Yongbing Sun

High-performance liquid chromatography/tandem mass spectrometry method for the simultaneous determination of cytarabine and its valyl prodrug valcytarabine in rat plasma.

A sensitive, specific and rapid HPLC-MS/MS method has been developed and validated for the simultaneous determination of cytarabine and valcytarabine (valyl prodrug of cytarabine) in rat plasma in the present study. The analytes were separated on a C18 column (50 mm x 2.1 mm, 1.7 microm) and a triple-quadrupole mass spectrometry equipped with an electrospray ionization (ESI) source was applied for detection. Cation exchange solid-phase extraction cartridge was employed to extract the analytes from rat plasma, with high recovery of cytarabine (>85%). The method was linear over the concentration ranges of 10-20,000 ng/mL for cytarabine and 25-1000 ng/mL for valcytarabine. The lower limit of quantitation (LLOQ) of cytarabine and valcytarabine was 10 and 25 ng/mL, respectively. The intra-day and inter-day relative standard deviation (RSD) were less than 15% and the relative error (RE) were all within 15%. Finally, the method was successfully applied to support the prodrug pharmacokinetic study after valcytarabine and cytarabine were orally administrated to the Sprague-Dawley rat, respectively.

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.

A rapid, sensitive and selective ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method with hydrophilic interaction chromatography has been developed and validated for the simultaneous determination of didanosine and valdidanosine (L-valine amino acid ester prodrug of didanosine) in rat plasma. Solid-phase extraction (SPE) column was employed to extract the analytes from rat plasma, with high extraction recovery (>85%) for both didanosine and valdidanosine. The analytes were then separated by hydrophilic interaction chromatography (HILIC column) and detected by a triple-quadrupole mass spectrometry equipped with an electrospray ionization (ESI) source. The method was linear over the concentration ranges of 2-20,000 ng/mL for didanosine and 4-300 ng/mL for valdidanosine. The lower limit of quantitation (LLOQ) of didanosine and valdidanosine was 2 and 4 ng/mL, respectively. The intra-day and inter-day relative standard deviation (RSD) were less than 15% and the relative errors (RE) were all within 15%. Finally, the validated UPLC-MS/MS method was successfully applied to the pharmacokinetic study after either didanosine or valdidanosine orally administrated to the Sprague-Dawley rats.

Prodrug Design Targeting Intestinal PepT1 for Improved Oral Absorption: Design and Performance

Oligopeptide transporter 1 (PepT1) plays an essential role in the oral absorption of di-and tripeptides from the digestion of ingested protein. PepT1 has become a striking prodrug-designing target recently, since some poorly absorbed drugs can be modified as peptidomimetic prodrugs targeting intestinal PepT1 to improve membrane permeability, and eventually oral absorption of the parent drug. However, little and no comprehensive attempts have been made to especially focus on the recent developments of prodrugs targeting intestinal PepT1. This article summarized biology, transport mechanism, structure-transport requirements for PepT1 and significant advances on the PepT1-targeted prodrugs within the two decades. The article also aimed to highlight some inspirations and knowledge on the multifunctional PepT1-targeted design, which are necessary for obtaining optimal prodrug candidates. That is the requirements of multifunctional rational PepT1 prodrugs include enough binding affinity for PepT1, controlled or targeted release of parent drug, escapement from P-gp mediated efflux and enhanced chemical/metabolic stability. Several types of peptidomimetic prodrugs reported recently were discussed in detail in this review.

Rapid and sensitive hydrophilic interaction chromatography/tandem mass spectrometry method for the determination of glycyl-sarcosine in cell homogenates

A rapid, selective and sensitive hydrophilic interaction chromatography/tandem mass spectrometry (HILIC/MS/MS) was developed and validated for the determination of glycyl-sarcosine (Gly-Sar) in Caco-2 cell homogenates. After a simple protein precipitation with acetonitrile, the analyte was separated on a HILIC column and detected by a triple quadrupole mass spectrometry equipped with an electrospray ionization (ESI) source. The method was linear among the concentration range of 1-2000 ng/mL for Gly-Sar and the lower limit of quantification (LLOQ) was 1 ng/mL using as l ittle as 50 microL of cell homogenates. The intra-day and inter-day relative standard deviations (RSD) were less than 15% and the relative errors (RE) were all within +/-15%. The validated method was successfully employed in the study of Gly-Sar uptake inhibition in Caco-2 cells by valcytarabine, a potential substrate of the peptide transporter 1 (PEPT1).