In this article, we will discuss Omacetaxine Mepesuccinate (Mechanism of Action). So, let’s get started.
Mechanism of Action
The mechanism of action of omacetaxine mepesuccinate has not been fully elucidated but includes inhibition of protein synthesis
and is independent of direct Bcr-Abl binding. Omacetaxine mepesuccinate binds to the A-site cleft in the peptidyl-transferase center of the large ribosomal subunit from a strain of archaeabacteria. In vitro, omacetaxine mepesuccinate reduced protein levels of the Bcr-Abl oncoprotein and Mcl-1, an anti-apoptotic Bcl-2 family member. Omacetaxine mepesuccinate showed activity in mouse models of wild-type and T315I mutated Bcr-Abl CML.
The dose proportionality of omacetaxine mepesuccinate is unknown. A 90% increase in systemic exposure to omacetaxine
mepesuccinate was observed between the first dose and steady state.
The absolute bioavailability of omacetaxine mepesuccinate has not been determined. Omacetaxine mepesuccinate is absorbed
following subcutaneous administration, and maximum concentrations are achieved after approximately 30 minutes.
The steady-state (mean ± SD) volume of distribution of omacetaxine mepesuccinate is approximately 141±93.4 L following
subcutaneous administration of 1.25 mg/m2
twice daily for 11 days . The plasma protein binding of omacetaxine mepesuccinate is
less than or equal to 50%.
Omacetaxine mepesuccinate is primarily hydrolyzed to 4′-DMHHT via plasma esterases with little hepatic microsomal oxidative and/or esterase-mediated metabolism in vitro.
The major elimination route of omacetaxine mepesuccinate is unknown. The mean percentage of omacetaxine mepesuccinate
excreted unchanged in the urine is less than 15%. The mean half-life of omacetaxine mepesuccinate following subcutaneous
administration is approximately 6 hours.
Cytochrome P450 Enzymes (CYPs): Omacetaxine mepesuccinate is not a substrate of CYP450 enzymes in vitro. Omacetaxine mepesuccinate and 4′-DMHHT do not inhibit major CYPs in vitro at concentrations that can be expected clinically. The potential for omacetaxine mepesuccinate or 4′-DMHHT to induce CYP450 enzymes has not been determined.
Transporter Systems: Omacetaxine mepesuccinate is a P-glycoprotein (P-gp) substrate in vitro. Omacetaxine mepesuccinate and 4′-DMHHT do not inhibit P-gp mediated efflux of loperamide in vitro at concentrations that can be expected clinically.