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

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.

Evaluation of dispersive liquid-liquid microextraction in the stereoselective determination of cetirizine following the fungal biotransformation of hydroxyzine and analysis by capillary electrophoresis.

We developed a capillary electrophoresis (CE) and dispersive liquid-liquid microextraction (DLLME) method to stereoselectively analyze hydroxyzine (HZ) and cetirizine (CTZ) in liquid culture media. The CE analyses were performed on an uncoated fused-silica capillary; 50mmolL(-1) sodium borate buffer (pH 9.0) containing 0.8% (w/v) S-ß-CD was used as the background electrolyte. The applied voltage and temperature were +6 kV and 15 °C, respectively, and the UV detector was set to 214 nm. Chloroform (300 µL) and ethanol (400 µL) were used as the extraction and disperser solvents, respectively, for the DLLME. Following the formation of a cloudy solution, the samples were subjected to vortex agitation at 2000 rpm for 30s and to centrifugation at 3000 rpm for 5 min. The recoveries ranged from 87.4 to 91.7%. The method was linear over a concentration range of 250-12,500 ng mL(-1) for each HZ enantiomer (r>0.998) and 125-6250 ng mL(-1) for each CTZ enantiomer (r>0.998). The limits of quantification were 125 and 250 ng mL(-1) for CTZ and HZ, respectively. Among the six fungi studied, three species were able to convert HZ to CTZ enantioselectively, particularly the fungus Cunninghamella elegans ATCC 10028B, which converted 19% of (S)-HZ to (S)-CTZ with 65% enantiomeric excess.