Received for publication March 27, 2008.
Revised August 8, 2008.
Accepted for publication August 12, 2008.

Preclinical Pharmacokinetics of a HepDirect Prodrug of a Novel Phosphonate-Containing Thyroid Hormone Receptor Agonist

Abstract

The prodrug (MB07811) of a novel phosphonate-containing thyroid hormone receptor (TR) agonist (MB07344) is the first application of the HepDirect¹ 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 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 following portal and jugular vein administration to rats, which demonstrated a hepatic extraction ratio of >0.6 with liver CYP3A-mediated conversion to MB07344 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 liver is the major target organ of MB07811 and that conversion to MB07344 was high in the liver relative to other tissues. Hepatic first pass extraction and metabolism of MB07811, coupled with likely selective distribution of MB07811-derived MB07344, led to a high degree of liver targeting of MB07344.

Key words: biliary excretion, CYP3A, drug disposition, drug targeting, first-pass metabolism, hepatobiliary disposition, liver microsomes, oral absorption, pharmacokinetics, prodrugs