Pre-Clinical Pharmacokinetics, Tissue Distribution and Physicochemical Studies of CLBQ14, a Novel Methionine Aminopeptidase Inhibitor for the Treatment of Infectious Diseases
Oscar Ekpenyong, Xiuqing Gao, Jing Ma, Candace Cooper, Linh Nguyen, Omonike A Olaleye, Dong Liang, Huan Xie Department of Pharmaceutical and Environmental Health Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USACorrespondence: Huan XieDepartment of Pharma...
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2020-03-01
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| Series: | Drug Design, Development and Therapy |
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| Online Access: | https://www.dovepress.com/pre-clinical-pharmacokinetics-tissue-distribution-and-physicochemical--peer-reviewed-article-DDDT |
| _version_ | 1818150868433764352 |
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| author | Ekpenyong O Gao X Ma J Cooper C Nguyen L Olaleye OA Liang D Xie H |
| author_facet | Ekpenyong O Gao X Ma J Cooper C Nguyen L Olaleye OA Liang D Xie H |
| author_sort | Ekpenyong O |
| collection | DOAJ |
| description | Oscar Ekpenyong, Xiuqing Gao, Jing Ma, Candace Cooper, Linh Nguyen, Omonike A Olaleye, Dong Liang, Huan Xie Department of Pharmaceutical and Environmental Health Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USACorrespondence: Huan XieDepartment of Pharmaceutical and Environmental Health Sciences, College of Pharmacy and Health Sciences, Texas Southern University, 3100 Cleburne Street, Houston, TX 77004, USAEmail huan.xie@tsu.eduIntroduction: CLBQ14, a derivative of 8-hydroxyquinoline, exerts its chemotherapeutic effect by inhibiting methionine aminopeptidase (MetAP), the enzyme responsible for the post-translational modification of several proteins and polypeptides. MetAP is a novel target for infectious diseases. CLBQ14 is selective and highly potent against replicating and latent Mycobacterium tuberculosis making it an appealing lead for further development.Methods: The physicochemical properties (solubility, pH stability and lipophilicity), in vitro plasma stability and metabolism, pre-clinical pharmacokinetics, plasma protein binding and tissue distribution of CLBQ14 in adult male Sprague-Dawley rats were characterized.Results: At room temperature, CLBQ14 is practically insoluble in water (< 0.07 mg/mL) but freely soluble in dimethyl acetamide (> 80 mg/mL); it has a log P value of 3.03 ± 0.04. CLBQ14 exhibits an inverse Z-shaped pH decomposition profile; it is stable at acidic pH but is degraded at a faster rate at basic pH. It is highly bound to plasma proteins (> 91%), does not partition to red blood cells (B/P ratio: 0.83 ± 0.03), and is stable in mouse, rat, monkey and human plasma. CLBQ14 exhibited a bi-exponential pharmacokinetics after intravenous administration in rats, bioavailability of 39.4 and 90.0%, respectively from oral and subcutaneous route. We observed a good correlation between predicted and observed rat clearance, 1.90 ± 0.17 L/kg/h and 1.67 ± 0.08 L/kg/h, respectively. Human hepatic clearance predicted from microsomal stability data and from the single species scaling were 0.80 L/hr/kg and 0.69 L/h/kg, respectively. CLBQ14 is extensively distributed in rats; following a 5 mg/kg intravenous administration, lowest and highest concentrations of 15.6 ± 4.20 ng/g of heart and 405.9 ± 77.11 ng/g of kidneys, respectively, were observed. In vitro CYP reaction phenotyping demonstrates that CLBQ14 is metabolized primarily by CYP 1A2.Conclusion: CLBQ14 possess appealing qualities of a drug candidate. The studies reported herein are imperative to the development of CLBQ14 as a new chemical entity for infectious diseases.Keywords: CLBQ14, 8-hydroxyquinoline, methionine aminopeptidase, clioquinol, pharmacokinetics, tissue distribution, physicochemical, drug development |
| first_indexed | 2024-12-11T13:29:46Z |
| format | Article |
| id | doaj.art-784dd6e1f4a344aba1eeecd1cdd96589 |
| institution | Directory Open Access Journal |
| issn | 1177-8881 |
| language | English |
| last_indexed | 2024-12-11T13:29:46Z |
| publishDate | 2020-03-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Drug Design, Development and Therapy |
