Pharmacokinetics of Sustained-release, Oral, and Subcutaneous Meloxicam over 72 Hours in Male Beagle Dogs.

In cynomolgus macaques, plasma levels of sustained-release formulations of meloxicam meet or exceed efficacious concentrations for 48 to 72 h, thereby allowing less animal handling and providing more consistent efficacy than standard formulations of meloxicam. The goal of this study was to compare the pharmacokinetics of a single subcutaneous dose of a sustained-release formulation of meloxicam (Melox-SR) with those of oral (Melox-PO) and standard subcutaneous (Melox-SC) formulations dosed every 24 h for 3 consecutive days. Dogs (5 or 6 adult male Beagles) each received the following 3 treat- ments: first, Melox-SR (10 mg/mL, 0.6 mg/kg SC once), next Melox-SC (0.2 mg/kg SC once, followed by 0.1 mg/kg SC every 24 h), and finally Melox-PO (same dosage as Melox-SC), with a washout period of at least 2 wk between formulations. Blood was collected at 0 (baseline), 1, 4, 8, 12, 24, 48, and 72 h after the initial administration of each formulation for comparison of meloxicam plasma concentrations. Blood was also collected before administration and at 48 h after Melox-SR injection for CBC and chemistry analysis. Plasma concentrations (mean ± 1 SD) of Melox-SR peaked at the 1-h time point (2180 ± 359 ng/ mL), whereas those of Melox-PO (295 ± 55 ng/mL) and Melox-SC (551 ± 112 ng/mL) peaked at the 4-h time point. Melox-SR yielded significantly higher plasma concentrations than Melox-PO and Melox-SC until the 48 and 72-h time points, respec- tively. Melox-SC plasma concentrations were significantly higher than those of Melox-PO at 4, 8, 12, 24, 48 and 72 h. No lesions were noted at the Melox-SR injection sites, and Melox-SR administration was not associated with changes in the CBC and serum chemistry panels. A single 0.6-mg/kg dose of Melox-SR can yield plasma concentrations that exceed 350 ng/mL for at least 72 h in adult male dogs.

Determination of parecoxib and valdecoxib in rat plasma by UPLC-MS/MS and its application to pharmacokinetics studies.

BACKGROUND: The present study aimed to develop and validate a rapid, selective, and reproducible ultra-performance liquid chromatography-tandem mass spectrometry separation method for the simultaneous determination of the levels of parecoxib and its main metabolite valdecoxib in rat plasma. Moreover, this method was applied to investigate the pharmacokinetics of parecoxib and valdecoxib in rats. METHODS: Following the addition of celecoxib as an internal standard, one-step protein precipitation by acetonitrile was used for sample preparation. The effective chromatographic separation was carried out using an ACQUITY UPLC®BEH C18 reversed phase column (2.1 mm × 50 mm, 1.7 µm particle size) with acetonitrile and water (containing 0.1% formic acid) as the mobile phase. The procedure was performed in less than 3 min with a gradient elution pumped at a flow rate of 0.4 ml/min. The electrospray ionization source was applied and operated in the positive ion mode and multiple reaction monitoring mode was used for quantification using the following: target fragment ions: m/z 371 → 234 for parecoxib, m/z 315 → 132 for valdecoxib and m/z 382 → 362 for celecoxib. RESULTS: The method validation demonstrated optimal linearity over the range of 50-10,000 ng/ml (r2 ≥ 0.9996) and 2.5-500 ng/ml (r2 ≥ 0.9991) for parecoxib and valdecoxib in rat plasma, respectively. CONCLUSIONS: The present study demonstrated a simple, sensitive and applicable method for the quantification of parecoxib and its main pharmacologically active metabolite valdecoxib following sublingual vein administration of 5 mg/kg parecoxib in rats.

Nonlinear mixed-effects pharmacokinetic modeling of the novel COX-2 selective inhibitor vitacoxib in dogs.

