directing phosphorylation of specific cytoplasmic substrates (DeFea et al, 2000;Luttrell et al, 2001).…”

Section: Antidepressants Increase ␤-Arrestin2 Ubiquitinylation 973mentioning

confidence: 87%

Antidepressants Increase β-Arrestin2 Ubiquitinylation and Degradation by the Proteasomal Pathway in C₆Rat Glioma Cells

Golan

Schreiber²,

Avissar³

2009

J Pharmacol Exp Ther

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␤-Arrestins, regulators of G protein-coupled receptor-G protein coupling and receptor desensitization and internalization, function also as scaffolding proteins mediating cellular signaling events. ␤-Arrestin1 was previously implicated by us in the pathophysiology of depression and in the mechanism of action of antidepressants (ADs). The ubiquitously expressed ␤-arrestins1 and 2 are structurally highly homologous. There has been extensive investigation of these two proteins to determine whether they serve different roles in receptor signaling. In this study, we show that treatment of C 6 rat glioma cells with ADs of various types for 3 days resulted in decreased ␤-arrestin2 levels. In contrast, ␤-arrestin2 mRNA expression was found to be up-regulated by ADs. To unravel the mechanism for these opposite effects several possible ␤-arrestin2 post-transcriptional events and modifications were examined. C 6 rat glioma cells transfected with ␤-arrestin1-targeted short hairpin RNA showed similar effects of ADs on ␤-arrestin2 levels. AD-induced decreases in ␤-arrestin2 protein levels were not due to cytosolic membrane translocation. Immunoprecipitation experiments showed that ADs were able to increase coimmunoprecipitation of ubiquitin with ␤-arrestin2. AD-induced increases in ␤-arrestin2 ubiquitinylation led to its degradation by the proteasomal pathway, as the proteasome inhibitor N- [(phenylmethoxy)carbonyl]-L-leucyl-N-[(1S)-1-formyl-3-methylbutyl]-L-leucinamide (MG-132) prevented antidepressant-induced decreases in ␤-arrestin2 protein levels.

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Mechanisms of cellular distribution of psychotropic drugs. Significance for drug action and interactions

Cited by 89 publications

References 60 publications

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

Use of Isolated Hepatocyte Preparations for Cytochrome P450 Inhibition Studies: Comparison with Microsomes forK_iDetermination

Antidepressants Increase β-Arrestin2 Ubiquitinylation and Degradation by the Proteasomal Pathway in C₆Rat Glioma Cells

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Mechanisms of cellular distribution of psychotropic drugs. Significance for drug action and interactions

Cited by 89 publications

References 60 publications

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

Use of Isolated Hepatocyte Preparations for Cytochrome P450 Inhibition Studies: Comparison with Microsomes forKiDetermination

Antidepressants Increase β-Arrestin2 Ubiquitinylation and Degradation by the Proteasomal Pathway in C6Rat Glioma Cells

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Use of Isolated Hepatocyte Preparations for Cytochrome P450 Inhibition Studies: Comparison with Microsomes forK_iDetermination

Antidepressants Increase β-Arrestin2 Ubiquitinylation and Degradation by the Proteasomal Pathway in C₆Rat Glioma Cells