Determination of dalcetrapib by liquid chromatography–tandem mass spectrometry

Heinig, Katja; Bucheli, Franz; Kuhlmann, Olaf; Zell, Manfred; Pähler, Axel; Zwanziger, Elke; Gross, Günter; Tardio, Joseph; Ishikawa, Tomohiro; Yamashita, Tomoko

doi:10.1016/j.jpba.2012.03.056

Cited by 13 publications

(16 citation statements)

References 22 publications

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“…HDL-C and LDL-C were determined using standard clinical chemistry methods (Roche Diagnostics). The plasma concentration of compounds was determined using liquid chromatography-tandem mass spectrometry methods that measured the dal-thiol (the active form of dalcetrapib in plasma) (30). Plasma or serum obtained from rabbits or monkeys was stored at −80°C and used within 1 year after freezing.…”

Section: Methodsmentioning

confidence: 99%

Dalcetrapib and anacetrapib differently impact HDL structure and function in rabbits and monkeys

Brodeur

Rhainds

Charpentier

et al. 2017

Journal of Lipid Research

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Inhibition of cholesteryl ester transfer protein (CETP) increases HDL cholesterol (HDL-C) levels. However, the circulating CETP level varies and the impact of its inhibition in species with high CETP levels on HDL structure and function remains poorly characterized. This study investigated the effects of dalcetrapib and anacetrapib, the two CETP inhibitors (CETPis) currently being tested in large clinical outcome trials, on HDL particle subclass distribution and cholesterol efflux capacity of serum in rabbits and monkeys. New Zealand White rabbits and vervet monkeys received dalcetrapib and anacetrapib. In rabbits, CETPis increased HDL-C, raised small and large α-migrating HDL, and increased ABCA1-induced cholesterol efflux. In vervet monkeys, although anacetrapib produced similar results, dalcetrapib caused opposite effects because the LDL-C level was increased by 42% and HDL-C decreased by 48% (P < 0.01). The levels of α- and preβ-HDL were reduced by 16% (P < 0.001) and 69% (P < 0.01), resulting in a decrease of the serum cholesterol efflux capacity. CETPis modulate the plasma levels of mature and small HDL in vivo and consequently the cholesterol efflux capacity. The opposite effects of dalcetrapib in different species indicate that its impact on HDL metabolism could vary greatly according to the metabolic environment.

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Section: Methodsmentioning

confidence: 99%

Dalcetrapib and anacetrapib differently impact HDL structure and function in rabbits and monkeys

Brodeur

Rhainds

Charpentier

et al. 2017

Journal of Lipid Research

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show abstract

“…there is no concern associated with AG) appear to assume that an interfering metabolite, if present, is moderately stable, because a typical reference value is established from a sample that is collected without special care, shipped in a frozen state, and measured at a bioanalytical laboratory. A number of case studies typically determined frozen long-term stability [18][19][20][21][22][23][24][25][26], some of which also examined other test items. Test items and study design were surveyed by EBF [27] and GCC [7] and extensively discussed by Yadav et al [28].…”

Section: Discussionmentioning

confidence: 99%

Incurred sample stability of ASP3258 in the presence of its acyl glucuronide

Ohtsu¹

2017

J Appl Bioanal

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The acyl glucuronide (AG) of ASP3258 was abundant in incurred monkey samples, and because an AG generally back-converts to its aglycone, accurate quantification of ASP3258 in monkey plasma was a challenge. To prevent the back-conversion of ASP3258-AG, cooling and acidification were incorporated during sample collection, storage, and extraction. To demonstrate that the AG did not affect the determination of ASP3258, the present study used incurred samples to examine whole blood stability, short-term stability, freeze-thaw stability, frozen stability, and stability during extraction. The concentration changes were within −11.4% to 15.0% compared with a reference value and were therefore judged acceptable. The present study presents a detailed account of test items, a reference value, sample numbers, sample selection, and an equation for assessment in the incurred sample stability tests. This bioanalytical method was applied successfully to a study of the toxicokinetics of ASP3258 in monkeys.Keywords: incurred sample stability, acyl glucuronide, ASP3258, animal plasma, toxicokinetics. IntroductionThe potent phosphodiesterase 4 inhibitor ASP3258 (Figure 1) is a novel therapeutic agent for asthma and chronic obstructive pulmonary disease [1]. We previously developed and validated a bioanalytical method to quantify ASP3258 in rat plasma [2]. Because ASP3258 metabolite was not detected in rat plasma [3], this bioanalytical method was developed without encountering issues associated with the metabolite. Subsequently, monkey toxicity studies were planned that required an appropriate bioanalytical method. When ASP3258 was orally administered to monkeys in a preliminary study, the acyl glucuronide (AG) metabolite of ASP3258 was detected in abundance in monkey plasma (data on file), in contrast to our findings using rat plasma [3]. In general, AGs readily back-convert to aglycones, causing overestimation of