The objective of this study was to develop a nonlinear mixed-effects model of vitacoxib disposition kinetics in dogs after intravenous (I.V.), oral (P.O.), and subcutaneous (S.C.) dosing. Data were pooled from four consecutive pharmacokinetic studies in which vitacoxib was administered in various dosing regimens to 14 healthy beagle dogs. Plasma concentration versus time data were fitted simultaneously using the stochastic approximation expectation maximization (SAEM) algorithm for nonlinear mixed-effects as implemented in Monolix version 2018R2. Correlations between random effects and significance of covariates on population parameter estimates were evaluated using multiple samples from the posterior distribution of the random effects. A two-compartment mamillary model with first-order elimination and first-order absorption after P.O. and S.C. administration, best described the available pharmacokinetic data. Final parameter estimates indicate that vitacoxib has a low-to-moderate systemic clearance (0.35 L hr-1  kg-1 ) associated with a low global extraction ratio, but a large volume of distribution (6.43 L/kg). The absolute bioavailability after P.O. and S.C. administration was estimated at 10.5% (fasted) and 54.6%, respectively. Food intake was found to increase vitacoxib oral bioavailability by a fivefold, while bodyweight (BW) had a significant impact on systemic clearance, thereby confirming the need for BW adjustment with vitacoxib dosing in dogs.

Pharmacokinetic study of imrecoxib in patients with renal insufficiency.

OBJECTIVE: Renal insufficiency may influence the pharmacokinetics of drugs. We have investigated the pharmacokinetic parameters of imrecoxib and its two main metabolites in individuals with osteoarthritis (OA) with normal renal function and renal insufficiency, respectively. METHODS: This was a prospective, parallel, open, matched-group study in which 24 subjects were enrolled (renal insufficiency group, n = 12; healthy control group, n = 12). Blood samples of subjects administered 100 mg imrecoxib were collected at different time points and analyzed. Plasma concentrations of imrecoxib and its two metabolites (M1 and M2) were determined by the liquid chromatography-tandem mass spectrometry method, and pharmacokinetic parameters (clearance [CL], apparent volume of distribution [Vd], maximum (or peak) serum concentration [Cmax], amount of time drug is present in serum at Cmax [Tmax], area under the curve [AUC; total drug exposure across time], mean residence time [MRT] and elimination half-life [t1/2]) were calculated. RESULTS: The demographic characteristics of the two groups were not significantly different, with the exception of renal function. The mean Cmax and AUC0-t (AUC from time 0 to the last measurable concentration) of imrecoxib in the renal insufficiency group were 59 and 70%, respectively, of those of the healthy control volunteers with normal renal function, indicating a significant decline in the former group (P < 0. 05). The mean pharmacokinetic parameters of Ml in the renal insufficiency and healthy control groups did not significantly differ. In contrast, the mean Cmax and AUC0-t of M2 in the renal insufficiency group were 233 and 367%, respectively, of those of the normal renal function group, indicating a significant increase in the former group (P < 0.05). The mean CL/F (clearance/bioavailability) of M2 of the renal insufficiency group was 37% of that of the normal renal function group, indicating a notable reduction in the former group (P < 0.05). CONCLUSION: The exposure of imrecoxib in OA patients with renal insufficiency showed a decline compared to that in healthy subjects. However, in patients with renal insufficiency the exposure of M2 was markedly increased and the CL was noticeably reduced. These results indicate that the dosage of imrecoxib should be reduced appropriately in patients with renal insufficiency.

Pharmacokinetics, metabolism and excretion of celecoxib, a selective cyclooxygenase-2 inhibitor, in horses.

