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.