UPLC-MS/MS Method for Givinostat in Rat Plasma: Development, Validation, in vivo Pharmacokinetics Study and in vitro Metabolic Stability Research
Givinostat, a potent histone deacetylase (HDAC) inhibitor, is promising for the treatment of relapsed leukemia and myeloma. This study aimed to develop and verify a quick assay for the measurement of givinostat concentration using ultra-performance liquid chromatography tandem mass spectrometry (UPL...
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| creator | Zhan, Ruanjuan Liu, Yanan Wu, Jun Shen, Yuxin Xu, Xinhao Lin, Guanyang Chen, Xiaocheng |
| description | Givinostat, a potent histone deacetylase (HDAC) inhibitor, is promising for the treatment of relapsed leukemia and myeloma.
This study aimed to develop and verify a quick assay for the measurement of givinostat concentration using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) with eliglustat as the internal standard (IS), establishing a basic pharmacokinetic profile for its pre-clinical application and metabolic stability in vitro.
Sample preparation was performed via protein precipitation using acetonitrile. The analyte (givinostat) and IS were gradient eluted on a Waters ACQUITY UPLC BEH C18 column (1.7 μm, 2.1 × 50 mm) with 0.1% formic acid (A) and acetonitrile (B) as the mobile-phase system. The multiple reaction monitoring (MRM) in positive ion mode was used to detect the mass transition pairs for givinostat and IS as follows:
422.01→186.11 for givinostat, and
405.40→84.10 for IS, respectively.
In the bioanalytical method, good linearity was observed between 2 and 4000 ng/mL (
=0.998). The intra- and inter-day precisions (RSD%) were lower than 15%, with an accuracy (RE%) of 95.8%-108.6%. The recovery exceeded 90%, and the matrix effect was within the range of 98.2%-107.6%. Additionally, this method was successful in evaluating pharmacokinetics in rats after an oral dose of 10 mg/kg givinostat. Finally, in vitro results showed that givinostat had a slow intrinsic clearance (CLint) value of 14.92 μL/min/mg protein with a half-life (t
) value of 92.87 min.
Givinostat was rapidly absorbed and cleared slowly in vivo, and it was confirmed by in vitro experiments. This study provides a potential reference for givinostat in clinical studies. |
| doi_str_mv | 10.2147/DDDT.S497308 |
| format | Article |
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This study aimed to develop and verify a quick assay for the measurement of givinostat concentration using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) with eliglustat as the internal standard (IS), establishing a basic pharmacokinetic profile for its pre-clinical application and metabolic stability in vitro.
Sample preparation was performed via protein precipitation using acetonitrile. The analyte (givinostat) and IS were gradient eluted on a Waters ACQUITY UPLC BEH C18 column (1.7 μm, 2.1 × 50 mm) with 0.1% formic acid (A) and acetonitrile (B) as the mobile-phase system. The multiple reaction monitoring (MRM) in positive ion mode was used to detect the mass transition pairs for givinostat and IS as follows:
422.01→186.11 for givinostat, and
405.40→84.10 for IS, respectively.
In the bioanalytical method, good linearity was observed between 2 and 4000 ng/mL (
=0.998). The intra- and inter-day precisions (RSD%) were lower than 15%, with an accuracy (RE%) of 95.8%-108.6%. The recovery exceeded 90%, and the matrix effect was within the range of 98.2%-107.6%. Additionally, this method was successful in evaluating pharmacokinetics in rats after an oral dose of 10 mg/kg givinostat. Finally, in vitro results showed that givinostat had a slow intrinsic clearance (CLint) value of 14.92 μL/min/mg protein with a half-life (t
) value of 92.87 min.
Givinostat was rapidly absorbed and cleared slowly in vivo, and it was confirmed by in vitro experiments. This study provides a potential reference for givinostat in clinical studies.</description><identifier>ISSN: 1177-8881</identifier><identifier>EISSN: 1177-8881</identifier><identifier>DOI: 10.2147/DDDT.S497308</identifier><identifier>PMID: 39830785</identifier><language>eng</language><publisher>New Zealand: Dove</publisher><subject>Administration, Oral ; Animals ; Carbamates - administration & dosage ; Carbamates - blood ; Carbamates - pharmacokinetics ; Chromatography, High Pressure Liquid ; givinostat ; Histone Deacetylase Inhibitors - administration & dosage ; Histone Deacetylase Inhibitors - blood ; Histone Deacetylase Inhibitors - pharmacokinetics ; Liquid Chromatography-Mass Spectrometry ; Male ; Microsomes, Liver - metabolism ; Original Research ; pharmacokinetic study ; rat plasma ; Rats ; Rats, Sprague-Dawley ; Tandem Mass Spectrometry ; uplc-ms/ms ; vitro metabolic stability</subject><ispartof>Drug design, development and therapy, 2025-01, Vol.19, p.219-228</ispartof><rights>2025 Zhan et al.</rights><rights>2025 Zhan et al. 2025 Zhan et al.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c338t-944955ec1d34becda39ca165673cb96f1eea4d8edb6de047e32a4a15bbc017f23</cites><orcidid>0000-0002-5046-9806</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742092/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742092/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,3849,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39830785$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhan, Ruanjuan</creatorcontrib><creatorcontrib>Liu, Yanan</creatorcontrib><creatorcontrib>Wu, Jun</creatorcontrib><creatorcontrib>Shen, Yuxin</creatorcontrib><creatorcontrib>Xu, Xinhao</creatorcontrib><creatorcontrib>Lin, Guanyang</creatorcontrib><creatorcontrib>Chen, Xiaocheng</creatorcontrib><title>UPLC-MS/MS Method for Givinostat in Rat Plasma: Development, Validation, in vivo Pharmacokinetics Study and in vitro Metabolic Stability Research</title><title>Drug design, development and therapy</title><addtitle>Drug Des Devel Ther</addtitle><description>Givinostat, a potent histone deacetylase (HDAC) inhibitor, is promising for the treatment of relapsed leukemia and myeloma.
