Deuterium isotope effects in drug pharmacokinetics II: Substrate-dependence of the reaction mechanism influences outcome for cytochrome P450 cleared drugs

Abstract

Two chemotypes were examined in vitro with CYPs 3A4 and 2C19 by molecular docking, metabolic profiles, and intrinsic clearance deuterium isotope effects with specifically deuterated form to assess the potential for enhancement of pharmacokinetic parameters. The results show the complexity of deuteration as an approach for pharmacokinetic enhancement when CYP enzymes are involved in metabolic clearance. With CYP3A4 the rate limiting step was chemotype-dependent. With one chemotype no intrinsic clearance deuterium isotope effect was observed with any deuterated form, whereas with the other chemotype the rate limiting step was isotopically sensitive, and the magnitude of the intrinsic clearance isotope effect was dependent on the position(s) and extent of deuteration. Molecular docking and metabolic profiles aided in identifying sites for deuteration and predicted the possibility for metabolic switching. However, the potential for an isotope effect on the intrinsic clearance cannot be predicted and must be established by examining select deuterated versions of the chemotypes. The results show how in a deuteration strategy molecular docking, in-vitro metabolic profiles, and intrinsic clearance assessments with select deuterated versions of new chemical entities can be applied to determine the potential for pharmacokinetic enhancement in a discovery setting. They also help explain the substantial failures reported in the literature of deuterated versions of drugs to elicit a systemic enhancement on pharmacokinetic parameters.

Twelfth-Position Deuteration of Nevirapine Reduces 12-Hydroxy-Nevirapine Formation and Nevirapine-Induced Hepatocyte Death

“…We found these results as well as the lack of change observed for both 2- and 3-OHNVP production in hepatocyte medium intriguing, as metabolic switching, in which other drug metabolite levels increase in response to decreased metabolism at one position, has been known to occur with deuterium substitution. 5 , 7 , 39 − 41 Our observation may be due to differences in P450 contributions to metabolism at these different positions of the NVP scaffold. Since we did not see a significant decrease in 12-OHNVP with inhibitors that reduced production of 2-OHNVP and 3-OHNVP, this suggests that the enzymes responsible for 2- and 3-OHNVP production (CYP3A4 and CYP2B6, respectively) do not play a measurable role in the conversion of NVP to 12-OHNVP.…”

“… 1 Deuteration at one site can also result in “metabolic switching,” in which metabolism by P450s at another position is increased following a reduction of metabolism at the deuterated site. 5 , 7 …”

A Simplified Protocol for the ortho-Deuteration of Acidic Aromatic Compounds in D2O

“…Furan-3-carboxylic Acid (33.6 mg, 0.300 mmol) was used, giving the deuterated product as an offwhite solid (9.4 mg, 27%), showing 99% deuteration at C 2 and C 4 , and 24% deuteration at C 5 . 1 H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 1.6 Hz, 0.01 H), 7.46 (s, 0.76 H), 6.78 (d, J = 1.9 Hz, 0.01 H).…”

Deuteration enhances the anti-tumor effects and relative anti-inflammatory effects via affecting proliferation and apoptosis

“…Some encouraging clinical outcomes with deuterated anti-tumour drugs have been achieved; for example, sorafenib, ceritinib, and enzalutamide, which are currently being tested in clinical trials, have exhibited longer half-lives and lower effective doses [ 16 , 17 ]. Additionally, HDX can reduce the formation of toxic metabolites, thereby increasing the biosafety of drugs [ 18 ]. Hence, HDX is a promising strategy for enhancing the anti-tumour effect of AP.…”