Pharmacokinetics, Tissue Distribution, Metabolism and Excretion of a Novel COX-2 Inhibitor, Vitacoxib, in Rats.

The objectives of this study were to elucidate absorption, tissue distribution, excretion, and metabolism of vitacoxib, a novel selective cyclooxygenase-2 inhibitor, in Wistar rats. Vitacoxib was detected in most tissues within 15 min, suggesting that it was well distributed. Moreover, it could cross the intestinal barrier. Vitacoxib was mainly eliminated as two metabolites. Nine proposed metabolites of vitacoxib were found in the plasma, bile, urine, and feces of rats. Two main metabolites, 4-(4-chloro-1-(5-(methyl-sulfonyl) pyridin-2-yl)-1H-imidazol-5-yl) phenyl methanol (M1) and 4-(4-chloro-1-(5-(methyl-sulfonyl) pyridin-2-yl)-1H-imidazol-5-yl) benzoic acid (M2), were identified in rat feces and urine. Further, the authentic standards of M1 and M2 were synthesized to confirm their structures. The carboxylic acid derivative was the major metabolite of vitacoxib excreted in the urine and feces. Hydroxylation of the aromatic methyl group of vitacoxib and additional oxidation of the hydroxymethyl metabolite to a carboxylic acid metabolite were the proposed metabolic pathways. Vitacoxib displayed a high AUC last (4895.73 ± 604.34 ng·h/ml), long half-life (4.25 ± 0.30 h), slow absorption (T max , 5.00 ± 2.00 h), and wide tissue distribution in rats. Our findings provide significant information for the further development and investigation of vitacoxib as an effective nonsteroidal anti-inflammatory agent, and highly its potential for use future in a clinical setting.

Non-Linear Mixed-Effects Pharmacokinetic Modeling of the Novel COX-2 Selective Inhibitor Vitacoxib in Cats.

The objective of this study was to develop a non-linear mixed-effects (NLME) model to describe the disposition kinetics of vitacoxib in cats following intravenous (I.V) and oral (P.O) (single and multiple) dosing. Data from six consecutive studies with 16 healthy neutered domestic short hair cats were pooled together to build a pharmacokinetic (PK) model using NLME. Population PK parameters were estimated using the stochastic approximation expectation maximization (SAEM) algorithm implemented in Monolix 2019R2. A two-compartment mammillary disposition model with simultaneous zero- and first-order absorption best described the PK of vitacoxib in plasma after oral dosing. The systemic CL of vitacoxib was found to be low (110 ml/h), with a steady-state volume of distribution (VSS) of 3.42 L in cats. Results from the automated covariate search in Monolix 2019R2 showed that bodyweight had a significant effect on the central volume of distribution of vitacoxib. Lastly, using Monte Carlo simulations, we investigated the time course of several dosages of vitacoxib from 0.01 to 8 mg/kg. Using this simulation set, we found a range of reasonable dosages that produce therapeutic plasma concentrations of vitacoxib for 24 h or more in cats.

Pharmacokinetics of three formulations of vitacoxib in horses.

The pharmacokinetic properties of three formulations of vitacoxib were investigated in horses. To describe plasma concentrations and characterize the pharmacokinetics, 6 healthy adult Chinese Mongolian horses were administered a single dose of 0.1 mg/kg bodyweight intravenous (i.v.), oral paste, or oral tablet vitacoxib in a 3-way, randomized, parallel design. Blood samples were collected prior to and at various times up to 72 hr postadministration. Plasma vitacoxib concentrations were quantified using UPLC-MS/MS, and pharmacokinetic parameters were calculated using noncompartmental analysis. No complications resulting from the vitacoxib administration were noted on subsequent administrations, and all procedures were tolerated well by the horses throughout the study. The elimination half-life (T1/2λz ) was 4.24 ± 1.98 hr (i.v.), 8.77 ± 0.91 hr (oral paste), and 8.12 ± 4.24 hr (oral tablet), respectively. Maximum plasma concentration (Cmax ) was 28.61 ± 9.29 ng/ml (oral paste) and 19.64 ± 9.26 ng/ml (oral tablet), respectively. Area under the concentration-versus-time curve (AUClast ) was 336 ± 229 ng hr/ml (i.v.), 221 ± 94 ng hr/ml (oral paste), and 203 ± 139 ng hr/ml, respectively. The results showed statistically significant differences between the 2 oral vitacoxib groups in Tmax value. T1/2λz (hr), AUClast (ng hr/ml), and MRT (hr) were significantly different between i.v. and oral groups. The longer half-life observed following oral administration was consistent with the flip-flop phenomenon.

Pharmacokinetics of the novel COX-2 selective inhibitor vitacoxib in cats: The effects of feeding and dose.

