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SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
VOLUME 9 NUMBER 1 • MARCH 2012
11
Table 2.
Biochemistry, pharmacodynamic and pharmacokinetic profiles of DPP-4 inhibitors.
DPP-4 inhibitor Class
Metabolised
Excretion
Selectivity
DPP-4 inhibition t1/2 (h)
Dosing
Sitagliptin
B-amino acid-based Not
Renal
High
Max 97%
> 80% 24 h post
dose
8–24
100 mg/day
Vildagliptin
Cyanopyrrolidine
Hydrolysed in
liver, inactivated
Renal, 22% as parent,
55% metabolite
Moderate
Max 95%
> 80% 12 h post
dose
1.5–4.5
50 mg bd
Saxagliptin
Cyanopyrrolidine
Liver, active
metabolite
Renal, ± half as active
metabolite
Moderate
Max 80%
70% 24 h post
dose
2–4 parent
3–7 metabolite
5 mg/day
Alogliptin
Modified pyrimidin-
edione
Not
Renal > 70%
unchanged
High
Max 90%
75% 24 h post
dose
12–21
25 mg/day
Linagliptin
Xanthine based
Not
Biliary > 70%
unchanged
Moderate
Max 80%
70% 24 h post
dose
10–40
5 mg/day
extent of plasma DPP-4 inhibition drops to around 50% after 24
hours with 50 mg once daily, but the twice-daily therapeutic dosing
regimen maintains plasma DPP-4 inhibition at > 80% over the full
24-hour period.
10-12
One of the potential problems of these drugs is that DPP-4 is a
member of a large family of protease enzymes. The selectivity of the
drugs to block only the breakdown of the required DPP-4 enzyme is
critical to limit unwanted side effects. It is therefore very important
to assess the selectivity of these drugs because inhibition of, for
example, DPP-8 and -9 have been linked to unwanted toxicities and
side effects, especially on T-cell activation and proliferation.
26,27
The
selectivity for the enzyme is summarised in Table 2.
Sitagliptin and alogliptin are the most selective of the five
molecules discussed and have practically no inhibitory activity
on the other members of the family. Vildagliptin and saxagliptin
are less selective with regard to inhibition of DPP-8/9
in vitro,
28,29
although the significance
in vivo
is questionable because DPP-8/9
are located intracellularly.
Linagliptin is very selective with regard to DPP-8/9 and is less
selective with regard to fibroblast activation protein-
α
(FAP
α
). FAP
α
is an extracellular enzyme which is not generally present in normal
adult tissue (although it is expressed in stromal fibroblasts and
upregulated during tissue remodelling).
30
The clinical relevance of this
is not clear because the extent of any FAP
α
inhibition
in vivo
with the
therapeutic dose of linagliptin in humans has not been reported.
These agents have also been studied for possible drug
interactions by assessing their activity against CYP-450 and many
other enzymes. No activity could be demonstrated, except for
linagliptin which has weak activity against CYP-3A4.
21
In general this group of drugs has very few reported drug
interactions. Many drug interactions have been studied, including
other oral diabetic drugs as well as simvastatin, and none of them
had any relevant interactions.
12,15,17
However, CYP3A4/5 is important for the activation of saxagliptin,
and potent inhibitors of these enzymes (such as ketoconazole)
increase the concentration of the parent drug, requiring dose
reduction of saxagliptin to half dose when co-administered with
these drugs.
31
Linagliptin has been shown to be a weak inhibitor of
these enzymes and the potential for drug interactions are considered
weak, with less than a two-fold increase in drug concentration.
21
Pharmacokinetics
One of the major benefits of DPP-4 inhibitors is that they can be
taken orally (compared to the GLP-analogues), with rapid absorption
and onset of action as quickly as five minutes after ingestion. Their
oral bioavailability varies but is generally high.
32-35
The volume of distribution of DPP-4 inhibitors varies widely
and is greater than the total body water, suggesting wide tissue
distribution. Their chemistry suggests that they might not penetrate
cell membranes; the only molecule which has been shown to
penetrate cell membranes in high concentration is vildagliptin.
12,15,24,34
This was shown in rat studies at more than 600 times the human
dose and it is unlikely to be relevant for human use.
28
Saxagliptin has
been shown to have very little potential for membrane permeability,
and few data are available on the other drugs.
17
These drugs have variable reversible protein binding, but seem
not to cross the blood–brain barrier.
12,34,36
They do however cross
the placenta freely and should not be used in pregnancy and
lactation.
12,15,17
Three of these drugs, sitagliptin, alogliptin and linagliptin are
not metabolised significantly and are predominately eliminated
unchanged.
22
Although sitagliptin has three active metabolites,
their concentration and affinity are low and they are not clinically
significant.
15
In contrast, vildagliptin and saxagliptin are extensively
metabolised. Vildagliptin is predominantly metabolised in the
liver by a CYP-450-independent mechanism.
12
Saxagliptin is also
metabolised by the liver using the CYP3A4/5 enzymes and has an
active metabolite which is responsible for 50% of its potency.
17
The DPP-4 inhibitors are mainly excreted via the kidneys by
an active transport mechanism.
22
Sitagliptin is actively excreted
in the proximal tubule.
37
Alogliptin is renally excreted, mainly
unchanged.
24,38
Saxagliptin and its main metabolite are also renally
eliminated. Vildagliptin is excreted by the kidneys although only
22% is unchanged and the remainder is eliminated as metabolites
from liver metabolism.
11
Linagliptin is the exception to this rule and
will be important in the renally impaired patient because the drug
has a high degree of protein binding and is excreted via the hepatic/
biliary route, mostly unchanged, in the faeces.
21,25
In patients with renal impairment, sitagliptin has been fairly well
studied and shown to be reasonably safe, even in moderate renal
impairment.
39,40
Patients with severe renal impairment have not been
as well studied with any of the drugs. Current recommendations
are that patients with mild renal impairment (CrCl > 50 ml/min)
can use these drugs safely without dose change. In moderate renal
impairment (CrCl 30–50 ml/min), halving of the sitagliptin and
alogliptin doses is recommended.
22,39
In severe renal impairment
(CrCl < 30 ml/min), the safest current recommendation would
probably be not to use this class until more data become available.