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Poster Abstracts Drug Metabolism Reviews ISSN: 0360-2532 (Print) 1097-9883 (Online) Journal homepage: http://www.tandfonline.com/loi/idmr20 Poster Abstracts To cite this article: (2011) Poster Abstracts, Drug Metabolism Reviews, 43:sup2, 37-211, DOI: 10.3109/03602532.2011.629832 To link to this article: http://dx.doi.org/10.3109/03602532.2011.629832 Published online: 07 Nov 2011. Submit your article to this journal Article views: 2899 View related articles Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=idmr20 Download by: [176.12.237.34] Date: 26 January 2017, At: 12:03 Drug Metabolism Reviews Drug Metabolism Reviews, 2011; 43(S2): 37–211 2011 © 2011 Informa Healthcare USA, Inc. ISSN 0360-2532 print/ISSN 1097-9883 online 43 DOI: 10.3109/03602532.2011.629832 S2 37 Poster Abstracts 211 00 00 0000 P1. A method for monitoring drug exposure in hematopoietic stem cell transplant recipients 00 00 0000 Isabelle Laverdiere1, Patrick Caron2, Félix Couture3, Éric Lévesque4 and Chantal Guillemette5 00 00 0000 1Laval University, CHUL Research Center, Quebec, QC, Canada, 2CHUL Research Center, Quebec, QC, Canada, 0360-2532 3Hematology-oncology, Hôtel-Dieu de Québec Hospital, Québec, QC, Canada, 4Pharmacogenomics Laboratory, CHUQ Research Center, Québec, QC, Canada, 5Pharmacogenomics Laboratory, CHUQ Research Center and Faculty of 1097-9883 Pharmacy, Laval University, Québec, QC, Canada © 2011 Informa Healthcare USA, Inc. The use of combinations of immunosuppressant drugs is considered the therapeutic gold standard for post-allogeneic hematopoietic stem cell transplantation (HSCT) to prevent serious complications such as graft versus host disease and rejec- 10.3109/03602532.2011.629832 tion. However, these drugs have a narrow therapeutic index and wide inter-individual pharmacokinetic fluctuations, result- ing in unpredictable levels of drugs in the blood. Systemic concentrations of several immunosuppressive drugs have been correlated with their efficacy and potential life-threatening complications, thus supporting the need for a pharmacokinetic monitoring. Some chromatographic techniques have been proposed for the simultaneous monitoring of multiple immuno- suppressive drugs, but none offers the possibility of measuring cyclosporine, tacrolimus, methotrexate, prednisone, pred- nisolone, and methylprednisone in addition to total and free mycophenolic acid (MPA) and its phenolic (MPAG) and acyl (AcMPAG) glucuronides. To address this critical deficiency, a liquid chromatography–coupled tandem mass spectrometry method was developed for the quantification of circulating levels of these multiple immunosuppressant drugs. Linearity, pre- cision and accuracy were validated within the typical therapeutic range of concentrations for each compound. The method could measure individual drugs with high sensitivity, accuracy (bias <14%), and reproducibility (CV <12.8%). Its clinical appli- cation was validated by measuring levels of these drugs in samples obtained from HSCT recipients treated with combined immunosuppressive drug therapy. Our results indicate that this approach is suitable for simultaneous determination of in vivo levels of immunosuppressive drugs commonly used in combined therapies. This method requires a small-volume peripheral blood sample, an attribute that may be beneficial to HSCT patients in the clinic. Indeed, owing to the frequent administration of myeloablative conditioning regimens in the pre-transplantation period, the recovery of hematologic function is slow and gradual after engraftment. It is therefore favorable to limit blood sample collection in the immediate post-transplantation period. This method may be convenient for large-scale clinical studies aimed at improving and optimizing patient outcomes. It could also be useful in therapeutic drug monitoring to promote the efficient use of immunosuppressive drugs and thus to limit life-threatening complications related to non-optimal exposure to immunosuppressive medications. P2. Abstract withdrawn P3. Absolute UGT protein quantification by LC-MS3 Richard King1, Carmen Fernandez-Metzler1 and J. Larry Campbell2 1PharmaCadence Analytical Services, LLC, Hatfield, PA, 2AB SCIEX, Concord, ON, Canada The absolute quantification of proteins involved in drug metabolism is a new area that is gaining in popularity and utility. By far the most often used strategy is the surrogate peptide approach. These methods rely on detection of peptides created from the protein of interest by enzymatic or chemical digestion. Typically, the protein of interest and a stable isotopically labeled internal standard peptide are digested in a relevant sample such as a microsomal fraction or plasma containing often large amounts of other proteins. The final digested