The pharmacokinetics of tolfenamic acid in Himalayan Griffon vultures. A better understanding for the safety of the drug in old world vultures.

The metabolic fate and pharmacokinetics of tolfenamic acid, a new anti-inflammatory agent, was studied after intravenous and oral administration of14C-tolfenamic acid to one healthy volunteer. The recovery in urine was 77% of the intravenous dose and 93% of the oral dose. About 11% of the doses was found in faeces after both routes of administration whereas no radioactivity was detected in expired air, saliva or red cells. In plasma 90–99% of the radioactive compounds were bound to proteins whereasin vitro protein-binding of tolfenamic acid was 99.7%. Tolfenamic acid was biotransformed into several metabolites and only less than 10% of the doses was excreted into urine as the glucuronide/sulphate conjugate of unchanged drug. Tolfenamic acid and four metabolites were separated by TLC, together they accounted for 90–100% of urine radioactivity. Two major metabolites with preliminary identification as hydroxylation products of tolfenamic acid were isolated in pure form for further structural analysis. After fast initial decline the total plasma radioactivity decreased slowly with a mean half life of 58 hours. The elimination rate of tolfenamic acid into urine was fast with a half life of 1.9 hours whereas the metabolites were eliminated more slowly. Their elimination showed three phases, a rapid initial phase up to six hours, second phase up to 48 hours with half lives ranging from 9 to 13 hours and a third terminal slow, quantitatively minor, phase thereafter.

To study its pharmacokinetics and especially microCi/100 mg was infused i.v. in 8 patients with a T-tube inserted in the common bile duct at choledocholithotomy 7-10 days prior to the study. Bile was collected in fractions by continuous suction over a 24 h period. Blood samples were taken and urine collected up to 48 h after the dose. Tolfenamic acid and its metabolites were separated by TLC and were quantitated by liquid scintillation counting. The pharmacokinetics of tolfenamic acid could be described by a two compartment open model with V1 of 3.67 +/- 0.681 and VSS of 8.0 +/- 1.01. The total plasma clearance of tolfenamic acid averaged 106 +/- 8 ml/min and t1/2 beta was 1.38 +/- 0.32 h. A three compartment open model was required to describe the kinetics of total 14C. The plasma clearance of total 14C was 15.4 +/- 3.9 ml/min and its terminal half life averaged 19.0 +/- 4.1 h. The long half-life was caused by the slow elimination of tolfenamic acid metabolites. Four metabolites were measured in plasma and bile. The principal metabolites in bile were glucuronide/sulphate conjugates of hydroxylated derivatives of tolfenamic acid. The recovery of tolfenamic acid in bile was 1.1 +/- 0.3% of the dose, whereas the recovery of total 14C was 18.6 +/- 4.9%. The biliary clearances of tolfenamic acid and total 14C were 1.2 +/- 0.3 and 5.0 +/- 2.1 ml/min, respectively. Thus, biliary excretion plays a considerable part in the pharmacokinetics of tolfenamic acid.

Elevated serum uric acid is commonly seen in association with obesity, glucose intolerance, hypertension and dyslipidemia. There is currently no satisfactory explanation for the relation of uric acid and the metabolic syndrome (MetSyn). This study aimed to evaluate the relations of change in serum uric acid with changes in components of the MetSyn in young adults. We studied 1,249 male and 1,362 female black and white subjects aged 17-35 years (baseline) from the Coronary Artery Risk Development in Young Adults (CARDIA) Study, which attended a 10-year follow-up. Metabolic factors assessed at both time periods included BMI, waist circumference, blood pressure, fasting glucose, insulin, and lipids. Confounders examined (baseline and change variables) were serum creatinine, alcohol, smoking, physical activity, and oral contraceptives. Mean uric acid increased the most in black males (+0.5 mg/dl), followed by white males (+0.3 mg/dl) and black females (+0.2 mg/dl) (all P < 0.01), with the least change among white females (+0.1 mg/dl) (ns). Although change in all of the metabolic factors was associated with change in uric acid in the anticipated directions, in multivariable analyses only BMI and triglycerides had a significant independent association with uric acid in all race-sex-groups. Among confounders, only change in serum creatinine showed a strong independent association with uric acid. In conclusion, besides weight gain and renal excretion, increasing uric acid concentrations in young adults are strongly related to corresponding changes in triglycerides. The correlation of uric acid and triglycerides was found within the normal range and could not be explained by obesity.

