Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors

Clin Pharmacokinet. 2012 Aug 1;51(8):501-14. doi: 10.1007/BF03261927.


Dipeptidyl peptidase-4 (DPP-4) inhibitors collectively comprise a presently unique form of disease management for persons with type 2 diabetes mellitus. The aim of this review is to compare the clinical pharmacokinetics of available DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin) for the purpose of identifying potential selection preferences according to individual patient variables and co-morbidities. DPP-4 inhibitors are readily absorbed orally. Following oral ingestion, absorption occurs mainly in the small intestine, with median times to maximum (peak) plasma concentration ranging from 1 to 3 hours. The fraction of each dose absorbed ranges from approximately 30% with linagliptin to 75-87% for all others. Numerical differences in maximum (peak) plasma drug concentrations and areas under the plasma concentration-time curve among the DPP-4 inhibitors vary by an order of magnitude. However, functional capacity measured in terms of glucose-lowering ability remains comparable among all available DPP-4 inhibitors. Distribution of DPP-4 inhibitors is strongly influenced by both lipophilicity and protein binding. Apparent volumes of distribution (V(d)) for most agents range from 70 to 300 L. Linagliptin exhibits a V(d) of more than 1000 L, indicating widespread distribution into tissues. Binding to target proteins in plasma and peripheral tissues exerts a major influence upon broadening linagliptin distribution. DPP-4 inhibitor metabolism is widely variable, with reported terminal half-lives ranging from approximately 3 to more than 200 hours. Complex relationships between rates of receptor binding and dissociation appear to strongly influence the durations of action of those DPP-4 inhibitors with comparatively shorter half-lives. Durations of activity often are not reflective of clearance and, with the exception of vildagliptin which may be administered either once daily in the evening or twice daily, these medications are effective when used with a once-daily dosing schedule. Saxagliptin and, to a lesser extent, sitagliptin are largely metabolized by hepatic cytochrome P450 (CYP) 3A4 and 3A5 isoforms. With the exception of the primary hydroxylated metabolite of saxagliptin, which is 2-fold less potent than its parent molecule, metabolic products of hepatic biotransformation are minimally active and none appreciably contribute to either the therapeutic or the toxic effects of DPP-4 inhibitors. No DPP-4 inhibitor has been shown to inhibit or to induce hepatic CYP-mediated drug metabolism. Accordingly, the number of clinically significant drug-drug interactions associated with these agents is minimal, with only saxagliptin necessitating dose adjustment if administered concurrently with medications that strongly inhibit CYP3A4. Linagliptin undergoes enterohepatic cycling with a large majority (85%) of the absorbed dose eliminated in faeces via biliary excretion. Other DPP-4 inhibitors predominantly undergo renal excretion, with 60-85% of each dose eliminated as unchanged parent compound in the urine. Systematic reviews of clinical trials suggest that the overall efficacy of DPP-4 inhibitors in patients with type 2 diabetes generally is similar. Apart from these generalizations, pharmacokinetic distinctions that potentially influence product selection are tentative. When considered in total, data reviewed in this report suggest that the best overall balance between potency and the clinical pharmacokinetic characteristics of distribution, metabolism and elimination may be observed with linagliptin followed closely by vildagliptin, saxagliptin, sitagliptin and alogliptin.

Publication types

  • Comparative Study
  • Review

MeSH terms

  • Age Factors
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dipeptidyl-Peptidase IV Inhibitors / chemistry
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacokinetics*
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use
  • Drug Interactions
  • Humans
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacokinetics*
  • Hypoglycemic Agents / therapeutic use
  • Kidney Diseases / complications
  • Liver Diseases / complications
  • Sex Factors
  • Structure-Activity Relationship


  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents