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


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.
Burkey
B F
BF
Novartis Institutes of BioMedical Research Basel, Cambridge, MA, USA.
Hoffmann
P K
PK
Hassiepen
U
U
Trappe
J
J
Juedes
M
M
Foley
J E
JE
D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology; D004150:Dipeptidases / Q000037:antagonists & inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects* / Q000494:pharmacology / Q000633:toxicity; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009570:Nitriles / Q000009:adverse effects* / Q000494:pharmacology / Q000633:toxicity; D011759:Pyrrolidines / Q000009:adverse effects* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D018675:Toxicity Tests; D000077597:Vildagliptin
D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D011994:Recombinant Proteins; D004150:Dipeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C527707:Dpp8 protein, rat; C527708:Dpp9 protein, rat; C487997:DPP8 protein, human; C585325:dipeptidyl peptidase 8, mouse; D000077597:Vildagliptin; D000218:Adamantane