Academic Journal
Preclinical pharmacokinetics of a HepDirect prodrug of a novel phosphonate-containing thyroid hormone receptor agonist
| العنوان: | Preclinical pharmacokinetics of a HepDirect prodrug of a novel phosphonate-containing thyroid hormone receptor agonist |
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| المؤلفون: | Fujitaki, James M., Cable, Edward Earl, Ito, Bruce R., Zhang, Bao-Hong, Hou, Jinzhao, Yang, Chun, Bullough, David A., Ferrero, James L., van Poelje, Paul D., Linemeyer, David L., Erion, Mark D. |
| المساهمون: | Department of Biological Sciences, Graduate School of Biomedical Sciences |
| المصدر: | Drug metabolism and disposition: the biological fate of chemicals ; 36 ; 11 ; 2393-403 |
| سنة النشر: | 2022 |
| المجموعة: | University of Massachusetts, Medical School: eScholarship@UMMS |
| مصطلحات موضوعية: | Life Sciences, Medicine and Health Sciences |
| الوصف: | The prodrug [(2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylben zyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane (MB07811)] of a novel phosphonate-containing thyroid hormone receptor agonist [3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxylmethylphosphonic acid (MB07344)] is the first application of the HepDirect liver-targeting approach to a non-nucleotide agent. The disposition of MB07811 was characterized in rat, dog, and monkey to assess its liver specificity, which is essential in limiting the extrahepatic side effects associated with this class of lipid-lowering agents. MB07811 was converted to MB07344 in liver microsomes from all species tested (CL(int) 1.23-145.4 microl/min/mg). The plasma clearance and volume of distribution of MB07811 matched or exceeded 1 l/h/kg and 3 l/kg, respectively. Although absorption of prodrug was good, its absolute oral bioavailability as measured systemically was low (3-10%), an indication of an extensive hepatic first-pass effect. This effect was confirmed by comparison of systemic exposure levels of MB07811 after portal and jugular vein administration to rats, which demonstrated a hepatic extraction ratio of >0.6 with liver CYP3A-mediated conversion to MB07344 being a major component. The main route of elimination of MB07811 and MB07344 was biliary, with no evidence for enterohepatic recirculation of MB07344. Similar metabolic profiles of MB07811 were obtained in liver microsomes across the species tested. Tissue distribution and whole body autoradiography confirmed that the liver is the major target organ of MB07811 and that conversion to MB07344 was high in the liver relative to that in other tissues. Hepatic first-pass extraction and metabolism of MB07811, coupled with possible selective distribution of MB07811-derived MB07344, led to a high degree of liver targeting of MB07344. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | Link to Article in PubMed; http://dx.doi.org/10.1124/dmd.108.021642; Drug Metab Dispos. 2008 Nov;36(11):2393-403. Epub 2008 Aug 14. Link to article on publisher's site; 1521-009X (Electronic); http://hdl.handle.net/20.500.14038/33030; https://escholarship.umassmed.edu/gsbs_sp/1579; 740118; gsbs_sp/1579 |
| DOI: | 10.1124/dmd.108.021642 |
| الاتاحة: | https://doi.org/10.1124/dmd.108.021642 https://hdl.handle.net/20.500.14038/33030 https://escholarship.umassmed.edu/gsbs_sp/1579 |
| رقم الانضمام: | edsbas.E8FD4082 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1124/dmd.108.021642 |
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