sample may contain thousands of peptides derived from any combination of the proteins present in the sample matrix. The complexity of the digested sample makes selective detection a challenge, even 37 38 Poster Abstracts by LC-MS/MS. Selected reaction monitoring (SRM) of HPLC separated samples is most often considered the gold standard for selectivity; however, SRM often does not have the selectivity needed to allow absolute quantification of surrogate peptides from biological matrices. Vastly improved selectivity can be realized using MS3. MS3 is a term used to describe multiple steps of mass dependent isolation and fragmentation followed by mass analysis and detection. The extra step of isolation and fragmentation associated with MS3 provides the enhanced selectivity of the technique. In this presentation, we discuss the implementation of MS3 with 40ms cycle time on the 5500QTRAP and we compare the quantitative results for six UGT isoforms measured from human liver microsomes using selected reaction monitoring and MS3. The work was done using the ABSciex QTRAP 5500 mass spectrometer and an Eksigent HT Express HPLC with 1.0 mm ID × 30 mm C18 reverse phase column and gradient elution. The enhanced selectivity of MS3 improves assay precision as measured by %CV and the assay LLOQ as compared to SRM. The improvement in signal to noise also makes automated data processing of the MS3 data for quantitative analysis of protein practical. The time required to integrate the MS3 mass chromatograms and provide quantita- tive results is approximately 30% of the time required to process the SRM data for the same samples. P4. Application of the narrow window mass extraction technique for in vitro adme screening in drug discovery Barry Press, Rima Al-Awar and Ahmed Aman Medicinal Chemistry, Ontario Institute for Cancer Research, Toronto, ON, Canada Incorporating higher throughput analytical methods and enhancing the ability for data mining of in vitro ADME samples can greatly benefit drug discovery teams during lead optimization. Standard bioanalytical techniques generally rely on triple quadrupole mass spectrometers using the technique of multiple reaction monitoring (MRM) for quantification (QUAN). Although this conventional MRM approach can provide high specificity and sensitivity, this practice is also time-consuming since it is a two-step process and requires the optimization of multiple parameters (cone voltage, colli- sion energy, and Q1/Q3 m/z values) for each and every compound being analyzed. Furthermore, MRM techniques only detect the initial compound of interest and data mining for other, qualitative (QUAL) information (such as metabolite formation) is not possible. The use of a sensitive hybrid Q-Tof instrument in a full scan acquisition mode and subse- quent narrow window mass eliminates the need for compound optimization while also providing both qualitative and quantitative (QUAL/QUAN) data to assist chemistry efforts in structure-property-relationships (SPR). The Xevo-Q-TOF mass spectrometer is a high resolution accurate mass instrument which possesses the speed, sensitivity, linearity, and wide mass range needed to screen in vitro ADME samples. The high resolution capabilities of Q-TOF-MS, combined with mass defect filtering and monitoring of isotopic peak patterns, allows for the discrimination against background noise when performing narrow window mass extraction from a full scan analysis. Samples were generated from multiple ADME assays including cellular (Caco-2) permeability, microsomal and hepatocyte stability, plasma stability, protein binding, and CYP450 inhibition of (known) metabolite formation. Chromatographic separations were obtained utilizing an Acquity UPLC and generic gradient conditions. Quantitative results obtained by narrow m/z windows were com- pared with traditional MRM analysis of the same samples analyzed using the high-sensitivity QTRAP 5500 system.. Data mining was then performed on the full scan analysis to identify known metabolites such as glucuronide, de-methylated, and hydroxylated metabolites from metabolic assays, as well as to determine possible non-hepatic compound instability and isomerization from in vitro plasma stability and permeability samples. Results indicate that the use of the Xevo-Q- TOF, combined with narrow window mass extraction and full scan analysis, gives comparable quantitative data (e.g. percent loss of parent compound) to conventional MRM techniques without the need for time-consuming compound optimization of new chemical entities (NCEs) or known CYP-dependent metabolites. In addition, valuable qualitative information could be obtained only from Xevo-Q-TOF full scans showing the susceptibility of reference compounds and NCEs
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