Celecoxib, a nonsteroidal anti-inflammatory drug, is frequently used to treat arthritis in humans with minimal gastrointestinal side effect compared to traditional NSAIDs. The primary aim of this study was to determine the pharmacokinetic profile of celecoxib-a selective cyclooxygenase-2 (COX-2) inhibitor in horses. Six horses were administered a single oral dose of celecoxib at 2 mg/kg (body weight). After oral dosing, the drug reached a maximum concentration (mean ± SD) in blood of 1,088 ± 324 ng/ml in 4.58 hr. The elimination half-life was 13.60 ± 3.18 hr, and the area under the curve was 24,142 ± 1,096 ng hr ml-1 . The metabolism of celecoxib in horses was via a single oxidative pathway in which the methyl group of celecoxib is oxidized to a hydroxymethyl metabolite and is further oxidized to form a carboxylic acid metabolite. Celecoxib is eliminated mainly through faeces as unchanged drug and as metabolites in urine. Therefore, instructions for a detection time following therapeutic dosing of celecoxib can be set by the racing practitioner and veterinarians to control illegal use in horse racing based on the results of this study.

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.

In vivo evaluation of [11C]TMI, a COX-2 selective PET tracer, in baboons.

Overexpression of Cyclooxygenase-2 (COX-2) enzyme is associated with the pathogenesis of inflammation, cancers, stroke, arthritis, and neurological disorders. Because of the involvement of COX-2 in these diseases, quantification of COX-2 expression using Positron Emission Tomography (PET) may be a biological marker for early diagnosis, monitoring of disease progression, and an indicator of effective treatment. At present there is no target-specific or validated PET tracer available for in vivo quantification of COX-2. The objective of this study is to evaluate [11C]TMI, a selective COX-2 inhibitor (Ki ≤ 1 nM) in nonhuman primates using PET imaging. PET imaging in baboons showed that [11C]TMI penetrates the blood brain barrier (BBB) and accumulates in brain in a somewhat heterogeneous pattern. Metabolite analyses indicated that [11C]TMI undergoes no significant metabolism of parent tracer in the plasma for baseline scans, however a relative faster metabolism was found for blocking scan. All the tested quantification approaches provide comparable tracer total distribution volume (VT) estimates in the range of 3.2-7 (mL/cm3). We observed about 25% lower VT values in blocking studies with meloxicam, a nonselective COX-2 inhibitor, compared to baseline [11C]TMI binding. Our findings indicate that [11C]TMI may be a suitable PET tracer for the quantification of COX-2 in vivo. Further experiments are needed to confirm the potential of this tracer in COX-2 overexpressing models for brain diseases.

The Effect of Food on Tramadol and Celecoxib Bioavailability Following Oral Administration of Co-Crystal of Tramadol-Celecoxib (CTC): A Randomised, Open-Label, Single-Dose, Crossover Study in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Co-Crystal of Tramadol-Celecoxib (CTC), in development for the treatment of moderate to severe acute pain, is a first-in-class co-crystal containing a 1:1 molecular ratio of two active pharmaceutical ingredients; rac-tramadol·HCl and celecoxib. This randomised, open-label, crossover study compared the bioavailability of both components after CTC administration under fed and fasting conditions. METHODS: Healthy adults received single doses of 200 mg CTC under both fed and fasting conditions (separated by a 7-day washout). Each dose of CTC was administered orally as two 100 mg tablets, each containing 44 mg tramadol·HCl and 56 mg celecoxib. In the fed condition, a high-fat, high-calorie meal [in line with recommendations by the US Food and Drug Administration (FDA)] was served 30 min before CTC administration. Tramadol, O-desmethyltramadol and celecoxib plasma concentrations were measured pre- and post-dose up to 48 h. Pharmacokinetic parameters were calculated using non-compartmental analysis. Safety was also assessed. RESULTS: Thirty-six subjects (18 female/18 male) received one or both doses of CTC; 33 provided evaluable pharmacokinetic data under fed and fasting conditions. For tramadol and O-desmethyltramadol, fed-to-fasting ratios of geometric least-squares means and corresponding 90% confidence interval (CI) values for maximum plasma concentration (Cmax) and extrapolated area under the plasma concentration-time curve to infinity (AUC∞) were within the pre-defined range for comparative bioavailability (80-125%). For celecoxib, Cmax and AUC∞ fed-to-fasting ratios (90% CIs) were outside this range, at 130.91% (116.98-146.49) and 129.34% (121.78-137.38), respectively. The safety profile of CTC was similar in fed and fasting conditions. CONCLUSIONS: As reported for standard-formulation celecoxib, food increased the bioavailability of celecoxib from single-dose CTC. Food had no effect on tramadol or O-desmethyltramadol bioavailability. CLINICAL TRIAL REGISTRATION NUMBER: 152052 (registered with the Therapeutic Products Directorate of Health Canada).