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“…A challenging selectivity or matrix effect issue associated with an acidic mobile phase may be easily resolved by simply changing the mobile phase to a basic one. For example, Heinig et al () reported fewer endogenous compound peaks in the analysis of dalcetrapib‐ S ‐methyl using basic mobile phases, compared with another method utilizing acidic mobile phases.…”

Section: Benefits Of Using High‐ph Mobile Phasesmentioning

confidence: 99%

“…In comparison with the acidic mobile phases, a single symmetrical chromatographic peak was obtained and the sensitivity increased by 7‐fold or more under the equivalent conditions (Tan et al, ) (Figure ).One more example is the determination of dalcetrapib (a nonbasic compound). The use of a basic analytical mobile phase provided high S/N, particularly for dalcetrapib‐ S ‐glucuronide, and fewer endogenous compound peaks in the analysis of dalcetrapib‐ S ‐methyl compared with a previous method utilizing acidic mobile phases, thus providing improved precision during routine analysis (Heinig et al, ).…”

Section: Exemplary Applicationsmentioning

confidence: 99%

“…Once chromatographers experience the benefits of high‐pH mobile phases, they will not limit themselves just to acidic mobile phases anymore. Whenever a situation calls for it, they will not hesitate to use high‐pH mobile phases (Berg, Lundanes, Christophersen, & Strang, ; Berg, Jørgenrud, & Strand, ; Heinig et al, ; Heinig et al, ; Tan et al, ; Tan et al, ; Verplaetse and Tytgat, & ; Verplaetse, Cuypers, & Tytgat, ).…”

Section: Exemplary Applicationsmentioning

confidence: 99%

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Use of high‐pH (basic/alkaline) mobile phases for LC–MS or LC–MS/MS bioanalysis

Tan

Fanaras

2018

Biomedical Chromatography

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High-pH or basic/alkaline mobile phases are not commonly used in LC-MS or LC-MS/MS bioanalysis because of the deeply rooted concern with column instability and reduced detection sensitivity for basic compounds in high-pH mobile phases owing to charge neutralization. With the advancement of LC column technology and the wide recognition of the "wrong-way-round" phenomena, high-pH mobile phases are more and more used in LC-MS or LC-MS/MS bioanalysis to improve chromatographic peak shape, retention, selectivity, resolution, and detection sensitivity, not only for basic compounds, but also for many other compounds. In this article, the benefits, practical considerations, application examples and cautions for using high-pH mobile phases in LC-MS or LC-MS/MS bioanalysis are reviewed, with a focus on quantification. Furthermore, the future trends in this field are also envisaged.A total of 84 references are cited in this review. KEYWORDS alkaline mobile phase, basic mobile phase, bioanalysis, high pH, LC-MS, LC-MS/MS

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Determination of dalcetrapib by liquid chromatography–tandem mass spectrometry

Cited by 13 publications

References 22 publications

Dalcetrapib and anacetrapib differently impact HDL structure and function in rabbits and monkeys

Dalcetrapib and anacetrapib differently impact HDL structure and function in rabbits and monkeys

Incurred sample stability of ASP3258 in the presence of its acyl glucuronide

Use of high‐pH (basic/alkaline) mobile phases for LC–MS or LC–MS/MS bioanalysis

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