Introduction
Disease status has been recognized to affect drug pharmacokinetics and
drug response [1-3]. In type 2 diabetes (DM2), chronic
hyperglycaemia leads to protein glycation, alters gene expression and
modulates epigenetics, which is associated with the “hyperglycaemic
memory” [3-14]. Inflammation biomarkers in diabetes have been
associated with complications of the disease, including nephropathy and
neuropathy [15-19]. The complex effects of diabetes on
pharmacokinetics are related to the altered physiology and changes in
protein levels and/or activity of drug-metabolizing enzymes and
transporters. Patients with poor glycaemic control in diabetes exhibit
different pattern of pharmacokinetic alterations if compared with
patients with diabetes and normal glycaemic levels, suggesting that
glycaemic control plays an important role in pharmacokinetics
[20-22].
Chronic hyperglycaemia affects the
sympathetic and parasympathetic nervous systems, including functions
linked to intestinal motility [23]. This may lead to reduced
intestinal transit time in 20-50% of diabetic patients [23,24].
Depending on the status of diabetes-induced nephropathy, the glomerular
filtration rate can be increased, unchanged or decreased [3].
Clinical and experimental studies have shown that diabetes changes the
abundance or activity of drug-metabolizing enzymes and drug transporters
[9,12,13,25-27]. Rats with DM2 induced by hypercaloric diet and
streptozotocin [28,29] showed a 50% reduction in renal levels of
organic cation transporter 2 (Oct2) [7]. The mRNA and protein levels
of Oct1, Oct2 and Oct3 were lower in rats with diabetes [4,5]. High
glycaemic levels were associated with increased P-glycoprotein
expression in the gut and reduced expression in the kidneys [30,31].
Despite the potential effects of diabetes in pharmacokinetics, clinical
data showing the role of glycaemic control on interindividual
variability in drug plasma levels and pharmacokinetic parameters are
scarce.
Gabapentin (GBP) is an organic cation drug commonly used as an add-on
treatment for epilepsy and to treat diabetic neuropathic pain
[32-36]. Randomized, double-blind, placebo-controlled clinical
trials showed the efficacy of GBP to improve neuropathic manifestations
[32,33]. GBP has a saturable absorption at the gastrointestinal
tract and a variable bioavailability [25,26]. The drug is not
metabolized in humans and it does not bind to plasma proteins
[36-38]. The maximum plasma concentration of 2.7 µg/mL is reached
between 2 and 3 hours, after a single dose of 300 mg GBP [39,40].
Its elimination is mainly renal as unchanged drug and partially
dependent on renal tubular secretion mediated by the transporters for
organic cations, mainly organic cation transporter novel 1 (OCTN1) and
multidrug and toxin extrusion protein (MATE), but also the organic
cation transporter 2 (OCT2) [41-44].
Considering the potential disease-drug pharmacokinetic interaction when
diabetic neuropathic pain is treated with GBP, a prospective clinical
trial was conducted to evaluate the effect of hyperglycaemia on GBP
population pharmacokinetics. Patients diagnosed with neuropathic pain
with score ≥ 4 on a visual analogue scale (VAS), induced or not by
diabetes, were investigated. The population pharmacokinetic analysis
was conducted to evaluate the
inter-individual variability and to test as covariates demographical and
clinical variables, including biomarkers of renal function and diabetes,
such as estimated glomerular filtration rate (eGFR) and glycaemic
levels.