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

To evaluate the association between inhibition of dipeptidyl peptidase (DPP)-8 and/or DPP-9 organ toxicities and mortality in rodents.

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.

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.

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.