This study aimed to develop and verify a quick assay for the measurement of givinostat concentration using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) with eliglustat as the internal standard (IS), establishing a basic pharmacokinetic profile for its pre-clinical application and metabolic stability in vitro.
Sample preparation was performed via protein precipitation using acetonitrile. The analyte (givinostat) and IS were gradient eluted on a Waters ACQUITY UPLC BEH C18 column (1.7 μm, 2.1 × 50 mm) with 0.1% formic acid (A) and acetonitrile (B) as the mobile-phase system. The multiple reaction monitoring (MRM) in positive ion mode was used to detect the mass transition pairs for givinostat and IS as follows:
422.01→186.11 for givinostat, and
405.40→84.10 for IS, respectively.
In the bioanalytical method, good linearity was observed between 2 and 4000 ng/mL (
=0.998). The intra- and inter-day precisions (RSD%) were lower than 15%, with an accuracy (RE%) of 95.8%-108.6%. The recovery exceeded 90%, and the matrix effect was within the range of 98.2%-107.6%. Additionally, this method was successful in evaluating pharmacokinetics in rats after an oral dose of 10 mg/kg givinostat. Finally, in vitro results showed that givinostat had a slow intrinsic clearance (CLint) value of 14.92 μL/min/mg protein with a half-life (t
) value of 92.87 min.
Givinostat was rapidly absorbed and cleared slowly in vivo, and it was confirmed by in vitro experiments. This study provides a potential reference for givinostat in clinical studies.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Carbamates - administration & dosage</subject><subject>Carbamates - blood</subject><subject>Carbamates - pharmacokinetics</subject><subject>Chromatography, High Pressure Liquid</subject><subject>givinostat</subject><subject>Histone Deacetylase Inhibitors - administration & dosage</subject><subject>Histone Deacetylase Inhibitors - blood</subject><subject>Histone Deacetylase Inhibitors - pharmacokinetics</subject><subject>Liquid Chromatography-Mass Spectrometry</subject><subject>Male</subject><subject>Microsomes, Liver - metabolism</subject><subject>Original Research</subject><subject>pharmacokinetic study</subject><subject>rat plasma</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Tandem Mass Spectrometry</subject><subject>uplc-ms/ms</subject><subject>vitro metabolic stability</subject><issn>1177-8881</issn><issn>1177-8881</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNpVksFuEzEQhleIipbCjTPykUPS2mvv2ssFoQTaSomImparNWvPNi6762A7kfIYvDEbEqr2NKOZT_-Mx3-WfWD0ImdCXk6n07uLpagkp-pVdsaYlGOlFHv9LD_N3sb4SGnJy5y-yU55pTiVqjjL_twvZpPxfHk5X5I5ppW3pPGBXLmt631MkIjrye0QFi3EDj6TKW6x9esO-zQiP6F1FpLz_WjPbd3Wk8UKQgfG_3I9JmciWaaN3RHo7QFJwe8nQe1bZ4Ym1K51aUduMSIEs3qXnTTQRnx_jOfZ_fdvd5Pr8ezH1c3k62xsOFdpXAlRFQUaZrmo0VjglQFWFqXkpq7KhiGCsAptXVqkQiLPQQAr6tpQJpucn2c3B13r4VGvg-sg7LQHp_8VfHjQEIYHtKhRIANTGoVMiSYXNaNSYlPJ4f7CMDZofTlorTd1h9YMxwnQvhB92endSj_4rR5-SOS02m_z6agQ_O8NxqQ7Fw22LfToN1FzVsiiYKrkAzo6oCb4GAM2T3MY1XtL6L0l9NESA_7x-W5P8H8P8L-eDbQI</recordid><startdate>20250101</startdate><enddate>20250101</enddate><creator>Zhan, Ruanjuan</creator><creator>Liu, Yanan</creator><creator>Wu, Jun</creator><creator>Shen, Yuxin</creator><creator>Xu, Xinhao</creator><creator>Lin, Guanyang</creator><creator>Chen, Xiaocheng</creator><general>Dove</general><general>Dove Medical Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-5046-9806</orcidid></search><sort><creationdate>20250101</creationdate><title>UPLC-MS/MS Method for Givinostat in Rat Plasma: Development, Validation, in vivo Pharmacokinetics Study and in vitro Metabolic Stability Research</title><author>Zhan, Ruanjuan ; Liu, Yanan ; Wu, Jun ; Shen, Yuxin ; Xu, Xinhao ; Lin, Guanyang ; Chen, Xiaocheng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c338t-944955ec1d34becda39ca165673cb96f1eea4d8edb6de047e32a4a15bbc017f23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Carbamates - administration & dosage</topic><topic>Carbamates - blood</topic><topic>Carbamates - pharmacokinetics</topic><topic>Chromatography, High Pressure Liquid</topic><topic>givinostat</topic><topic>Histone Deacetylase Inhibitors - administration & dosage</topic><topic>Histone Deacetylase Inhibitors - blood</topic><topic>Histone Deacetylase Inhibitors - pharmacokinetics</topic><topic>Liquid Chromatography-Mass Spectrometry</topic><topic>Male</topic><topic>Microsomes, Liver - metabolism</topic><topic>Original Research</topic><topic>pharmacokinetic study</topic><topic>rat plasma</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Tandem Mass Spectrometry</topic><topic>uplc-ms/ms</topic><topic>vitro metabolic stability</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhan, Ruanjuan</creatorcontrib><creatorcontrib>Liu, Yanan</creatorcontrib><creatorcontrib>Wu, Jun</creatorcontrib><creatorcontrib>Shen, Yuxin</creatorcontrib><creatorcontrib>Xu, Xinhao</creatorcontrib><creatorcontrib>Lin, Guanyang</creatorcontrib><creatorcontrib>Chen, Xiaocheng</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Drug design, development and therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhan, Ruanjuan</au><au>Liu, Yanan</au><au>Wu, Jun</au><au>Shen, Yuxin</au><au>Xu, Xinhao</au><au>Lin, Guanyang</au><au>Chen, Xiaocheng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>UPLC-MS/MS Method for Givinostat in Rat Plasma: Development, Validation, in vivo Pharmacokinetics Study and in vitro Metabolic Stability Research</atitle><jtitle>Drug design, development and therapy</jtitle><addtitle>Drug Des Devel Ther</addtitle><date>2025-01-01</date><risdate>2025</risdate><volume>19</volume><spage>219</spage><epage>228</epage><pages>219-228</pages><issn>1177-8881</issn><eissn>1177-8881</eissn><abstract>Givinostat, a potent histone deacetylase (HDAC) inhibitor, is promising for the treatment of relapsed leukemia and myeloma.
This study aimed to develop and verify a quick assay for the measurement of givinostat concentration using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) with eliglustat as the internal standard (IS), establishing a basic pharmacokinetic profile for its pre-clinical application and metabolic stability in vitro.
Sample preparation was performed via protein precipitation using acetonitrile. The analyte (givinostat) and IS were gradient eluted on a Waters ACQUITY UPLC BEH C18 column (1.7 μm, 2.1 × 50 mm) with 0.1% formic acid (A) and acetonitrile (B) as the mobile-phase system. The multiple reaction monitoring (MRM) in positive ion mode was used to detect the mass transition pairs for givinostat and IS as follows:
422.01→186.11 for givinostat, and
405.40→84.10 for IS, respectively.
In the bioanalytical method, good linearity was observed between 2 and 4000 ng/mL (
=0.998). The intra- and inter-day precisions (RSD%) were lower than 15%, with an accuracy (RE%) of 95.8%-108.6%. The recovery exceeded 90%, and the matrix effect was within the range of 98.2%-107.6%. Additionally, this method was successful in evaluating pharmacokinetics in rats after an oral dose of 10 mg/kg givinostat. Finally, in vitro results showed that givinostat had a slow intrinsic clearance (CLint) value of 14.92 μL/min/mg protein with a half-life (t
) value of 92.87 min.
Givinostat was rapidly absorbed and cleared slowly in vivo, and it was confirmed by in vitro experiments. This study provides a potential reference for givinostat in clinical studies.</abstract><cop>New Zealand</cop><pub>Dove</pub><pmid>39830785</pmid><doi>10.2147/DDDT.S497308</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-5046-9806</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Administration, Oral Animals Carbamates - administration & dosage Carbamates - blood Carbamates - pharmacokinetics Chromatography, High Pressure Liquid givinostat Histone Deacetylase Inhibitors - administration & dosage Histone Deacetylase Inhibitors - blood Histone Deacetylase Inhibitors - pharmacokinetics Liquid Chromatography-Mass Spectrometry Male Microsomes, Liver - metabolism Original Research pharmacokinetic study rat plasma Rats Rats, Sprague-Dawley Tandem Mass Spectrometry uplc-ms/ms vitro metabolic stability |
| title | UPLC-MS/MS Method for Givinostat in Rat Plasma: Development, Validation, in vivo Pharmacokinetics Study and in vitro Metabolic Stability Research |
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