Validation of an HPLC method for analysis of DB-67 and its water soluble prodrug in mouse plasma

Horn, Jamie; Jordan, Sherri; Song, Lin; Roberts, Michael J.; Anderson, Bradley D.; Leggas, Markos

doi:10.1016/j.jchromb.2006.06.022

Cited by 11 publications

(21 citation statements)

References 19 publications

(25 reference statements)

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“…AR-67 (DB-67; Novartis, New York, NY) was solubilized in dimethylsulfoxide at a concentration of 1 mg/ml (AR-67 lactone stock solution) and stored at 280°C. AR-67 carboxylate working solutions were prepared by dilution of one volume of lactone stock solution with 9 volumes of 0.005 N NaOH and were allowed to convert to carboxylate overnight at 4°C (AR-67 carboxylate stock solution) (Horn et al, 2006). Working solutions were stored at 280°C after their preparation and at 4°C during the experimental procedure.…”

Section: Methodsmentioning

confidence: 99%

“…The cells were lysed with 200 ml of 0.5 N NaOH and placed on a rocker (4°C) for 10 minutes. Extraction and quantification of AR-67 was performed as indicated in a high-performance liquid chromatography (HPLC) fluorescence method under conditions that ensure system suitability (Horn et al, 2006). Protein was quantified using the BCA Protein Assay Kit (Pierce/Thermo Fisher Scientific, Rockford, IL).…”

Section: Methodsmentioning

confidence: 99%

“…At the end of the incubation period, the cells were washed twice with Opti-MEM (4°C) before being lysed; AR-67, calculated as the sum of the two forms, was extracted from the cell lysate and quantified as described earlier (Horn et al, 2006).…”

Section: Methodsmentioning

confidence: 99%

“…Phosphate-buffered saline was added; the cells were scrapped off and lysed by sonication. AR-67 lactone and carboxylate were extracted and quantified using HPLC (Horn et al, 2006).…”

Section: Methodsmentioning

confidence: 99%

“…AR-67 carboxylate (1 mM) or lactone (1 mM) were added into the media at t = 0 hours. The AR-67 carboxylate and lactone concentrations were quantified at 0, 0.5, 1, 2, 4, and 6 hours using HPLC (Horn et al, 2006) Cytotoxicity Assays. Cells were seeded in 96-well plates at initial densities that ensured their exponential growth for the duration of the experiment.…”

Section: Methodsmentioning

confidence: 99%

See 4 more Smart Citations

The Effect of Breast Cancer Resistance Protein, Multidrug Resistant Protein 1, and Organic Anion-Transporting Polypeptide 1B3 on the Antitumor Efficacy of the Lipophilic Camptothecin 7-t-Butyldimethylsilyl-10-Hydroxycamptothecin (AR-67) In Vitro

et al. 2013

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AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin) is a lipophilic camptothecin analog, currently under early stage clinical trials. Transporters are known to have an impact on the disposition of camptothecins and on the response to chemotherapeutics in general due to their expression in tumor tissues. Therefore, we investigated the interplay between the breast cancer resistance protein (BCRP), multidrug resistant protein 1 (MDR1), and organic anion-transporting polypeptide (OATP) 1B1/1B3 transporters and AR-67 and their impact on the toxicity profile of AR-67. Using cell lines expressing the aforementioned transporters, we showed that the lipophilic AR-67 lactone form is a substrate for efflux transporters BCRP and MDR1. Additionally, OATP1B1 and OATP1B3 facilitated the uptake of AR-67 carboxylate in SLCO1B1-and SLCO1B3-transfected cell systems compared with the mocktransfected ones. Notably, both BCRP and MDR1 conferred resistance to AR-67 lactone. Prompted by recent studies showing increased OATP1B3 expression in certain cancer types, we investigated the effect of OATP1B3 expression on cell viability after exposure to AR-67 carboxylate. OATP1B3-expressing cells had increased carboxylate uptake as compared with mock-transfected cells but were not sensitized because the intracellular amount of lactone was 50-fold higher than that of carboxylate and comparable between OATP1B3-expressing and OATP1B3-nonexpressing cells.In conclusion, BCRP-and MDR1-mediated efflux of AR-67 lactone confers resistance to AR-67, but OATP1B3-mediated uptake of the AR-67 carboxylate does not sensitize OATP1B3-expressing tumor cells.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Phosphate-buffered saline was added; the cells were scrapped off and lysed by sonication. AR-67 lactone and carboxylate were extracted and quantified using HPLC (Horn et al, 2006).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

The Effect of Breast Cancer Resistance Protein, Multidrug Resistant Protein 1, and Organic Anion-Transporting Polypeptide 1B3 on the Antitumor Efficacy of the Lipophilic Camptothecin 7-t-Butyldimethylsilyl-10-Hydroxycamptothecin (AR-67) In Vitro

et al. 2013

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Silicon‐containing analogs of camptothecin as anticancer agents

Lazareva

Baryshok

Lazarev

2017

Archiv der Pharmazie

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Pharmacokinetic modeling of the blood‐stable camptothecin analog AR‐67 in two different formulations

Liu

Adane

Tang

et al. 2019

Biopharm & Drug Disp

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AR-67 is a lipophilic camptothecin analog currently under clinical investigation using a Cremophor EL based formulation. However, as potential toxicity limitations exist in the clinical use of Cremophor, an alternative cyclodextrin (SBE-β-CD) based formulation has been proposed. Pharmacokinetic (PK) studies were conducted in mice and the SBE-β-CD based formulation was compared with the Cremophor EL formulation.PK studies were conducted following intravenous or oral administration of AR-67 in either Cremophor or SBE-β-CD formulation in mice. Noncompartmental analysis was used to determine the plasma and tissue drug distribution. A non-linear mixed effects (population) PK model was developed to fit both the oral and intravenous data and to estimate key PK parameters. The effect of formulation was explored as a covariate in the PK model. AR-67 in the SBE-β-CD formulation had similar plasma PK and biodistribution to that in the Cremophor EL formulation. The proposed twocompartment model described the plasma PK of AR-67 in both formulations adequately. AR-67 in the SBE-β-CD formulation exhibited dose linearity following both oral and intravenous administration. Our studies indicate that SBE-β-CD is a viable alternative to Cremophor EL as a pharmaceutical excipient for formulating AR-67.

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Validation of an HPLC method for analysis of DB-67 and its water soluble prodrug in mouse plasma

Cited by 11 publications

References 19 publications

The Effect of Breast Cancer Resistance Protein, Multidrug Resistant Protein 1, and Organic Anion-Transporting Polypeptide 1B3 on the Antitumor Efficacy of the Lipophilic Camptothecin 7-t-Butyldimethylsilyl-10-Hydroxycamptothecin (AR-67) In Vitro

The Effect of Breast Cancer Resistance Protein, Multidrug Resistant Protein 1, and Organic Anion-Transporting Polypeptide 1B3 on the Antitumor Efficacy of the Lipophilic Camptothecin 7-t-Butyldimethylsilyl-10-Hydroxycamptothecin (AR-67) In Vitro

Silicon‐containing analogs of camptothecin as anticancer agents

Pharmacokinetic modeling of the blood‐stable camptothecin analog AR‐67 in two different formulations

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