Pharmacokinetic and Metabolism Studies of Monomethyl Auristatin F via Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry
A simple liquid chromatography−quadrupole-time-of-flight−mass spectrometric assay (LC-TOF-MS/MS) has been developed for the evaluation of metabolism and pharmacokinetic (PK) characteristics of monomethyl auristatin F (MMAF) in rat, which is being used as a payload for antibody-dr...
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| Format: | Article |
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MDPI AG
2019-07-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/24/15/2754 |
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| author | Min-Ho Park Byeong ill Lee Jin-Ju Byeon Seok-Ho Shin Jangmi Choi Yuri Park Young G. Shin |
| author_facet | Min-Ho Park Byeong ill Lee Jin-Ju Byeon Seok-Ho Shin Jangmi Choi Yuri Park Young G. Shin |
| author_sort | Min-Ho Park |
| collection | DOAJ |
| description | A simple liquid chromatography−quadrupole-time-of-flight−mass spectrometric assay (LC-TOF-MS/MS) has been developed for the evaluation of metabolism and pharmacokinetic (PK) characteristics of monomethyl auristatin F (MMAF) in rat, which is being used as a payload for antibody-drug conjugates. LC-TOF-MS/MS method was qualified for the quantification of MMAF in rat plasma. The calibration curves were acceptable over the concentration range from 3.02 to 2200 ng/mL using quadratic regression. MMAF was stable in various conditions. There were no significant matrix effects between rat and other preclinical species. The PK studies showed that the bioavailability of MMAF was 0% with high clearance. Additionally, the metabolite profiling studies, in vitro/in vivo, were performed. Seven metabolites for MMAF were tentatively identified in liver microsome. The major metabolic pathway was demethylation, which was one of the metabolic pathways predicted by MedChem Designer. Therefore, these results will be helpful to understand the PK, catabolism, and metabolism behavior of MMAF comprehensively when developing antibody-drug conjugates (ADCs) in the future. |
| first_indexed | 2024-12-21T08:24:47Z |
| format | Article |
| id | doaj.art-1937c08029fd4848b762197dda7acf70 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-21T08:24:47Z |
| publishDate | 2019-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-1937c08029fd4848b762197dda7acf702022-12-21T19:10:21ZengMDPI AGMolecules1420-30492019-07-012415275410.3390/molecules24152754molecules24152754Pharmacokinetic and Metabolism Studies of Monomethyl Auristatin F via Liquid Chromatography-Quadrupole-Time-of-Flight Mass SpectrometryMin-Ho Park0Byeong ill Lee1Jin-Ju Byeon2Seok-Ho Shin3Jangmi Choi4Yuri Park5Young G. Shin6College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, KoreaCollege of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, KoreaCollege of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, KoreaCollege of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, KoreaCollege of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, KoreaCollege of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, KoreaCollege of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, KoreaA simple liquid chromatography−quadrupole-time-of-flight−mass spectrometric assay (LC-TOF-MS/MS) has been developed for the evaluation of metabolism and pharmacokinetic (PK) characteristics of monomethyl auristatin F (MMAF) in rat, which is being used as a payload for antibody-drug conjugates. LC-TOF-MS/MS method was qualified for the quantification of MMAF in rat plasma. The calibration curves were acceptable over the concentration range from 3.02 to 2200 ng/mL using quadratic regression. MMAF was stable in various conditions. There were no significant matrix effects between rat and other preclinical species. The PK studies showed that the bioavailability of MMAF was 0% with high clearance. Additionally, the metabolite profiling studies, in vitro/in vivo, were performed. Seven metabolites for MMAF were tentatively identified in liver microsome. The major metabolic pathway was demethylation, which was one of the metabolic pathways predicted by MedChem Designer. Therefore, these results will be helpful to understand the PK, catabolism, and metabolism behavior of MMAF comprehensively when developing antibody-drug conjugates (ADCs) in the future.https://www.mdpi.com/1420-3049/24/15/2754MMAFADCbioanalysismetabolismpharmacokinetics |
| spellingShingle | Min-Ho Park Byeong ill Lee Jin-Ju Byeon Seok-Ho Shin Jangmi Choi Yuri Park Young G. Shin Pharmacokinetic and Metabolism Studies of Monomethyl Auristatin F via Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry Molecules MMAF ADC bioanalysis metabolism pharmacokinetics |
| title | Pharmacokinetic and Metabolism Studies of Monomethyl Auristatin F via Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry |
| title_full | Pharmacokinetic and Metabolism Studies of Monomethyl Auristatin F via Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry |
| title_fullStr | Pharmacokinetic and Metabolism Studies of Monomethyl Auristatin F via Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry |
| title_full_unstemmed | Pharmacokinetic and Metabolism Studies of Monomethyl Auristatin F via Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry |
| title_short | Pharmacokinetic and Metabolism Studies of Monomethyl Auristatin F via Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry |
| title_sort | pharmacokinetic and metabolism studies of monomethyl auristatin f via liquid chromatography quadrupole time of flight mass spectrometry |
| topic | MMAF ADC bioanalysis metabolism pharmacokinetics |
| url | https://www.mdpi.com/1420-3049/24/15/2754 |
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