Effect of Fluconazole on the Pharmacokinetic Properties of Imrecoxib, a Novel NSAID: A Single-center, Open-label, Self-controlled Study in Healthy Chinese Male Volunteers.

PURPOSE: Imrecoxib is one type of cyclooxygenase-2 inhibitor with the capability of reducing the potential cardiovascular risk caused by other NSAIDs. Co-administration with other medications can affect the cytochrome P450 (CYP) 2C9 enzyme function; thus, imrecoxib metabolism can be affected. The purpose of this research was to evaluate the effects of fluconazole, which is known to inhibit CYP2C9, on imrecoxib's pharmacokinetic (PK) parameters. METHODS: In this single-center, single-arm, open-label, self-controlled study, 12 healthy Chinese male volunteers (mean [SD] age, 22.6 [2.43] years) received the following 2 treatments separated by a washout period of 8 days under a fasting state: (1) a single oral dose of imrecoxib 100 mg; and (2) fluconazole 200 mg/d over 6 days followed by concurrent dosing of imrecoxib 100 mg and fluconazole 200 mg. Plasma concentrations of imrecoxib (M0) and its metabolites (4'-hydroxymethyl metabolite [M1] and 4'-carboxylic acid metabolite [M2]) for PK analysis were obtained at 0 (baseline) and 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, and 72 hours after imrecoxib dosing. Safety and tolerability assessments were performed throughout the study. FINDINGS: All subjects completed the study. There was 1 adverse event; drug-induced liver damage in 1 subject occurred after he received imrecoxib plus fluconazole, and the subject recovered without any sequelae. Coadministration with fluconazole resulted in much higher plasma imrecoxib concentrations, with an increase of 88% in Cmax and 72% in AUC0-t compared with only imrecoxib treatment, which showed that fluconazole may increase plasma exposure to imrecoxib. Fluconazole also caused a small, but not clinically relevant, decrease in M1 and M2 mean Cmax (13% and 14%, respectively), but there was minimal change in M1 and M2 mean AUC0-t (3% and 2%). However, there were no statistically significant differences in vital signs, clinical laboratory test results, ECGs, or adverse events between treatments. IMPLICATIONS: Concurrent administration of imrecoxib and fluconazole did not seem to change imrecoxib's safety profile. The ratio (imrecoxib + fluconazole/imrecoxib) for AUC0-t was 1.72 (90% CI, 1.41-2.11) and for Cmax it was 1.88 (90% CI, 1.59-2.21). Hence, it is necessary to adjust the imrecoxib dose when it is concurrently used with other CYP2C9 inhibitors.

Simultaneous determination of parecoxib and its main metabolites valdecoxib and hydroxylated valdecoxib in mouse plasma with a sensitive LC-MS/MS method to elucidate the decreased drug metabolism of tumor bearing mice.

