Simultaneous determination of didanosine and its amino acid prodrug, valdidanosine by hydrophilic interaction chromatography coupled with electrospray ionization tandem mass spectrometry: Application to a pharmacokinetic study in rats

Yan, Zhongtian; Sun, Jin; Wang, Jinling; Xu, Youjun; Chang, Y.Y.; Meng, Ping; Zhu, Meng; Fu, Qiang; Sun, Yongbing; Zhang, He

doi:10.1016/j.jchromb.2009.11.041

Cited by 15 publications

(5 citation statements)

References 25 publications

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“…For analysis of DDI and compound 4a and lamivudine (the internal standard), oasis HLB cartridges obtained from Waters Corporation (1 cc, 30 mg, Milford, MA, USA) were used to extract analytes from rat plasma. 41 The same chromatographic column as mentioned above was used for analysis. UPLC elution was carried out using a mobile phase consisting of water containing 0.1% formic acid and methanol (85:15, v/v).…”

Section: Hydrolysis Stability Studies 1 Stability In Phosphate Buffermentioning

confidence: 99%

Bifunctional Peptidomimetic Prodrugs of Didanosine for Improved Intestinal Permeability and Enhanced Acidic Stability: Synthesis, Transepithelial Transport, Chemical Stability and Pharmacokinetics

Yan¹,

Sun²,

Chang³

et al. 2011

Mol. Pharmaceutics

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Five peptidomimetic prodrugs of didanosine (DDI) were synthesized and designed to improve bioavailability of DDI following oral administration via targeting intestinal oligopeptide transporter (PepT1) and enhancing chemical stability. The permeability of prodrugs was screened in Caco-2 cells grown on permeable supports. 5'-O-L-valyl ester prodrug of DDI (compound 4a) demonstrated the highest membrane permeability and was selected as the optimal target prodrug for further studies. The uptake of glycylsarcosine (Gly-Sar, a typical substrate of PepT1) by Caco-2 cells could be inhibited by compound 4a in a concentration-dependent manner. The Caco-2 cells were treated with 0.2 nM leptin for enhanced PepT1 expression. The uptake of compound 4a was markedly increased in the leptin-treated Caco-2 cells compared with the control Caco-2 cells, both of which were obviously inhibited by 20 mM Gly-Sar. The K(m) and V(max) values of kinetic study of compound 4a transported by PepT1 in Caco-2 cells were 0.91 mM and 11.94 nmol/mg of protein/10 min, respectively. The chemical stability studies were performed in simulated gastric fluid (SGF), phosphate buffers under various pH conditions, rat tissue homogenates and plasma at 37 °C. The concentrations of DDI could not be detected in the two minutes in SGF. But compound 4a could significantly increase DDI acidic stability, and its t(½) was extended to as long as 36 min in SGF. Compound 4a was stable in pH 6.0 phosphate buffer but could be quickly transformed into DDI in plasma and tissue homogenates. The oral absolute bioavailability of DDI was 47.2% and 7.9% after compound 4a and DDI were orally administered to rats at a dose of 15 mg/kg, respectively. The coadministration with antiacid agent could also suggest that compound 4a was more stable under harsh acidic conditions compared with DDI. Compound 4a bioavailability in rats was reduced to 33.9% when orally co-administered with Gly-Sar (100 mg/kg). The In Vivo bioactivation mechanism of compound 4a was investigated by comparing the levels of DDI and compound 4a in the jugular and portal veins in rats. The plasma concentration of intact compound 4a was very low in portal veins and could hardly be detected in the jugular vein. In conclusion, compound 4a could significantly improve the oral bioavailability of DDI in rats through PepT1-mediated absorption and enhanced acidic stability, followed by rapid and mostly intracellular bioactivation, the majority in the intestinal cells but the minority in the liver. Additionally, the prodrug strategy targeted to intestinal PepT1 could offer a promising strategy to improve oral bioavailability of poorly absorbed didanosine.