The purpose of this study was to determine the pharmacokinetics and dose-scaling model of vitacoxib in either fed or fasted cats following either oral or intravenous administration. The concentration of the drug was quantified by UPLC-MS/MS on plasma samples. Relevant parameters were described using noncompartmental analysis (WinNonlin 6.4 software). Vitacoxib is relatively slowly absorbed and eliminated after oral administration (2 mg/kg body weight), with a Tmax of approximately 4.7 hr. The feeding state of the cat was a statistically significant covariate for both area under the concentration versus time curve (AUC) and mean absorption time (MATfed ). The absolute bioavailability (F) of vitacoxib (2 mg/kg body weight) after oral administration (fed) was 72.5%, which is higher than that in fasted cats (F = 50.6%). Following intravenous administration (2 mg/kg body weight), Vd (ml/kg) was 1,264.34 ± 343.63 ml/kg and Cl (ml kg-1  hr-1 ) was 95.22 ± 23.53 ml kg-1  hr-1 . Plasma concentrations scaled linearly with dose, with Cmax (ng/ml) of 352.30 ± 63.42, 750.26 ± 435.54, and 936.97 ± 231.27 ng/ml after doses of 1, 2, and 4 mg/kg body weight, respectively. No significant undesirable behavioral effects were noted throughout the duration of the study.

Mutagenicity and teratogenicity studies of vitacoxib in rats and mice.

Vitacoxib is a new drug candidate for treatment of inflammation, pain and fever as selective cyclooxygenase-2 inhibitors. In the current study, the mice sperm abnormality, mammalian erythrocyte micronucleus and in vivo chromosome aberration, and teratogenicity in SD rats were evaluated. Vitacoxib did not cause an increase in the frequency of structural chromosome aberrations, nor did it produce an increase in the number of micro nucleated polychromatic erythrocytes at dose of 1250-5000 mg/kg body weight (BW). There were no toxicological signs observed in teratogenicity test in female SD rats at dose of 200-5000 mg/kg BW. Based on these results of these studies, vitacoxib does not appear to be observed mutagenicity and teratogenicity.

Evaluation of pharmacokinetic properties of vitacoxib in fasted and fed horses.

The pharmacokinetic properties of vitacoxib have not been established completely; current dosage recommendations are based on clinical experiences. The primary objective of this study was to describe plasma concentrations and characterize the pharmacokinetics of vitacoxib formulation following oral administrations in horses. Also, the effect of the state of stomach contents on the absorption of vitacoxib was investigated in fed/fasted horses. Blood samples were collected prior to and at various times up to 72 hr post-administration. Drug concentrations were measured using ultra high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using Non-Compartmental Analysis Model 200 in WinNonlin™ software. No complications resulting from the vitacoxib administration were noted. All procedures were tolerated well by the horses throughout the study. Cmax was 17.5 ± 9.36 ng/ml (fasted) and 9.47 ± 3.53 ng/ml (fed) following oral administrations. AUClast was 173.7 ± 137.9 ng hr/ml (fasted) and 113.2 ± 70.8 ng h/ml (fed). No significant differences in pharmacokinetic parameters were noted and the results from the pharmacokinetic analysis were similar between the studies, regardless of precision of dosage and fasted and fed conditions. The study extends previous studies describing the pharmacokinetics of vitacoxib following p.o. administration to the horses. Further studies investigating the pharmacokinetics/pharmacodynamics of vitacoxib are necessary to establish adequate therapeutic protocols (optimal dosage and frequency of administration) in horses.

Safety assessment of vitacoxib: 180-day chronic oral toxicity studies.

Vitacoxib, a selective COX-2 inhibitor, is approved for the relief of pain and inflammation associated with orthopedic surgery and osteoarthritis in dogs. In the current study, a chronic toxicity research was performed to evaluate the safety of vitacoxib in male and female rats for long-term. Vitacoxib was dosed orally to groups of rats for 180 days at 1.2, 6, 30 mg/kg bw/day by gavage. The chronic study oral administration of vitacoxib did not show observational or toxicological effects on the body or organ weights, food consumption, hematology and biochemistry at dose 6 mg/kg bw. However, vitacoxib (30 mg/kg) showed minor alterations to histopathology of liver, kidney and stomach related to treatment. These results provide further indication that vitacoxib is safe and well-tolerated in rats after 180 days of daily oral administration at 6 mg/kg bw and the NOAEL for both sexes was 6 mg/kg bw for 180 consecutive days.

Evaluation of dermal irritation and skin sensitization due to vitacoxib.