Parecoxib (PX), a prodrug of valdecoxib (VX), is an injectable selective COX-2 inhibitor, and is recommended for the treatment of cancer pain. PX can be rapidly hydrolyzed into its active metabolite VX, and VX is further metabolized into hydroxylated valdecoxib (OH-VX) by cytochrome P450 enzymes. However, cancer patients have been reported to possess reduced drug metabolism ability, which might cause excessive drug accumulation. Such overdose of PX significantly increased the risk of renal safety and cardiovascular events. Therefore, it is necessary to elucidate the concentration profiles of PX and its metabolites in cancer status. In this study, a sensitive, rapid and specific LC-MS/MS method for quantification of PX, VX and OH-VX in the plasma of tumor bearing mouse was developed and validated. After protein precipitation, all the analytes were separated on an Agilent ZORBAX Extend-C18 HPLC column (2.1 × 100 mm, 3.5 µm) with gradient elution. The analytes were detected by an electrospray negative ionization mass spectrometry in the multiple reaction monitoring mode. The transition m/z 369.0 → 119.0, m/z 312.9 → 117.9, m/z 329.0 → 196.0, and m/z 307.1 → 161.3 were used for monitoring PX, VX, OH-VX and IS respectively. The calibration curves of the analytes showed good linearity over the concentration range of 3-3000 ng/mL for PX and VX, and 3-1000 ng/mL for OH-VX. Intra- and inter-batch accuracies (in terms of relative error, RE < 9.9%) and precisions (in terms of relative standard deviation, RSD < 8.8%) satisfied the standard of validation. The matrix effect, recovery and stability were also within acceptable criteria. The method was successfully applied to the pharmacokinetics study of PX in tumor bearing mice, and PX and VX levels were found elevated with the growth of tumor volume, which might increase the risk of drug overdose.

Silver-choline chloride modified graphene oxide: Novel nano-bioelectrochemical sensor for celecoxib detection and CCD-RSM model.

In this study, silver nanoparticles modified choline chloride functionalized graphene oxide (AgNPs-ChCl-GO) was synthesized using sonochemical method and utilized as a bioelectrochemical sensor for detection of celecoxib (CEL). The characterization studies were ultimately performed in order to acheive a more complete understanding of the morphological and structural features of the AgNPs-ChCl-GO using different techniques including FT-IR, AFM, FE-SEM, EDX, and XRD. AgNPs-ChCl-GO demonstrated a significant improvement in the reduction activity of CEL due to the enhancement in the current response compared to the bare carbon paste electrode (CPE). The optimum experimental conditions, were optimized using central composite design (CCD) methodology. The differential pulse voltammetry (DPVs) showed an expanded linear dynamic ranges of 9.6 × 10-9-7.4 × 10-7 M for celecoxib in Britton-Robinson buffer in pH 5.0 with. LOD (S/N = 3) and LOQ (S/N = 10) were obtained 2.51 × 10-9 M and 6.58 × 10-9 M respectively. AgNPs-ChCl-GO-carbon paste electrode exhibited suitable properties and high accuracy determination of celecoxib in the human plasma sample.

Plasma firocoxib concentrations after intra-articular injection of autologous conditioned serum prepared from firocoxib positive horses.

Orthobiologics such as autologous conditioned serum (ACS) are often used to treat joint disease in horses. Because ACS is generated from the horse's own blood, any medication administered at the time of preparation would likely be present in stored ACS, which could lead to an inadvertent positive drug test following intra-articular (IA) injection. The main objective of this study was to determine if ACS prepared from firocoxib positive horses could result in detectable plasma concentrations of the drug following IA injection. Firocoxib was administered to six horses at 0.1mg/kg PO twice at a 24h interval. Blood was obtained at 4h following the second dose and transferred to a separate syringe (Arthrex IRAP II) for ACS preparation. Plasma and ACS concentrations of firocoxib were analysed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). When horses were confirmed firocoxib negative, 7.5mL of ACS was injected into both tarsocrural joints. Blood samples were collected at 0, 4, 8, 12, 24, and 48h, and firocoxib concentration was measured. Mean (±standard error of the mean, SEM) plasma concentration of firocoxib 4h following the second dose was 33.3±4.72ng/mL. Mean (±SEM) firocoxib concentration in ACS was 35.4±4.47ng/mL. Fourteen days following the second and last dose of firocoxib, mean plasma concentration was below the lower limit of detection (LOD=1ng/mL) in all horses. Following IA injection of ACS, plasma concentrations of firocoxib remained below LOD at all times in all horses. ACS generated from horses with therapeutic plasma concentrations of firocoxib did not contain sufficient firocoxib to lead to a positive plasma drug test following IA administration.

