RT Journal Article SR Electronic T1 Preclinical Pharmacokinetics of a HepDirect Prodrug of a Novel Phosphonate-Containing Thyroid Hormone Receptor Agonist JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 2393 OP 2403 DO 10.1124/dmd.108.021642 VO 36 IS 11 A1 James M. Fujitaki A1 Edward E. Cable A1 Bruce R. Ito A1 Bao-Hong Zhang A1 Jinzhao Hou A1 Chun Yang A1 David A. Bullough A1 James L. Ferrero A1 Paul D. van Poelje A1 David L. Linemeyer A1 Mark D. Erion YR 2008 UL http://dmd.aspetjournals.org/content/36/11/2393.abstract AB The prodrug [(2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4′-hydroxy-3′-isopropylbenzyl)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 (CLint 1.23-145.4 μl/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. The American Society for Pharmacology and Experimental Therapeutics