Discussion
This was the first manuscript investigating the role of diabetes on GBP
pharmacokinetics in humans. A population pharmacokinetic model was
developed to investigate the influence of type 2 diabetes and glycaemic
control and other potential covariates on GBP kinetic disposition. The
pharmacokinetic estimates presented here are similar to parameter values
previously reported for GBP, except for the lower values of volume of
distribution and ka when compared to clinical trials with non-diabetic
participants [44,48]. Our data showed that the volume of
distribution of GBP was affected by body height and serum levels of
glucose, while the total clearance was affected by eGFR (Table 3). GBP
is primarily eliminated unchanged in urine and associations between eGFR
and GBP pharmacokinetics have been reported previously [53-56].
Increased renal clearance of GBP was observed in rats with experimental
diabetes induced by streptozotocin [57], suggesting that the effects
of diabetes on the kinetic disposition of GBP occurred by inducing
glomerular hyperfiltration [58]. While the experimental model of
diabetes follows a strict protocol in rats in terms of duration of the
disease, this clinical study includes patients with different levels of
renal function and duration of diabetes. The results presented here have
shown that eGFR is a covariate on renal clearance of GBP. This finding
means that GBP kinetic disposition depends on the nephropathy level,
which is indirectly related to the glycaemic levels [59]. Among type
2 diabetic patients, 20 to 40% develop diabetic nephropathy (DN)
[60], which consists of 5 steps: 1. Increase in eGFR and glomerular
hypertrophy; 2. Hyperfiltration and microalbuminuria (> 30
mg/24 h); 3. Higher microalbuminuria (> 300 mg/24 h) and
hypertension; 4. Microalbuminuria (> 300 mg/24 h), decrease
on eGFR and increase in creatinine and blood urea nitrogen; 5. eGFR
< 10 mL/min, which leads to haemodialysis [61]. A
well-accepted theory for DN is that hyperglycaemia increases reactive
oxygen species and pro-inflammatory cytokines [62-64].
Diabetes typically alters the expression and function of transporters
for organic cations in mice with experimentally induced type 2 diabetes,
probably due to the accumulation of end products of advanced glycation
and inflammation [7]. Drug transporters for organic cations such as
OCT2, MATE 1 and 2-K, and OCNT1 have been described to contribute to GBP
renal excretion [43,44]. Although GBP has been described as an OCT2
substrate [42,43], the interaction with OCT2 is not relevant at
therapeutic drug concentrations [44]. No significant changes in GBP
kinetic disposition were observed after the coadministration of
cimetidine (a known inhibitor of OCT2) or metformin (a known substrate
of OCT2) in rats [57]. Moreover, cetirizine, an inhibitor of OCT2,
MATE1 and 2-K [65,66], reduced the systemic exposure to GBP with no
changes in renal clearance in patients with neuropathic pain, suggesting
an interaction in the oral absorption process mediated by active
transport (probably OCTN1) and not by renal drug transporters [44].
The effect of glycaemic control on the clinical pharmacokinetics of GBP
observed here could be explained by the saturation of absorption
processes, since the apparent volume of distribution is dependent on
oral bioavailability [67,68]. OCTN1 is expressed in gut cells and
might be responsible for the saturable absorption of GBP [69,70]. In
type 1 diabetic mice, the renal protein expression of Octn1 is decreased
[71]. The protein level of intestinal Octn1 follows a circadian
rhythm, both in mice with diabetes induced by streptozotocin and in mice
without diabetes [72]. However, there is no information in the
literature about the impact of high glycaemic levels on the gut levels
of OCTN1.
GBP intestinal uptake is mediated by L-type transporter (LAT) 2
[73-76] and by the system b0,+ together with
peptide transporter (PEPT) 1. These transporters might be associated
with the saturable absorption of GBP [77]. Rats with experimental
diabetes showed a reduction in the expression and activity of the pept1
transporter mRNA [78]. In rabbits with maternal diabetes induced by
alloxan, the transcripts of LAT2 were increased in blastocysts, when
compared to blastocysts of non-diabetic rabbits [79]. The reduction
in the activity of PEPT1 by hyperglycaemia [76] seems to be a
reasonable explanation for our findings which showed glycaemic level was
a covariate in GBP apparent volume of distribution.
In therapeutic concentrations, the distribution of GBP to the central
nervous system is regulated by LAT1 uptake [80]. The high
concentration of glucose reduced LAT1 expression by 80%, compared to
cells without the excess of glucose [81]. In opposition to the
expected reduction on LAT1 expression, the effect of hyperglycaemia on
LAT1 does not seem to influence GBP plasma concentrations since higher
glycaemic levels are associated with lowering GBP plasma concentrations.
Despite the lack of effect of LAT1 in GBP plasma levels, patients with
uncontrolled diabetes could have an impact on drug concentrations in the
effect compartment [75,82].
This work has some limitations. Firstly, participants were not genotyped
for genetic polymorphisms of drug transporters involved in the
absorption process of GBP. The polymorphisms c.438C>G
(rs1060253) of the gene SLC7A5 (LAT1) and 1347T>C
(rs1339067) of the gene SLC15A1 (PEPT1) are involved in
risperidone and sirolimus pharmacokinetics [83,84]. Secondly,
although the basal pain score on VAS was considered for inclusion of the
participants, this study focused only on GBP pharmacokinetics. A
population model relating pharmacokinetics to pharmacodynamics would be
of great importance. Thirdly, the diabetes-induced epigenetic
modifications on targets related to drug pharmacokinetics were not
investigated. The possibility of a maintained lesion secondary to the
hyperglycaemic memory [10,11] could not be ruled out to explain the
changes in GBP clearance and volume of distribution in hyperglycaemic
patients.
In conclusion, GBP population pharmacokinetics was influenced by renal
function and by the serum levels of glucose. Genetic polymorphisms of
OCT2 and OCTN1 transporters, sex, age, weight or BMI did not influence
GBP population pharmacokinetics. Our data suggest normal glycaemic
levels in diabetic patients, achieved either by adherence to diabetes
pharmacotherapy and changes in lifestyle (diet and physical exercise),
reduces the variability in the kinetic disposition of GBP. In addition
to the benefits related to diabetes comorbidities and patients’ quality
of life, the control of glycaemic levels is also relevant to achieve
positive pharmacotherapy outcomes.