Bioequivalence of 250 mg lysine clonixinate tablets after a single oral dose in a healthy female Mexican population under fasting conditions G. Marcelín-Jiménez 1 , A.C.P. Ángeles 1 , A. García 1 , M. Morales 1 , L. Rivera 1 and A. Martín-del-Campo 2 1 Clinical Pharmacology Research Service and 2 Mental Health Department, Hospital General de México, Mexico City, Mexico Bioequivalence study of lysine clonixinate Abstract. Objective: To evaluate the bio- equivalence between two 250 mg-tablets of lysine clonixinate, Dorixina Forte ® (Sieg- fried Rhein, México) as reference product, and Prestodol ® (Farmaceúticos Rayere, S.A., México) as test formulation. Methods: 26 healthy adult female Mexican volunteers re- ceived a single oral dose of 250-mg lysine clonixinate under fasting conditions. The drug was administered following a random- ized, two-period, two-sequence, cross-over design. Twelve serial blood samples were collected up to 8 h after dosing, and clonixin (CLX) was measured by ultra-performance liquid chromatography (UPLC) coupled with tandem mass spectrometry. Decimal loga- rithm values of C max and area under the curve (AUC) were used to construct a classic confi- dence interval at 90% (90% CI). Bioequiv- alence was established if 90% CI of mean ra- tios (test/reference) fall within the 0.8 – 1.25 range. Results: Volunteers formed a homoge- neous population in terms of age (27.2 ± 6.3 years), weight (55.9 ± 6.5 kg), height (1.6 ± 0.04 m), and body mass index (BMI) (22.91 ± 2.03 kg/m 2 ). Reference formulation exhibited the following pharmacokinetics: C max (32.39 ± 8.32 μg/ml); t max (0.64 ± 0.2 h); AUC 0–8h (48.92 ± 16.51 μg.h/ml); t 1/2 (1.3 ± 0.24 h); CL app (5.64 ± 1.99 l/h), and Vd app (10.22 ± 2.9 l). Concerning bioequivalence, 90% CI were: C max (82.32 – 98.79), AUC 0–t (94.59 – 106.29), and AUC 0–inf (94.61 – 106.42), with a statisti- cal power of > 0.90 at every tested interval. Conclusions: This single-dose study found that both 250-mg immediate-release tablets of lysine clonixinate met the Mexican regula- tory criteria for bioequivalence in these vol- unteers. Introduction Clonixin (CLX) is an anti-inflammatory non-steroidal analgesic drug without narcotic effects (NSAIDs) that belongs to the fenamates family; its salt, lysine clonixinate (Chemical Abstracts Society (CAS) registry no. 55837-30-4) is an amorphous white pow- der soluble in organic solvents. It is used to re- lieve middle to severe episodes of dental pain [11], dysmenorrhea [3], post-operative pains [2], and migraine [10]. The mechanism of action of CLX relies on the blunting of 5-lipoxygenase with dimin- ishing in the synthesis of the pro-inflamma- tory 5-HETE [6], and it has also been reported that CLX exerts an inhibitory effect on the ex- pression of nitric oxide synthase (NOS) in- duced, which participate during inflammation [5]. This selectivity of CLX in 5-lipoxygenase over cyclooxygenases may explain the lack of effect on platelet number and function during its therapeutic use associated with common NSAIDs [9]. Pharmacokinetic data of CLX are suc- cinct. The first attempt to determine the meta- bolic pathways of CLX in humans employed the tritium-labeled drug [8]. It showed three main metabolites both in plasma and urine: 5-OH-clonixin; 4´-OH-clonixin and 2´-ethoxyclonixin. Erratic values of plasma concentrations have been previously reported following an intravenous (IV) dose of lysine clonixinate solution in 10 children post-sur- gery [7]. These authors reported a distribution volume of ca. 1.3 l/kg, and a dose-dependent elimination half-life between 30 and 50 min. Serum concentrations were quite similar be- tween IV and oral administration after 45 min post-dose; and areas under the curve were also similar, demonstrating high degree of bioavailability by oral route. Key words lysine clonixinate – Chemical Abstracts Society (CAS) registry no. 55837-30-4 – bio- equivalence and phar- macokinetics – ultra- performance liquid chro- matography (UPLC) – tandem mass spectro- metry Received September 8, 2009; accepted January 10, 2010 Correspondence to G. Marcelín-Jiménez, PhD Servicio de Investiga- ción de Farmacología Clínica (405-E), Hospital General de México, Dr. Balmis No. 148, Col. Doctores, 06726 México, D.F., México gabmarcelin@ hotmail.com International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 5/2010 (349-354) Original ©2010 Dustri-Verlag Dr. K. Feistle ISSN 0946-1965