Quantitative analysis of the opioid peptide DAMGO in rat plasma and microdialysis samples using liquid chromatography–tandem mass spectrometry

Lindqvist, Anna-Karin; Jansson, Bjarne; Hammarlund‐Udenaes, Margareta

doi:10.1016/j.jchromb.2012.05.014

Cited by 9 publications

(8 citation statements)

References 19 publications

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“…36−38 The relatively high stability of DAMGO when incubated in plasma (t 1/2 > 2 h) indicates that the short half-life is not due to extensive metabolism by peptidases. 32,39,40 Szeto et al suggested that DAMGO is eliminated via renal glomerular filtration, since the clearance in sheep was similar to creatinine clearance (3.7 mL/min/kg). 40 This could not be confirmed in the present study in rats.…”

Section: ■ Discussionmentioning

confidence: 99%

“…The sample preparation and analytical methods have been described previously. 32 In brief, 50 μL of plasma was precipitated with 150 μL of ACN containing [ 13 C 2 , 15 N]-DAMGO as internal standard (IS). The supernatant was diluted in 1000 μL of the mixture of ACN:water:formic acid (16:84:0.01; v/v/v).…”

Section: ■ Methodsmentioning

confidence: 99%

“…Quantification of DAMGO in the samples was performed by liquid chromatography and electrospray ionization tandem mass spectrometry (ESI-LC–MS/MS). The sample preparation and analytical methods have been described previously . In brief, 50 μL of plasma was precipitated with 150 μL of ACN containing [ 13 C 2 , 15 N]-DAMGO as internal standard (IS).…”

Section: Methodsmentioning

confidence: 99%

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Enhanced Brain Delivery of the Opioid Peptide DAMGO in Glutathione PEGylated Liposomes: A Microdialysis Study

Lindqvist¹,

Rip²,

Gaillard³

et al. 2012

Mol. Pharmaceutics

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Glutathione PEGylated (GSH-PEG) liposomes were evaluated for their ability to enhance and prolong blood-to-brain drug delivery of the opioid peptide DAMGO (H-Tyr-d-Ala-Gly-MePhe-Gly-ol). An intravenous loading dose of DAMGO followed by a 2 h constant rate infusion was administered to rats, and after a washout period of 1 h, GSH-PEG liposomal DAMGO was administered using a similar dosing regimen. DAMGO and GSH-PEG liposomal DAMGO were also administered as a 10 min infusion to compare the disposition of the two formulations. Microdialysis made it possible to determine free DAMGO in brain and plasma, while the GSH-PEG liposomal encapsulated DAMGO was measured with regular plasma sampling. The antinociceptive effect of DAMGO was determined with the tail-flick method. All samples were analyzed using liquid chromatography-tandem mass spectrometry. The short infusion of DAMGO resulted in a fast decline of the peptide concentration in plasma with a half-life of 9.2 ± 2.1 min. Encapsulation in GSH-PEG liposomes prolonged the half-life to 6.9 ± 2.3 h. Free DAMGO entered the brain to a limited extent with a steady state ratio between unbound drug concentrations in brain interstitial fluid and in blood (Kp,uu) of 0.09 ± 0.04. GSH-PEG liposomes significantly increased the brain exposure of DAMGO to a Kp,uu of 0.21 ± 0.17 (p < 0.05). By monitoring the released, active substance in both blood and brain interstitial fluid over time, we were able to demonstrate that GSH-PEG liposomes offer a promising platform for enhancing and prolonging the delivery of drugs to the brain.

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Section: ■ Discussionmentioning

confidence: 99%

Section: ■ Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Enhanced Brain Delivery of the Opioid Peptide DAMGO in Glutathione PEGylated Liposomes: A Microdialysis Study

Lindqvist¹,

Rip²,

Gaillard³

et al. 2012

Mol. Pharmaceutics

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“…DAMGO and the microdialysis recovery calibrator [ 13 C 2 , 15 N]-DAMGO were quantified using liquid chromatography and electrospray ionization tandem mass spectrometry (ESI-LC-MS/MS) using a previously developed method (19). The 15 μl microdialysis samples were precipitated with 50 μl acetonitrile (ACN), 45 μl of the supernatant was diluted with 150 μl of 0.01% formic acid, and 75 μl of the subsequent solution was injected into the ESI-LC-MS/MS system.…”

Section: Sample Analysismentioning

confidence: 99%

In vivo Functional Evaluation of Increased Brain Delivery of the Opioid Peptide DAMGO by Glutathione-PEGylated Liposomes

Lindqvist

Rip²,

Kregten³

et al. 2015

Pharm Res

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“…The concentration of DAMGO and [ 13 C 2 , 15 N]-DAMGO in the microdialysis samples and the concentration of DAMGO, elacridar, and cyclosporine in plasma, blood, or brain homogenate samples were also determined by ESI-LC−MS/ MS using a different system. The analytical method for DAMGO is described in detail by Lindqvist et al 19 Microdialysis samples of 10 or 15 μL were precipitated with 50 μL of acetonitrile. The supernatant (40 and 45 μL for the 10 and 15 μL samples, respectively) was transferred to Eppendorf tubes prefilled with 150 μL of 0.01% formic acid.…”

Section: Molecular Pharmaceuticsmentioning

confidence: 99%

Exploring Factors Causing Low Brain Penetration of the Opioid Peptide DAMGO through Experimental Methods and Modeling

2016

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To advance the development of peptide analogues for improved treatment of pain, we need to learn more about the blood-brain barrier transport of these substances. A low penetration into the brain, with an unbound brain to blood ratio, Kp,uu, of 0.08, is an important reason for the lack of effect of the enkephalin analogue DAMGO (H-Tyr-d-Ala-Gly-MePhe-Gly-ol) according to earlier findings. The aim of this study was to investigate the role of efflux transporters, metabolism in the brain, and/or elimination through interstitial fluid bulk flow for the brain exposure of DAMGO. The in vivo brain distribution of DAMGO was evaluated using microdialysis in the rat. Data were analyzed with population modeling which resulted in a clearance into the brain of 1.1 and an efflux clearance 14 μL/min/g_brain. The efflux clearance was thus much higher than the bulk flow known from the literature. Coadministration with the efflux transporter inhibitors cyclosporin A and elacridar in vivo did not affect Kp,uu. The permeability of DAMGO in the Caco-2 assay was very low, of the same size as mannitol. The efflux ratio was <2 and not influenced by cyclosporin A or elacridar. These results indicate that the well-known efflux transporters Pgp and Bcrp are not responsible for the higher efflux of DAMGO, which opens up for an important role of other transporters at the BBB.

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Quantitative analysis of the opioid peptide DAMGO in rat plasma and microdialysis samples using liquid chromatography–tandem mass spectrometry

Cited by 9 publications

References 19 publications

Enhanced Brain Delivery of the Opioid Peptide DAMGO in Glutathione PEGylated Liposomes: A Microdialysis Study

Enhanced Brain Delivery of the Opioid Peptide DAMGO in Glutathione PEGylated Liposomes: A Microdialysis Study

In vivo Functional Evaluation of Increased Brain Delivery of the Opioid Peptide DAMGO by Glutathione-PEGylated Liposomes

Exploring Factors Causing Low Brain Penetration of the Opioid Peptide DAMGO through Experimental Methods and Modeling

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