The prediction of side-effects is a key issue in the REACH initiative on chemicals in the preclinical testing of drugs. The dermal irritation and skin sensitization toxicity potential of a new molecule, vitacoxib, were invested in rabbits and guinea pigs in compliance with the Organization for Economic Cooperation and Development guideline. To assess dermal irritation, rabbits were dermally attached to vitacoxib for 72 h or repeated application. The results showed that no adverse reactions such as erythema and edema were observed throughout the test. In skin sensitization test, guinea pigs were sensitized to vitaoxib, positive and negative article for 24 h. No sensitization reaction was shown in the vitacoxib and negative group whereas severe sensitization was observed in the positive group. Based on these findings, vitacoxib does not cause dermal irritation and skin sensitization toxicity, and seems to be safe for animal use.

Determination of vitacoxib, a novel COX-2 inhibitor, in equine plasma using UPLC-MS/MS detection: Development and validation of new methodology.

Vitacoxib is an imidazole derivative and the novel COX-2 selective inhibitor to be marketed for veterinary use as nonsteroidal anti-inflammatory drugs. No analytical assay to quantify vitacoxib in equine plasma samples has been published to date. In the current study, we aim to develop and validate a brief, quick and sensitive UPLC-MS/MS method for quantification of vitacoxib in equine plasma samples. Plasma samples were precipitated with methyl tert-butyl ether. The Phenomenex column (Kinetex 50×2.1mm i.d. particle size=2.6µm, C18, 100Å) at 25°C was used in chromatographic separation with mobile phase consisting of acetonitrile and water (containing 0.1% formic acid) at flow rate of 0.4mL/min. Vitacoxib and internal standard (IS, celecoxib) were detected under the multiple-reaction monitoring mode by mass spectrometer with ESI+ (m/z 347.9/269.03 for vitacoxib and m/z 382.0/362.0 for IS, respectively). The curve concentration range of was 0.5-500ng/mL with a lower limit of quantification 0.5ng/mL (r2=0.996309) in equine plasma samples. The selectivity, precision, recovery, accuracy, matrix effect and stability under various conditions were conformed to the acceptance requirements. Pharmacokinetic studies of vitacoxib in horses via oral administration (0.1mg/kg) demonstrated that the procedure was fully validated and successfully. A meaningful basis for assessing the vitacoxib or clinical applications of vitacoxib to horse is provided in the present study.

Safety assessment of vitacoxib: Acute and 90-day sub-chronic oral toxicity studies.

Vitacoxib, is a newly developed coxibs NSAID (selective inhibitors of cyclooxygenase-2). To date, no experimental data have been published concerning its safety for use as an additive in the human diet. In the present study, we assessed the acute and sub-chronic toxicity of vitacoxib administered by gavage. The acute toxicity tests in Sprague Dawley (SD) rats and ICR mice demonstrated that vitacoxib at a dose of 5000 mg/kg BW failed to alter any of the parameters studied. In the 90-day sub-chronic toxicity test, vitacoxib was administered to SD rats at the doses of 0 (control), 5, 10, 20, 30, and 60 mg/kg BW. The results demonstrated that there were no significant differences for most indexes of sub-chronic toxicity throughout the experiment at the dose of 5-20 mg/kg BW, indicating no apparent dose-dependent. However, there were significant histopathology changes in the liver and kidney, and alterations in some biochemical parameters in the 60 mg/kg BW group. Based on these findings, the gavage LD50 was determined to be > 5000 mg/kg in SD rats and ICR mice, and the 90-day gavage no-observed-adverse-effect level (NOAEL) of vitacoxib was considered to be 20 mg/kg BW under the present study conditions.

The anti-inflammatory and the analgesic effects of vitacoxib, a new molecular entity / 中国药学杂志

OBJECTIVE: To study the anti-inflammatory and analgesic effects of vitacoxib. METHODS: The in vitro COX-1 and COX-2 inhibitory activities of vitacoxib were tested in human whole blood assay as well as canine whole blood assay. The anti-inflammatory and analgesic effects of vitacoxib were evaluated in several in vivo models including croton oil induced mouse ear endema, carrageenan-induced rat paw swelling and mouse acetic acid writhing model. RESULTS: In vitro assay, vitacoxib has potent inhibitory COX-2 activity and selectivity for COX-2 over COX-1. In vivo anti-inflammatory experiments, vitacoxib has significant inhibitory activities both in croton oil-induced mouse ear oedema model test(P < 0.01) and the carrageenan-induced rat paw swelling test(P < 0.05). In vivo analgesic effect experiments, vitacoxib has significant inhibitory activity on acetic acid-induced writhing pain in mice (P < 0.05). CONCLUSION: Vitacoxib, a selective COX-2 inhibitor, demonstrates excellent anti-inflammatory activity in both in vitro and in vivo models tested.