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.

Single-dose pharmacokinetics of co-crystal of tramadol-celecoxib: Results of a four-way randomized open-label phase I clinical trial in healthy subjects.

AIMS: Co-crystal of tramadol-celecoxib (CTC) is a novel co-crystal molecule containing two active pharmaceutical ingredients under development by Esteve (E-58425) and Mundipharma Research (MR308). This Phase I study compared single-dose pharmacokinetics (PK) of CTC with those of the individual reference products [immediate-release (IR) tramadol and celecoxib] alone and in open combination. METHODS: Healthy adults aged 18-55 years were orally administered four treatments under fasted conditions (separated by 7-day wash-out period): 200 mg IR CTC (equivalent to 88 mg tramadol and 112 mg celecoxib; Treatment 1); 100 mg IR tramadol (Treatment 2); 100 mg celecoxib (Treatment 3); and 100 mg IR tramadol and 100 mg celecoxib (Treatment 4). Treatment sequence was assigned using computer-generated randomization. PK parameters were calculated using noncompartmental analysis with parameters for CTC adjusted according to reference product dose (100 mg). RESULTS: Thirty-six subjects (28 male, mean age 36 years) participated. Tramadol PK parameters for Treatments-1, -2 and -4, respectively, were 263, 346 and 349 ng ml-1 (mean maximum plasma concentration); 3039, 2979 and 3119 ng h ml-1 (mean cumulative area under the plasma concentration-time curve); and 2.7, 1.8 and 1.8 h (median time to maximum plasma concentration). For Treatments 1, 3 and 4, the respective celecoxib PK parameters were 313, 449 and 284 ng ml-1 ; 2183, 3093 and 2856 ng h ml-1 ; and 1.5, 2.3 and 3.0 h. No unexpected adverse events were reported. CONCLUSION: PK parameters of each API in CTC were modified by co-crystallization compared with marketed formulations of tramadol, celecoxib, and their open combination.

Pentafluorosulfanyl-Substituted Benzopyran Analogues As New Cyclooxygenase-2 Inhibitors with Excellent Pharmacokinetics and Efficacy in Blocking Inflammation.

In this report, we disclose the design and synthesis of a series of pentafluorosulfanyl (SF5) benzopyran derivatives as novel COX-2 inhibitors with improved pharmacokinetic and pharmacodynamic properties. The pentafluorosulfanyl compounds showed both potency and selectivity for COX-2 and demonstrated efficacy in several murine models of inflammation and pain. More interestingly, one of the compounds, R,S-3a, revealed exceptional efficacy in the adjuvant induced arthritis (AIA) model, achieving an ED50 as low as 0.094 mg/kg. In addition, the pharmacokinetics of compound R,S-3a in rat revealed a half-life in excess of 12 h and plasma drug concentrations well above its IC90 for up to 40 h. When R,S-3a was dosed just two times a week in the AIA model, efficacy was still maintained. Overall, drug R,S-3a and other analogues are suitable candidates that merit further investigation for the treatment of inflammation and pain as well as other diseases where COX-2 and PGE2 play a role in their etiology.

The pharmacokinetics and metabolism of lumiracoxib in chimeric humanized and murinized FRG mice.

The pharmacokinetics and metabolism of lumiracoxib were studied, after administration of single 10mg/kg oral doses to chimeric liver-humanized and murinized FRG mice. In the chimeric humanized mice, lumiracoxib reached peak observed concentrations in the blood of 1.10±0.08µg/mL at 0.25-0.5h post-dose with an AUCinf of 1.74±0.52µgh/mL and an effective half-life for the drug of 1.42±0.72h (n=3). In the case of the murinized animals peak observed concentrations in the blood were determined as 1.15±0.08µg/mL at 0.25h post-dose with an AUCinf of 1.94±0.22µgh/mL and an effective half-life of 1.28±0.02h (n=3). Analysis of blood indicated only the presence of unchanged lumiracoxib. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles obtained in humanized mice were different compared to murinized animals with e.g., a higher proportion of the dose detected in the form of acyl glucuronide metabolites and much reduced amounts of taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57bl/6J mice and humans, revealed a greater though not complete match between chimeric humanized mice and humans, such that the liver-humanized FRG model may represent a useful approach to assessing the biotransformation of such compounds in humans.