1. The objective of this research was to compare the pharmacokinetics and bioavailability of tolfenamic acid, analgesic, antipyretic and anti-inflammatory compound, after administration through different routes to Pekin ducks. The investigation was carried out over four time periods using a randomised cross-pharmacokinetic design. 2. Tolfenamic acid was administered to ducks intravenously, intramuscularly, subcutaneously and orally at a dose of 2 mg/kg. Tolfenamic acid analysis was performed using HPLC-UV and pharmacokinetic data were conducted by non-compartmental analysis. 3. The total clearance, volume of distribution at steady state and terminal elimination half‐life after intravenous administration were 0.14 l/h/kg, 0.29 l/kg and 1.80 h, respectively. The peak plasma concentration and bioavailability for intramuscular, subcutaneous and oral administration were 4.59, 3.55 and 2.23 μg/ml and 93.62, 74.30 and 43.43%, respectively. 4. Tolfenamic acid was absorbed rapidly, eliminated quickly and exhibited a small distribution volume in Pekin ducks. Pharmacokinetic parameters, including maximum concentration, area under the plasma concentration – time curve and bioavailability, were found to be different in ducks from other bird species.

The pharmacokinetics of tolfenamic acid is well described by a two-compartment model with relatively short half-lives (T/2 beta 1-2 hours) and tolfenamic acid is highly protein-bound with small volumes of distribution. It is cleared relatively fast (150-200 ml/min), mainly by hepatic metabolism and the metabolites are renally cleared as glucuronic acid conjugates. The peroral absorption is good and the peroral bioavailability is about 75%, as first pass metabolism accounts for about 20%. Tolfenamic acid shows linear pharmacokinetics and during multiple dosage regimen, i.e. thrice daily, no accumulation beyond the second dose is observed. The bioavailability in dependence of age and disease has been studied and only in the case of severe liver or kidney impairment, a change in dosage regimen seems warranted. The development of different formulations will be outlined, mainly on rectal delivery, on sustained release and rapid release oral formulations, on topical ointment, and on parenteral delivery. The problems with tolfenamic acid in pharmaceutical formulation caused mainly by poor solubility will be discussed. Formulations ready for the market now or very soon are Clotam capsules (tablets). Clotam retard tablets, Clotam suppositories, and Clotam oral suspension, whereas rapid tablets, topical ointments, and parenteral formulations need further development to be ready for marketing in the years to come.

The pharmacokinetics of tolfenamic acid were studied in five ponies after an intravenous (iv) administration (2 mg/kg bodyweight [bwt]) and in four horses after an oral administration (30 mg/kg bwt) of tolfenamic acid. The plasma levels were determined by high pressure liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). For the iv administration, a three-compartment model was used to represent the plasma concentration-time curve of the drug. The elimination half-life of the compound was 6.1 +/- 1.5 h, the total body clearance was 72.4 +/- 16.7 ml/kg bwt/h and the steady-state volume of distribution 0.32 +/- 0.11 litres/kg bwt. For the oral administration, absorbtion was delayed with a mean lag-time to absorption of 32 +/- 28 mins. The peak plasma concentration 11.1 +/- 0.69 micrograms/ml was observed after a highly variable delay ranging from 1.9 to 6.5 h post administration. The terminal half-life (4.2 +/- 0.48 h) was very similar to that obtained after iv administration. Tolfenamic acid could not be detected in equine plasma with the described analytical methods more than 48 h after drug administration.

