Improving the oral bioavailability of tapentadol via a carbamate prodrug approach: synthesis, bioactivation, and pharmacokinetics

Tapentadol suffers from rapid clearance due to extensive metabolism in vivo, which results in low oral bioavailability. In the present study, three novel prodrugs of tapentadol (WWJ01, WWJ02, and WWJ03) were synthesized to improve its metabolic stability and thereby improve its oral bioavailability. They all exhibited good stability in phosphate buffers, simulated gastrointestinal fluids, rat plasma, and intestinal and liver homogenates. Disappointingly, the N,N-diethylcarbamate prodrug of tapentadol (WWJ02) and the N,N-diisopropylcarbamate prodrug of tapentadol (WWJ03) were metabolized into inactive metabolites when incubated with liver microsomes. In contrast, the N,N-dimethylcarbamate prodrug of tapentadol (WWJ01) could be transformed into useful intermediates (M1, M2, and M3), followed by the further release of the active structure (tapentadol) with the addition of plasma. Additionally, the possible biotransformation pathway of WWJ01 was preliminarily studied with a qualitative approach by determining the molecular weight and fragment ions of its metabolic intermediates. Finally, pharmacokinetic studies were carried out to evaluate the oral absorption of WWJ01. WWJ01 showed distinct advantages in oral absorption efficiency, with a 2.3-fold higher bioavailability than tapentadol. These results suggest that the rational design of a carbamate prodrug of tapentadol is an efficient strategy to improve its metabolic stability and oral bioavailability.