Quantification of Etodolac in Human Plasma for Pharmacokinetics and Bioequivalence Studies in 27 Korean Subjects.

OBJECTIVE: We developed a simple and validated liquid chromatography tandem mass spectrometry( LC-MS/MS) for quantification of etodolac using pioglitazone as an internal standard (IS) to assess pharmacokinetics and to appraise bioequivalence of two formulations of etodolac (reference and tested) in 27 healthy Korean subjects. METHODS: Isocratic mobile phase consisted of 10 mM ammonium formate and acetonitrile were used to separate the analytes on a Gemini C18 column. Also, analytes were analyzed by MS/MS in multiple reaction monitoring (MRM) mode using the transitions of (M+H)+ ions, m/z 288.2→ 172.3 and m/z 357.1→ 134.2 for quantification of etodolac and IS each. The standard calibration curves displayed significant linearity within the range of 0.2-30.0 µ g/mL (r2=0.9956, 1/x2 weighting) with LLOQ of 0.1 µg/mL. RESULTS: The retention times of etodolac and the IS were 0.77 min and 0.57 min each, indicating the high-throughput potential of the proposed method. The pharmacokinetic parameters were calculated from the plasma samples and data form the reference and test drugs were represented as follows; Area under plasma concentration-time curve (AUCt) (78.03 vs. 84.00 µgxh/mL), AUC∞ (86.67 vs. 93.92 µgxh/mL), maximal plasma concentration (Cmax) (19.49 vs. 18.94 µg/mL), time for maximal concentrations (Tmax) (2.13 vs. 2.26 h), Plasma elimination half-life (T1/2) (8.12 vs. 8.47 h), elimination rate constant (λz) (0.0853 vs. 0.0818 h-1). Pharmacokinetic parameters with 90% confidence interval fall within the bioequivalence range of 80-125%. CONCLUSION: Thus, the new testified method was successfully applied for the pharmacokinetic and bioequivalence studies for two etodolac formulations.

Celecoxib interferes to a limited extent with aspirin-mediated inhibition of platelets aggregation.

AIMS: The aim of the study was to analyze the interaction between celecoxib and low dose aspirin for COX-1 binding and its consequences on the aspirin-mediated antiplatelet effects. METHODS: We investigated ex vivo the interaction between celecoxib and aspirin for COX-1 binding and measured the resulting antiplatelet effects. We applied mechanism-based pharmacokinetic-pharmacodynamic (PKPD) modelling to analyze these data and to predict in vivo platelet aggregation for different doses and administration schedules of aspirin and celecoxib. RESULTS: The predictions of the PK-PD model were consistent with results from previous studies that investigated interaction between aspirin and celecoxib. The modelling results indicate that celecoxib can attenuate to a limited extent the in vivo antiplatelet effects of low dose aspirin. The extent of this interaction can be substantial (up to 15% increase in platelet aggregation by 200 mg day(-1) celecoxib when combined with low dose aspirin) during the first days of aspirin administration in patients who are already treated with celecoxib, and it cannot be prevented by separate administration of the interacting drugs. CONCLUSIONS: At the recommended therapeutic doses, celecoxib can attenuate to a limited extent the in vivo antiplatelet effects of low dose aspirin. Patients receiving a combination of low dose aspirin and the recommended doses of celecoxib were not identified to have increased risk of cardiovascular and cerebrovascular events due to competition between these drugs for COX-1 binding. Interaction between low dose aspirin and other COX-2 inhibitors and its clinical consequences requires further investigation.

Influence of genetic polymorphisms on the pharmacokinetics of celecoxib and its two main metabolites in healthy Chinese subjects.