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Section: Hydrolysis Stability Studies 1 Stability In Phosphate Buffermentioning

confidence: 99%

Bifunctional Peptidomimetic Prodrugs of Didanosine for Improved Intestinal Permeability and Enhanced Acidic Stability: Synthesis, Transepithelial Transport, Chemical Stability and Pharmacokinetics

Yan¹,

Sun²,

Chang³

et al. 2011

Mol. Pharmaceutics

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“…Conventional approaches for cell counting include hemocytometer, microscope, or flow cytometry, but other indirect approaches using protein [23] and DNA [24] determination have also proven to be useful [18]. Manual cell counting using hemocytometry is often considered the gold standard of cell counting methods in many laboratories [18,25], [26]. However, this method has several limitations including: (1) Operator-dependent variability in distinguishing cells from cell clusters, cell debris or other particles; (2) errors in sample loading volume, dilution, and pipetting; (3) Trypan-blue toxicity to viable cells leading to cell lysis, which underestimates the actual number of viable cells in the sample; and (4) accuracy and precision associated with manual counting of cells.…”

Section: Cell Countingmentioning

confidence: 99%

Direct and indirect quantification of phosphate metabolites of nucleoside analogs in biological samples

Gautam

Alamoudi

Kumar

et al. 2020

Journal of Pharmaceutical and Biomedical Analysis

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Nucleoside reverse transcriptase inhibitors (NRTIs) are prodrugs that require intracellular phosphorylation to active triphosphate nucleotide metabolites (NMs) for their pharmacological activity. However, monitoring these pharmacologically active NMs is challenging due to their instability, high hydrophilicity, and their low concentrations in blood and tissues. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) is the gold standard technique for the quantification of NRTIs and their phosphorylated NMs. In this review, an overview of the publications describing the quantitative analysis of intracellular and total tissue concentration of NMs is presented. The focus of this review is the comparison of the different approaches and challenges associated with sample collection, tissue homogenization, cell lysis, cell counting, analyte extraction, sample storage conditions, and LC-MS analysis. Quantification methods of NMs via LC-MS can be categorized into direct and indirect methods. In the direct LC-MS methods, chromatographic retention of the NMs is accomplished by ion-exchange (IEX), ionpairing (IP), hydrophilic interaction (HILIC), porous graphitic carbon (PGC) chromatography, or capillary electrophoresis (CE). In indirect methods, parent nucleosides are 1 st generated from the dephosphorylation of NMs during sample preparation and are then quantified by reverse phase LC-MS as surrogates for their corresponding NMs. Both approaches have advantages and disadvantages associated with them, which are discussed in this review.

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“…It is a synthetic drug, intracellularly phosphorylated nucleoside analogue to the active metabolite, which inhibits the activity of HIV reverse transcriptase by competing with the natural substrate (Moreno et al, 2007;Nannemann et al, 2010). However, it exhibits a low oral bioavailability (F = 20-40 %) because of poor permeability across the intestinal epithelium (Yan et al, 2010;Ribera et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Didanosine phosphoramidates: synthesis, docking to viral NA, antibacterial and antiviral activity

et al. 2014

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In order to increase the binding energy with haemaglutinin-neuraminidase (HN) protein of Newcastle disease virus (NDV), to improve the membrane permeability and to increase antiviral activity, modified structures of didanosine (ddI) were designed by phosphorylation and substitution with various bio-active amines. The designed derivatives revealed better binding energy values (in between -7.9 and -10.6 kcal/mol) than ddI (-7.3 kcal/ mol) with HN of NDV. The docking simulations were encouraged for synthesis and screening of their antiviral activity against NDV in the chicken embryonated eggs. In vitro antibacterial activity is also evaluated for the title compounds. The title compounds exhibited three times of improved antiviral activity than that of the parent compound (ddI). In addition to this the title compounds were performed as good antibacterial agents.

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Simultaneous determination of didanosine and its amino acid prodrug, valdidanosine by hydrophilic interaction chromatography coupled with electrospray ionization tandem mass spectrometry: Application to a pharmacokinetic study in rats

Cited by 15 publications

References 25 publications

Bifunctional Peptidomimetic Prodrugs of Didanosine for Improved Intestinal Permeability and Enhanced Acidic Stability: Synthesis, Transepithelial Transport, Chemical Stability and Pharmacokinetics

Bifunctional Peptidomimetic Prodrugs of Didanosine for Improved Intestinal Permeability and Enhanced Acidic Stability: Synthesis, Transepithelial Transport, Chemical Stability and Pharmacokinetics

Direct and indirect quantification of phosphate metabolites of nucleoside analogs in biological samples

Didanosine phosphoramidates: synthesis, docking to viral NA, antibacterial and antiviral activity

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