TY - JOUR
T1 - Pre-clinical pharmacokinetics, tissue distribution and physicochemical studies of CLBQ14, a novel methionine aminopeptidase inhibitor for the treatment of infectious diseases
AU - Ekpenyong, Oscar
AU - Gao, Xiuqing
AU - Ma, Jing
AU - Cooper, Candace
AU - Nguyen, Linh
AU - Olaleye, Omonike A.
AU - Liang, Dong
AU - Xie, Huan
N1 - Funding Information:
This study was funded partially by the National Institute of Health SC3 (grant number 1SC3GM102018), by the National Institute of Health’s Research Centers in Minority Institutes Program (RCMI, grant number G12MD007605) and by the Cancer Prevention & Research Institute of Texas (CPRIT, grant number RP180748).
Funding Information:
This study was funded partially by the National Institute of Health SC3 (grant number 1SC3GM102018), by the National Institute of Health?s Research Centers in Minority Institutes Program (RCMI, grant number G12MD007605) and by the Cancer Prevention & Research Institute of Texas (CPRIT, grant number RP180748).
Publisher Copyright:
© 2020 Ekpenyong et al.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020
Y1 - 2020
N2 - Introduction: 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.
AB - Introduction: 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.
KW - 8-hydroxyquinoline
KW - CLBQ14
KW - Clioquinol
KW - Drug development
KW - Methionine aminopeptidase
KW - Pharmacokinetics
KW - Physicochemical
KW - Tissue distribution
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U2 - 10.2147/DDDT.S238148
DO - 10.2147/DDDT.S238148
M3 - Article
C2 - 32280198
AN - SCOPUS:85083261909
VL - 14
SP - 1263
EP - 1277
JO - Drug Design, Development and Therapy
JF - Drug Design, Development and Therapy
SN - 1177-8881
ER -