The pharmacokinetics of tolfenamic acid, a non-steroidal anti-inflammatory drug, were determined following administration of a 1 mg/kg single oral dose of tolfenamic acid suspension to 6 feverish children. Their ages were from 2-14 years (mean 7.5 years) and their weights were from 12-50 kg (mean 29.2 kg). Tolfenamic acid produced a significant fall in temperature (about 2 degrees C) compared to the initial value before oral intake of the drug and was well tolerated without adverse effects. Blood samples for determination of tolfenamic acid concentrations in plasma were obtained at timed intervals for up to 8 h post-dose. Plasma concentrations of tolfenamic acid were determined using a reversed phase HPLC method and pertinent pharmacokinetic parameters were estimated by model-independent standard methods and were the following: the mean peak plasma concentration (Cmax +/- SEM) was 1.09 +/- 0.44 micrograms/ml (range, 0.65-1.63 micrograms/ml) and the mean time (tmax +/- SEM) to reach peak plasma concentration was 1.4 +/- 0.4 h (range, 0.5-3.0 h). The mean area under the plasma concentration-time curve (AUC0-->infinity +/- SEM) was 4.61 +/- 0.40 micrograms.h/ml (range, 2.74-5.98 micrograms.h/ml), the mean elimination half-life (t1/2 +/- SEM) was 2.82 +/- 0.21 h (range, 2.19-3.40 h) and the mean apparent total clearance (CL/F +/- SEM) was 3.83 +/- 0.41 ml/min/kg (range, 2.79-6.08 ml/min/kg).

The lower levels of serum uric acid (UA) correlated with meningitis have been reported. However, comparison of UA levels among different kinds of infections of central nervous system (CNS) and changes of UA levels before and after treatment are unknown. Our study aimed to investigate the antioxidant status of serum UA in five common types of CNS infections. We retrospectively evaluated serum UA levels of 399 patients with different types of CNS infections including viral meningitis or meningoencephalitis (VM), brain cysticercosis (BC), tuberculous meningitis or meningoencephalitis (TM), cryptococcus meningitis or meningoencephalitis (CM) and bacterial meningitis or meningoencephalitis (BM), and 119 healthy controls. The changes of serum UA were examined and analyzed. The serum levels of UA in patients with CNS infections were significantly lower than those in normal subjects and among in TM, CM and BM groups were apparently lower when compared with VM and BC groups; otherwise, after effective therapy, serum UA levels were obviously higher than before. Our findings showed that patients with CNS infections had lower serum UA levels, which was independent of the classification and the serum UA levels increased obviously after valid treatment, the variation of UA levels might be considered as an indicator of clinical curative effect in patients with CNS infections.

Background: Fenofibrate increases renal clearance of uric acid (UA). Relationships between baseline and short-term changes in plasma UA with fenofibrate and subsequent cardiovascular risk in patients with type 2 diabetes (T2D) are unknown. Method: Post hoc analyses of the FIELD trial explored the relationships between CVD events and 1) baseline UA level; and 2) short-term change in UA level over 6-week single-blind active fenofibrate run-in. Results: The FIELD trial showed 11% fewer cardiovascular events in patients with T2D assigned to fenofibrate compared to placebo over 5 years (HR = 0.89, 95% CI: 0.80-0.99, p = 0.035). Baseline UA (n=9622) ranged between 0.11 to 0.79 mmol/L (mean = 0.33, SD = 0.078). Each 0.1 mmol/L higher baseline UA increased CVD events by 21% (HR = 1.21 95% CI: 1.13-1.29, p &amp;lt; 0.001; Fig. 1A), and remained after adjusting for other classic risk factors (HR = 1.12, 95% CI: 1.04-1.21, p = 0.002). Fall in UA level with fenofibrate run-in also predicted lower CVD risk, adjusted for baseline UA and irrespective of trial treatment allocation (HR = 0.86, 95% CI: 0.76-0.97, p = 0.015; Fig. 1B). Discussion: Baseline and short-term fenofibrate-induced lowering of UA predict cardiovascular risk in patients with T2D, irrespective of long-term trial treatment allocation. The reduction in total CVD events with fenofibrate was not shown to be mediated through lowering of UA levels. Disclosure J.Y. Cao: None. B. Waldman: None. R.L. OConnell: None. D. Sullivan: None. V. Gebski: None. A.S. Januszewski: None. I. Marschner: None. R. Scott: None. M. Taskinen: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Akcea Therapeutics, Chiesi USA, Inc. Research Support; Self; Amgen Inc., Novo Nordisk A/S. Speaker’s Bureau; Self; Amgen Inc. R. Simes: None. N. McGill: None. A.J. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. A.C. Keech: None.

