US EPA

7424753 

Journal Article 

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

Li, Y; Wang, Y; Zhang, R; Liu, C; Wei, Y; Sun, J; He, Z; Xu, Y; Zhang, T; , 

2018 

SPRINGER HEIDELBERG 

HEIDELBERG 

8 

5 

1335-1344 

English 

29777509 

10.1007/s13346-018-0524-6 

WOS:000442867500031 

http://link.springer.com/10.1007/s13346-018-0524-6
Exit
 

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. 

Bioconversion; Carbamate prodrug; Metabolic stability; Oral bioavailability; Tapentadol; carbamic acid; n demethylase; n,n diethylcarbamate; n,n diisopropylcarbamate; n,n dimethylcarbamate; tapentadol; unclassified drug; carbamic acid derivative; prodrug; tapentadol; animal cell; animal experiment; animal tissue; area under the curve; Article; biotransformation; carbon nuclear magnetic resonance; chemical structure; controlled study; dealkylation; drug bioavailability; drug stability; drug synthesis; human; human cell; hydrolysis; hydroxylation; limit of quantitation; liver homogenate; liver microsome; maximum plasma concentration; metabolic stability; molecular weight; nonhuman; pH; plasma concentration-time curve; priority journal; proton nuclear magnetic resonance; qualitative analysis; rat; retention time; stereospecificity; time to maximum plasma concentration; tissue homogenate; ultra performance liquid chromatography; animal; bioavailability; chemistry; drug design; oral drug administration; synthesis; Administration, Oral; Animals; Biological Availability; Carbamates; Drug Design; Drug Stability; Molecular Weight; Prodrugs; Rats; Tapentadol