| spelling | doaj.art-784dd6e1f4a344aba1eeecd1cdd965892022-12-22T01:05:20ZengDove Medical PressDrug Design, Development and Therapy1177-88812020-03-01Volume 141263127752789Pre-Clinical Pharmacokinetics, Tissue Distribution and Physicochemical Studies of CLBQ14, a Novel Methionine Aminopeptidase Inhibitor for the Treatment of Infectious DiseasesEkpenyong OGao XMa JCooper CNguyen LOlaleye OALiang DXie HOscar Ekpenyong, Xiuqing Gao, Jing Ma, Candace Cooper, Linh Nguyen, Omonike A Olaleye, Dong Liang, Huan Xie Department of Pharmaceutical and Environmental Health Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USACorrespondence: Huan XieDepartment of Pharmaceutical and Environmental Health Sciences, College of Pharmacy and Health Sciences, Texas Southern University, 3100 Cleburne Street, Houston, TX 77004, USAEmail huan.xie@tsu.eduIntroduction: CLBQ14, a derivative of 8-hydroxyquinoline, exerts its chemotherapeutic effect by inhibiting methionine aminopeptidase (MetAP), the enzyme responsible for the post-translational modification of several proteins and polypeptides. MetAP is a novel target for infectious diseases. CLBQ14 is selective and highly potent against replicating and latent Mycobacterium tuberculosis making it an appealing lead for further development.Methods: The physicochemical properties (solubility, pH stability and lipophilicity), in vitro plasma stability and metabolism, pre-clinical pharmacokinetics, plasma protein binding and tissue distribution of CLBQ14 in adult male Sprague-Dawley rats were characterized.Results: At room temperature, CLBQ14 is practically insoluble in water (< 0.07 mg/mL) but freely soluble in dimethyl acetamide (> 80 mg/mL); it has a log P value of 3.03 ± 0.04. CLBQ14 exhibits an inverse Z-shaped pH decomposition profile; it is stable at acidic pH but is degraded at a faster rate at basic pH. It is highly bound to plasma proteins (> 91%), does not partition to red blood cells (B/P ratio: 0.83 ± 0.03), and is stable in mouse, rat, monkey and human plasma. CLBQ14 exhibited a bi-exponential pharmacokinetics after intravenous administration in rats, bioavailability of 39.4 and 90.0%, respectively from oral and subcutaneous route. We observed a good correlation between predicted and observed rat clearance, 1.90 ± 0.17 L/kg/h and 1.67 ± 0.08 L/kg/h, respectively. Human hepatic clearance predicted from microsomal stability data and from the single species scaling were 0.80 L/hr/kg and 0.69 L/h/kg, respectively. CLBQ14 is extensively distributed in rats; following a 5 mg/kg intravenous administration, lowest and highest concentrations of 15.6 ± 4.20 ng/g of heart and 405.9 ± 77.11 ng/g of kidneys, respectively, were observed. In vitro CYP reaction phenotyping demonstrates that CLBQ14 is metabolized primarily by CYP 1A2.Conclusion: CLBQ14 possess appealing qualities of a drug candidate. The studies reported herein are imperative to the development of CLBQ14 as a new chemical entity for infectious diseases.Keywords: CLBQ14, 8-hydroxyquinoline, methionine aminopeptidase, clioquinol, pharmacokinetics, tissue distribution, physicochemical, drug developmenthttps://www.dovepress.com/pre-clinical-pharmacokinetics-tissue-distribution-and-physicochemical--peer-reviewed-article-DDDTclbq148-hydroxyquinolinemethionine aminopeptidaseclioquinolpharmacokineticstissue distributionphysicochemicaldrug development. |
| spellingShingle | Ekpenyong O Gao X Ma J Cooper C Nguyen L Olaleye OA Liang D Xie H Pre-Clinical Pharmacokinetics, Tissue Distribution and Physicochemical Studies of CLBQ14, a Novel Methionine Aminopeptidase Inhibitor for the Treatment of Infectious Diseases Drug Design, Development and Therapy clbq14 8-hydroxyquinoline methionine aminopeptidase clioquinol pharmacokinetics tissue distribution physicochemical drug development. |
| title | Pre-Clinical Pharmacokinetics, Tissue Distribution and Physicochemical Studies of CLBQ14, a Novel Methionine Aminopeptidase Inhibitor for the Treatment of Infectious Diseases |
| title_full | Pre-Clinical Pharmacokinetics, Tissue Distribution and Physicochemical Studies of CLBQ14, a Novel Methionine Aminopeptidase Inhibitor for the Treatment of Infectious Diseases |
| title_fullStr | Pre-Clinical Pharmacokinetics, Tissue Distribution and Physicochemical Studies of CLBQ14, a Novel Methionine Aminopeptidase Inhibitor for the Treatment of Infectious Diseases |
| title_full_unstemmed | Pre-Clinical Pharmacokinetics, Tissue Distribution and Physicochemical Studies of CLBQ14, a Novel Methionine Aminopeptidase Inhibitor for the Treatment of Infectious Diseases |
| title_short | Pre-Clinical Pharmacokinetics, Tissue Distribution and Physicochemical Studies of CLBQ14, a Novel Methionine Aminopeptidase Inhibitor for the Treatment of Infectious Diseases |
| title_sort | pre clinical pharmacokinetics tissue distribution and physicochemical studies of clbq14 a novel methionine aminopeptidase inhibitor for the treatment of infectious diseases |
| topic | clbq14 8-hydroxyquinoline methionine aminopeptidase clioquinol pharmacokinetics tissue distribution physicochemical drug development. |
| url | https://www.dovepress.com/pre-clinical-pharmacokinetics-tissue-distribution-and-physicochemical--peer-reviewed-article-DDDT |
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