Celecoxib is a selective cyclooxygenase-2 inhibitor used extensively for the treatment of rheumatism and osteoarthritis. The aim of this study was to evaluate the influence of the genetic polymorphisms of CYP2C9, CYP2D6 and CYP3A4 on the pharmacokinetics (PK) of celecoxib and its two main metabolites, hydroxyl-celecoxib and carboxy-celecoxib, in healthy Chinese subjects, based on a bioequivalence study of celecoxib. This study was an open-label, two-period, crossover study. 52 healthy Chinese male subjects were recruited and were genotyped for CYP2C9*3, CYP2C9*13, CYP2D6*10 and CYP3A4*18 by using polymerase chain reactions (PCR). They were randomly divided into two groups and each group received either 200mg test formulation followed by reference formulation or vice versa with a one-week washout period. Safety and tolerability were monitored throughout the study and no severe adverse events were observed. Genotyping using PCR revealed that none of the subjects carried the CYP3A4*18 and CYP2C9*13. Therefore, the influence of the CYP2C9*3 and CYP2D6*10 on the PK of celecoxib and its metabolites in Chinese was studied. Compared with CYP2C9*1/*1 group, pharmacokinetic parameters of celecoxib such as AUC0-48 and Cmax was increased by 90.6% and 45.8%, the t1/2 was extended by 21.8% and the CL/F was decreased by 51.1% in CYP2C9*1/*3 group. In terms of hydroxy-celecoxib, compared with CYP2C9*1/*1 group, the Cmax was decreased by 17.2%, the t1/2 prolonged 42.1% in CYP2C9*1/*3 group. In terms of carboxy-celecoxib, the AUC0-48 was increased by 25.2%, the t1/2 prolonged 16.1% and the CL/F was decreased by 21.2% in CYP2C9*1/*3 group. Except for the t1/2 of hydroxy-celecoxib, no statistically significant difference was observed in other pharmacokinetic parameters of hydroxy-celecoxib and carboxy-celecoxib between the two CYP2C9 genotypic groups. This study revealed that there was no significant influence of CYP2D6*10 on the metabolism of celecoxib, and the expression of CYP2C9*3 led to increased drug exposure and slowed drug disposition in healthy Chinese male subjects.

Quantitation of celecoxib and four of its metabolites in rat blood by UPLC-MS/MS clarifies their blood distribution patterns and provides more accurate pharmacokinetics profiles.

A sensitive UPLC-MS/MS method was established and validated for the quantitation of celecoxib and its metabolites in rat blood. The analytes were extracted from rat blood samples by a salting-out liquid-liquid extraction method followed by the UPLC chromatography. The mass analysis of effluent was performed on an API 5500 Qtrap mass spectrometer via multiple reactions monitoring (MRM). The linear response ranges were 0.3-20000nM for celecoxib, and 1.2-20000nM, 0.3-20000nM, 2.0-2000nM, 1.5-6000nM for its metabolites carboxycelecoxib (M2), hydroxycelecoxib (M3), hydroxycelecoxib glucuronide (M1), and carboxycelecoxib glucuronide (M5), respectively. The inter-day and intra-day accuracies were within 85-115%, and the inter-day and intra-day precision were acceptable (<12%) for all analytes. Recoveries were above 70% and no obvious matrix effects were observed. The validated UPLC-MS/MS method was successfully applied to a pharmacokinetics study of oral celecoxib (20mg/kg) in Sprague-Dawley rats, and the rat blood concentrations (0-48h) of celecoxib and two of its metabolites M2 and M3 were successfully determined. Using the same method, we also showed preferential distributions of celecoxib, M2 and M3 in the blood cells as compared to the plasma. In conclusion, our results showed that our validated LC-MS/MS method can be successfully used for the pharmacokinetic studies of celecoxib and that the blood cells are a very important compartment for this drug such that profiles of celecoxib and its metabolites in whole blood will be more comprehensive and accurate representation of their profiles in vivo than the plasma.