To determine if topical ophthalmic diclofenac sodium 0.1% solution alters renal parameters in the domestic chicken, and to determine if the drug is detectable in plasma after topical ophthalmic administration. Thirty healthy domestic chickens. Over 7days, six birds were treated unilaterally with one drop of artificial tear solution (group 1), 12 birds were treated unilaterally (group 2) and 12 bilaterally (group 3) with diclofenac sodium 0.1% ophthalmic solution. Treatments were provided every 12h in all groups. Pre- and post-treatment plasma samples from all birds were evaluated for changes in albumin, total protein, and uric acid. Post-treatment samples of all birds, collected 15min post-administration, were analyzed by high-performance liquid chromatography with mass spectrometry for diclofenac sodium detection. A randomly selected renal sample from each group was submitted for histopathologic review. Changes in pre- and post-treatment plasma albumin were significant (P<0.05) in groups 2 and 3, but not for group 1. Pre- and post-treatment changes in total protein and uric acid were not significant for any group. Diclofenac sodium was not detectable (limit of detection=0.10ng/mL) in plasma samples from birds in group 1. Post-treatment concentration of diclofenac in group 3 was statistically greater than group 2 (P=0.0008). Histopathologic changes did not identify diclofenac-induced acute renal tubular necrosis. Ophthalmic diclofenac sodium 0.1% administered topically every 12h in one or both eyes for 7days is detectable in systemic circulation in the domestic chicken, but does not cause overt significant changes in plasma uric acid or total protein.

To the Editor: Recently, an update from the Framingham study could not find uric acid to be an independent risk factor for cardiovascular disease.1 While serum uric acid levels correlated significantly with the risk for cardiovascular events and mortality in women, this relationship became insignificant after factoring for 11 additional variables including hypertension, body mass index, and diuretic use.1 Both the authors1 and an accompanying editorial2 interpreted these findings as showing that uric acid is not a true risk factor for cardiovascular disease and that it should not be routinely measured to assess cardiovascular risk. The careful analysis of the Framingham study is to be commended, but one must be cautious in the interpretation of the findings. While some epidemiologic studies such as the current one have not been able to show uric acid to be an independent risk factor for cardiovascular disease, other studies using multivariate analyses3 4 5 6 came to an opposite conclusion. Another recently completed study, the Worksite,7 also found uric acid to be an independent risk factor for cardiovascular events and mortality, especially in women. One might look for subtle explanations to account for the differences in these various studies, as Culleton et al1 have attempted, but most of the studies examined the very same variables. A more central issue is whether one should interpret the finding that a risk factor is not statistically independent to mean that it should not be considered biologically important. We would argue that this is not true in several situations. First, if the risk factors are causally linked, then one may not be able to show that they are independent of each other. For example, although smoking is a risk factor for mortality, it might no longer be independent if it is …

Pharmacodynamics and pharmacokinetics of tolfenamicacid in ruminating calves: Evaluation in models of acute inflammation

