Cetirizine Reduces Gabapentin Plasma Concentrations and Effect: Role of Renal Drug Transporters for Organic Cations

Abstract

Gabapentin (GBP) is an organic cation mainly eliminated unchanged in urine, and active drug secretion has been suggested to contribute to its renal excretion. Our objective was to evaluate the potential drug‐drug interaction between GBP and cetirizine (CTZ), an inhibitor of transporters for organic cations. An open‐label, 2‐period, crossover, nonrandomized clinical trial was conducted in patients with neuropathic pain to evaluate the effect of CTZ on GBP pharmacokinetics. Twelve participants were treated with a single dose of 300 mg GBP (treatment A) or with 20 mg/d of CTZ for 5 days and 300 mg GBP on the last day of CTZ treatment (treatment B). Blood sampling and pain intensity evaluation were performed up to 36 hours after GBP administration. The interaction of GBP and CTZ with transporters for organic cations was studied in human embryonic kidney (HEK) cells expressing the organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), and OCTN1. CTZ treatment resulted in reduced area under the concentration‐time curve and peak concentration compared with treatment A. In treatment B, the lower plasma concentrations of GBP resulted in reduced pain attenuation. GBP renal clearance was similar between treatments. GBP has low apparent affinity for OCT2 (concentration of an inhibitor where the response [or binding] is reduced by half [IC50] 237 µmol/L) and a high apparent affinity for hMATE1 (IC50 1.1 nmol/L), hMATE2‐K (IC50 39 nmol/L), and hOCTN1 (IC50 2.1 nmol/L) in HEK cells. At therapeutic concentrations, CTZ interacts with hMATE1 and OCTN1. In summary, CTZ reduced the systemic exposure to GBP and its effect on neuropathic pain attenuation. However, CTZ × GBP interaction is not mediated by the renal transporters.

Population pharmacokinetics of gabapentin in patients with neuropathic pain: Lack of effect of diabetes or glycaemic control

“…All participants were genotyped for the SNPs 808G > T (rs316019) of SLC22A2 gene and 1507C > T (rs1050152) of SLC22A4, as previously reported. 45,49 The Hardy-Weinberg equilibrium was evaluated using the χ 2 test. The clinical history and the use of concomitant drugs were registered for all participants.…”

“…GBP was determined in plasma by high-performance liquid chromatography-UV (Shimadzu Inc., Kyoto, Japan), as described previously. 45,49 In summary, the analytes were resolved on short-term, long-term, post-processing and freeze-thaw cycles).…”

“…and 2-K, 68,69 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. 45 The investigated genotypes of SLC22A2 and SLC22A4…”

“…were not relevant for the PopPK of GBP, and this is in accordance with previous published data. 45,49 Although not included in the final model, sex was included as a covariate for Ka on Model in the forward inclusion step (Table S4). A previous study showed that women had higher C max (4.6 μg/mL) for GBP when compared to men (3.7 μg/mL, P < .05) 38 after a single dose administration.…”

“…40,41 Its elimination is mainly renal as unchanged drug and dependent on renal tubular secretion mediated by the transporters for organic cations, mainly organic zwitterion/cation transporter 1 (OCTN1) and multidrug and toxin extrusion protein (MATE), but also OCT2. [42][43][44][45] Considering the potential disease-drug PK interaction when GBP is used to treat diabetic neuropathic pain and that hyperglycaemia is the main biomarker of diabetes, a clinical trial was conducted to evaluate the effect of hyperglycaemia or T2D on GBP population PK (or >4 cm) on a 10-cm visual analogue pain scale (0 = no pain; 10 = worst possible pain). 46,47 The diagnosis of diabetes was based on the criteria by the American Diabetes Association.…”