Ex vivo assessment of binding site occupancy of monoamine reuptake inhibitors: Methodology and biological significance

Lengyel, Kelly; Pieschl, Rick L.; Strong, Todd; Molski, Thaddeus F.; Mattson, Gail K.; Lodge, Nicholas J.; Li, Yuwen

doi:10.1016/j.neuropharm.2008.04.014

Cited by 39 publications

(38 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Accurate assessment of transporter (or receptor) occupancy using ex vivo methodology is sensitive to many factors including the temporal effects of tissue processing (Li et al, 2003(Li et al, , 2006. Time-dependent decreases in apparent transporter occupancy have been observed for SERT and NET by using venlafaxine and nomifensine, respectively (Lengyel et al, 2008). Because many standard 5-HT and NE reuptake inhibitors display rapid dissociation binding kinetics (e.g., dissociation half-lives Ͻ10 min at room temperature) (Tsuruda et al, 2010), transporter occupancy may be underestimated under conditions that use extended homogenate incubation times ex vivo (Lengyel et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Time-dependent decreases in apparent transporter occupancy have been observed for SERT and NET by using venlafaxine and nomifensine, respectively (Lengyel et al, 2008). Because many standard 5-HT and NE reuptake inhibitors display rapid dissociation binding kinetics (e.g., dissociation half-lives Ͻ10 min at room temperature) (Tsuruda et al, 2010), transporter occupancy may be underestimated under conditions that use extended homogenate incubation times ex vivo (Lengyel et al, 2008). Here, the temporal effects of incubation time were illustrated by determination of the apparent SERT occupancy by duloxetine at different time points after radioligand addition.…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, there are fewer ligands suitable for monitoring in vivo occupancy at NET in humans; however, the identification and characterization of such radioligands is ongoing (Logan et al, 2007;Ding et al, 2010;Hannestad et al, 2010;Gallezot et al, 2011). Studies to assess occupancy at NET have been conducted in rodents by using [ 3 H]nisoxetine and ex vivo binding approaches (Owens et al, 2000;Bymaster et al, 2001;Barbier et al, 2007;Aluisio et al, 2008;Lengyel et al, 2008). An assessment of transporter occupancy at both SERT and NET is required for compounds, such as duloxetine, with in vitro profiles consistent with the engagement of both transporters at therapeutically relevant doses.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Prediction of Human Serotonin and Norepinephrine Transporter Occupancy of Duloxetine by Pharmacokinetic/Pharmacodynamic Modeling in the Rat

Bourdet¹,

Tsuruda²,

Obedencio³

et al. 2012

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Translation of central nervous system occupancy and clinical effect from animal models to humans has remained elusive for many pharmacological targets. The current studies evaluate the ability of a rodent pharmacokinetic/pharmacodynamic (PK/PD) modeling approach to translate ex vivo occupancy determined in rats to that observed after positron emission tomography (PET) imaging in humans for the dual serotonin transporter (SERT) and norepinephrine transporter (NET) inhibitor duloxetine. Ex vivo transporter occupancy in rat spinal cord was evaluated after single oral doses of 0.3 to 60 mg/kg. A novel methodology, based on the initial rates of association of transporter selective radioligands to tissue homogenates, was developed and validated for the assessment of ex vivo transporter occupancy. Duloxetine exhibited selectivity for occupancy of SERT over NET in rat spinal cord with ED 50 values of 1 and 9 mg/kg, respectively. Corresponding EC 50 values for the inhibition of SERT and NET based on unbound duloxetine spinal cord concentrations were 0.5 and 8 nM. An effect compartment PK/PD modeling approach was used to analyze the relationship between the time course of duloxetine plasma concentration and SERT and NET occupancy. Duloxetine inhibited SERT and NET in rat spinal cord with a plasma EC 50 of 2.95 and 59.0 ng/ml, respectively. Similar plasma EC 50 values for the inhibition of SERT (2.29 -3.7 ng/ml) have been reported from human PET studies. This study illustrates the value of translational PK/PD modeling approaches and suggests that the preclinical modeling approach used in the current study is capable of predicting plasma concentrations associated with 50% occupancy of SERT in the human central nervous system.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Prediction of Human Serotonin and Norepinephrine Transporter Occupancy of Duloxetine by Pharmacokinetic/Pharmacodynamic Modeling in the Rat

Bourdet¹,

Tsuruda²,

Obedencio³

et al. 2012

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…It is a serotonin and NEpreferring TRI [147]. It has a similar mode of action like cocaine, but slower onset of action and potentially be useful to treat various drug addiction issues [148].…”

Section: Triple Reuptake Inhibitors As Potential Next-generation Antimentioning

confidence: 99%

Triple Reuptake Inhibitors as Potential Next-Generation Antidepressants: A New Hope?

Santra

Dutta

2015

Future Med. Chem.

View full text Add to dashboard Cite

The current therapy for depression is less than ideal with remission rates of only 25–35% and a slow onset of action with other associated side effects. The persistence of anhedonia originating from depressed dopaminergic activity is one of the most treatment-resistant symptoms of depression. Therefore, it has been hypothesized that triple reuptake inhibitors (TRIs) with potency to block dopamine reuptake in addition to serotonin and norepinephrine transporters should produce higher efficacy. The current review comprehensively describes the development of TRIs and discusses the importance of evaluation of in vivo transporter occupancy of TRIs, which should correlate with efficacy in humans.

show abstract

“…Indeed, it is interesting to note that in 2010-2011, the pharmacological profiles of nine new compounds, studying the structure activity relationship (SAR), have been reported (Shao et al, 2011a;2001b;2011c;Caldarone et al, 2010;Carter et al, 2010;Lee et al, 2010;Lucas et al, 2010;Micheli et al, 2010aMicheli et al, , 2010bSchoedel et al, 2010). Despite the emergence of these compounds, older molecules with the abilities to inhibit all three monoamines transporters were already available such as the tryciclic agent nefopam approved in Europe (Heel et al, 1980), bicifadine in phase III (Basile et al, 2007) or indatraline (Lengyel et al, 2008) (Figure 2). …”

Section: Pharmacological Properties Of Trismentioning

confidence: 99%

A New Class of Antidepressant Drugs in the Treatment of Psychiatric Disorders: The Triple Reuptake Inhibitors

Guiard¹

2011

Psychiatric Disorders - Trends and Developments

View full text Add to dashboard Cite

Ex vivo assessment of binding site occupancy of monoamine reuptake inhibitors: Methodology and biological significance

Cited by 39 publications

References 33 publications

Prediction of Human Serotonin and Norepinephrine Transporter Occupancy of Duloxetine by Pharmacokinetic/Pharmacodynamic Modeling in the Rat

Prediction of Human Serotonin and Norepinephrine Transporter Occupancy of Duloxetine by Pharmacokinetic/Pharmacodynamic Modeling in the Rat

Triple Reuptake Inhibitors as Potential Next-Generation Antidepressants: A New Hope?

A New Class of Antidepressant Drugs in the Treatment of Psychiatric Disorders: The Triple Reuptake Inhibitors

Contact Info

Product

Resources

About