The pharmacokinetics and bioavailability of tolfenamic acid were determined in geese (Anser cygnoides) following intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral administrations at 2mg/kg dose. In this study, eight healthy geese (3.5±0.5kg) were used. The study was performed in four periods according to a crossover design with a 15-day washout period between two administrations. The plasma concentrations of tolfenamic acid were analyzed using HPLC-UV, and pharmacokinetic parameters were calculated by noncompartmental analysis. The elimination half-life was 1.73, 2.51, 2.34, and 2.31hr for IV, IM, SC, and oral routes, respectively. The volume of distribution at steady state and total clearance after IV administration were 0.25 L/kg and 0.16 Lhr-1 kg-1 , respectively. The peak plasma concentrations of tolfenamic acid after IM, SC, and oral administrations were 4.89, 2.94, and 2.92μg/ml at 0.25, 0.75, and 1hr, respectively. The bioavailability was 87.91, 77.87, and 76.03% for the IM, SC, and oral routes, respectively. Tolfenamic acid, which exhibits the good bioavailability and plasma concentration following IM, SC, and oral administrations at 2mg/kg dose, may be useful in the treatment of inflammatory disease conditions in geese.

To the best of our knowledge, limited pharmacokinetic information to establish suitable therapeutic plans is available for Hawksbill turtles. Therefore, the present study aimed to assess the pharmacokinetic features of tolfenamic acid (TA) in Hawksbill turtles, Eretmochelys imbricata, after single intravenous (i.v.) and intramuscular (i.m.) administration at dosage 4mg/kg body weight (b.w.). The study (parallel design) used 10 Hawksbill turtles randomly divided into equal groups. Blood samples were collected at assigned times up to 144hr. The concentrations of TA in plasma were quantified by a validated liquid chromatography tandem mass spectrometry (LC-ESI-MS/MS). The concentration of TA in the experimental turtles with respect to time was pharmacokinetically analyzed using a noncompartment model. The Cmax values of TA were 89.33±6.99µg/ml following i.m. administration. The elimination half-life values were 38.92±6.31hr and 41.09±9.32hr after i.v. and i.m. administration, respectively. The absolute i.m. bioavailability was 94.46%, and the average binding percentage of TA to plasma protein was 31.39%. TA demonstrated a long half-life and high bioavailability following i.m. administration. Therefore, the i.m. administration is recommended for use in clinical practice because it is both easier to perform and provides similar plasma concentrations to the i.v. administration. However, further studies are needed to determine the clinical efficacy of TA for treatment of inflammatory disease after single and multiple dosages.

Context and ObjectiveObesity and SLC2A9 genotype are strong determinants of uric acid levels. However, data on SLC2A9 variants and weight loss induced changes in uric acid levels are missing. We examined whether the changes in uric acid levels two- and ten-years after weight loss induced by bariatric surgery were associated with SLC2A9 single nucleotide polymorphisms (SNPs) in the Swedish Obese Subjects study.MethodsSNPs (N = 14) identified by genome-wide association studies and exonic SNPs in the SLC2A9 gene locus were genotyped. Cross-sectional associations were tested before (N = 1806), two (N = 1664) and ten years (N = 1201) after bariatric surgery. Changes in uric acid were compared between baseline and Year 2 (N = 1660) and years 2 and 10 (N = 1172). A multiple testing corrected threshold of P = 0.007 was used for statistical significance.ResultsOverall, 11 of the 14 tested SLC2A9 SNPs were significantly associated with cross-sectional uric acid levels at all three time points, with rs13113918 showing the strongest association at each time point (R2 = 3.7−5.2%, 3.9×10−22≤p≤7.7×10−11). One SNP (rs737267) showed a significant association (R2 = 0.60%, P = 0.002) with change in uric acid levels from baseline to Year 2, as common allele homozygotes (C/C, N = 957) showed a larger decrease in uric acid (−61.4 µmol/L) compared to minor allele carriers (A/X: −51.7 µmol/L, N = 702). No SNPs were associated with changes in uric acid from years 2 to 10.ConclusionsSNPs in the SLC2A9 locus contribute significantly to uric acid levels in obese individuals, and the associations persist even after considerable weight loss due to bariatric surgery. However, we found little evidence for an interaction between genotype and weight change on the response of uric acid to bariatric surgery over ten years. Thus, the fluctuations in uric acid levels among the surgery group appear to be driven by the weight losses and gains, independent of SLC2A9 genotypes.