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Lee, Kyoung-Jin; Mower, Rachel; Hollenbeck, Tom; Castelo, Jesus; Johnson, Nikole; Gordon, Perry; Sinko, Patrick J.; Holme, Kevin R.; Lee, Jun Young

doi:10.1023/a:1024406221962

Cited by 113 publications

(50 citation statements)

References 20 publications

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“…Smith et al [19] [20] evaluated blood-binding parameters of IM and its metabolite NDI in healthy males (n = 3) and female AML patients (n = 5). Protein binding of IM and NDI were determined in vitro using (14) C labeled compounds. Plasma was centrifuged in Centrifree devices (10 min, 2000 × g, 37 • C).…”

Section: (%) Accuracy (%) CV (%) Accuracy (%)mentioning

confidence: 99%

“…The disadvantage of both equilibrium dialysis and conventional ultrafiltration is that they can be susceptible to non-specific binding (NSB) of drugs to the polymer-constructed components of filter membranes or glass and plastic recipients. NSB could be reduced using different approaches of pre-treatment (tween 80, benzalkonium chloride [14]) of the filter.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Determination of unbound fraction of imatinib and N-desmethyl imatinib, validation of an UPLC–MS/MS assay and ultrafiltration method

Arellano

Gandia

Lafont

et al. 2012

Journal of Chromatography B

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Section: (%) Accuracy (%) CV (%) Accuracy (%)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Determination of unbound fraction of imatinib and N-desmethyl imatinib, validation of an UPLC–MS/MS assay and ultrafiltration method

Arellano

Gandia

Lafont

et al. 2012

Journal of Chromatography B

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“…Moreover, the lack of a mucus layer renders the Caco-2 cells more 32 sensitive to pH changes of the apical media, as compared to 33 mammalian intestinal tissue (Lee et al, 2005). Additionally, the 34 Caco-2 model cannot be used for regional absorption studies, for 35 obvious reasons.…”

mentioning

confidence: 99%

In situ perfusion in rodents to explore intestinal drug absorption: Challenges and opportunities

Stappaerts

Brouwers

Annaert

et al. 2015

International Journal of Pharmaceutics

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The in situ intestinal perfusion technique in rodents is a very important absorption model, not only because of its predictive value, but it is also very suitable to unravel the mechanisms underlying intestinal drug absorption. This literature overview covers a number of specific applications for which the in situ intestinal perfusion set-up can be applied in favor of established in vitro absorption tools, such as the Caco-2 cell model. Qualities including the expression of drug transporters and metabolizing enzymes relevant for human intestinal absorption and compatibility with complex solvent systems render the in situ technique the most designated absorption model to perform transporter-metabolism studies or to evaluate the intestinal absorption from biorelevant media. Over the years, the in situ intestinal perfusion model has exhibited an exceptional ability to adapt to the latest challenges in drug absorption profiling. For instance, the introduction of the mesenteric vein cannulation allows determining the appearance of compounds in the blood and is of great use, especially when evaluating the absorption of compounds undergoing intestinal metabolism. Moreover, the use of the closed loop intestinal perfusion set-up is interesting when compounds or perfusion media are scarce. Compatibility with emerging trends in pharmaceutical profiling, such as the use of knockout or transgenic animals, generates unparalleled possibilities to gain mechanistic insight into specific absorption processes. Notwithstanding the fact that the in situ experiments are technically challenging and relatively time-consuming, the model offers great opportunities to gain insight into the processes determining intestinal drug absorption.

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“…The pretreatment of the ultrafiltration device with 5% Triton-X was found to be able to eliminate the non-specific binding. Without Triton X-100 treatment, the recovery of MNP001 (dissolved in phosphate saline buffer) in filtrate was only 41-49%, whereas the recovery was complete (100712.0%) with the surfactant pretreatment [26]. MNP001 was found to be distributed mostly into the plasma rather than the blood cell.…”

Section: Discussionmentioning

confidence: 96%

Preclinical pharmacokinetics and metabolism of MNP001, a piperidine analog of 3‐carbamyl compounds

Xia

Wang

Fox

2010

Biopharm & Drug Disp

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MNP001 is a newly synthesized 3-carbamyl-4-methylpyrrole analog with dual pharmacophores simultaneously to inhibit phosphodiesterase type 4 (PDE4) and to antagonize L-type calcium channels. The physicochemical properties of MNP001, including solubility, pKa, Log P, plasma protein binding and plasma/blood partitioning, were determined to support the pharmacokinetic characterization. The preclinical pharmacokinetic parameters were determined in an in vivo rat model and the metabolic pathways of MNP001 were characterized by incubating the compound in vitro in rat or human microsomes/supersomes cocktails. MNP001 was found to have a low solubility in simulated intestinal fluid but a high solubility in simulated gastric fluid. MNP001 is a highly lipophilic compound with a Log P value greater than 4. MNP001 was highly bound to the plasma protein and had an uneven partition between red blood cells and plasma. MNP001 exhibited a rapid absorption, broad distribution, slow systemic clearance and a low but pharmacologically relevant oral bioavailability in rats. The low oral bioavailability was possibly caused by the low aqueous solubility of MNP001 in the gastrointestinal tract. However, 8 h after oral dosing, the mean plasma level of MNP001 was able to remain about 2-fold greater than the minimum effective concentration. The major metabolite of MNP001 was defined as a tetrahydropyridine product (MNP001-M4) of CYP3A4-mediated phase I oxidation. The possibility that the major metabolite MNP001-M4 may have a comparable antihypertensive efficacy to MNP001 needs to be studied.

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Abstract: The pretreated membrane with TW 80 or BAK showed significantly less NSB for compounds that had a tendency toward high membrane binding. A modified UF method with pretreatment improved the performance of UF and was able to produce comparable PB results to ED.

Cited by 113 publications

References 20 publications

Determination of unbound fraction of imatinib and N-desmethyl imatinib, validation of an UPLC–MS/MS assay and ultrafiltration method

Determination of unbound fraction of imatinib and N-desmethyl imatinib, validation of an UPLC–MS/MS assay and ultrafiltration method

In situ perfusion in rodents to explore intestinal drug absorption: Challenges and opportunities

Preclinical pharmacokinetics and metabolism of MNP001, a piperidine analog of 3‐carbamyl compounds

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