Preclinical pharmacokinetics of a HepDirect prodrug of a novel phosphonate-containing thyroid hormone receptor agonist.

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 (CL(int) 1.

Implication of P450-metabolite complex formation in the nonlinear pharmacokinetics and metabolic fate of (+/-)-(1'R*,3R*)-3-phenyl-1-[(1',2',3',4'-tetrahydro-5',6'-methylene-dioxy-1'-naphthalenyl) methyl] pyrrolidine methanesulfonate (ABT-200) in dogs.

Following a single oral or intravenous administration of the R,R(+) and S,S(-) (14)C-pseudoracemate of (+/-)-(1'R*,3R*)-3-phenyl-1-[(1',2',3',4'-tetrahydro-5',6'-methylene-dioxy-1'-naphthalenyl) methyl] pyrrolidine methanesulfonate (ABT-200/I) to dogs, a total of six (R,R[+]) and eight (S,S[-]) metabolites were identified by high-pressure liquid chromatography/mass spectral techniques. Greater than 99% of the dose was eliminated as metabolites indicating that the clearance of I was predominantly metabolic. The catechol was the major excreted metabolite (fecal), whereas the urine and bile predominantly contained metabolites resulting from secondary biotransformation of the catechol via O-methylation, glucuronidation, and sulfation.