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.