Adverse effects of dipeptidyl peptidases 8 and 9 inhibition in rodents revisited

Aim: To evaluate the association between inhibition of dipeptidyl peptidase (DPP)‐8 and/or DPP‐9 organ toxicities and mortality in rodents. Research Design and Methods: The relative selectivity of the DPP‐4 inhibitor, vildagliptin, was determined by comparing its K I (concentration of compound yielding 50% inhibition of the enzyme) values for inhibition of recombinant human DPP‐4, DPP‐8 and DPP‐9 assessed in vitro . In experiments performed in vivo , vildagliptin was administered by gavage for 13 weeks, at doses up to 1500 mg/kg/day in CD‐1 mice and at doses up to 900 mg/kg/day in Wistar rats. Plasma concentrations of vildagliptin were assessed at week 12, and toxicities previously ascribed to inhibition of DPP‐8 and/or DPP‐9 were assessed at week 13. Results: The K I values for vildagliptin‐induced inhibition of DPP‐4, DPP‐8 and DPP‐9 were 3, 810 and 95 nM respectively. The mean plasma concentration 24 h after dose after 12‐week daily dosing with 1500 mg/kg/day in mice was 2279 nM. The mean plasma drug level 24 h after dose after 12‐week daily dosing with 900 mg/kg/day in rats was 5729 nM. These high doses maintained plasma drug levels well above the K I values for DPP‐8 and DPP‐9 throughout a 24‐h period. At these high doses, the toxicities of a selective DPP‐8/DPP‐9 inhibitor that were reported previously (100% mortality in mice, alopecia, thrombocytopenia, reticulocytopenia, enlarged lymph nodes, splenomegaly and 20% mortality in rats) were not observed. Conclusions: Inhibition of DPP‐8 and DPP‐9 per se does not lead to organ toxicities and mortality in rodents. Thus, a mechanism other than DPP‐8/DPP‐9 inhibition likely underlies the toxicity previously reported to be associated with a selective DPP‐8/DPP‐9 inhibitor.