An epigenome-wide association study meta-analysis of educational attainment.

The epigenome is associated with biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here we provide evidence on the associations between epigenetic modifications-in our case, CpG methylation-and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10 767 individuals. We find nine CpG probes significantly associated with EA. However, robustness analyses show that all nine probes have previously been found to be associated with smoking. Only two associations remain when we perform a sensitivity analysis in the subset of never-smokers, and these two probes are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, the effect sizes of the associations with EA are far smaller than the known associations with the biologically proximal environmental factors alcohol consumption, body mass index, smoking and maternal smoking during pregnancy. Follow-up analyses that combine the effects of many probes also point to small methylation associations with EA that are highly correlated with the combined effects of smoking. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.

Synovial fluid bupivacaine concentrations following single intra-articular injection in normal and osteoarthritic canine stifles.

Intra-articular bupivacaine helps alleviate pain in animals receiving joint surgery, but its use has become controversial as ex vivo studies have illuminated the potential for chondrotoxicity. Such studies typically involve cell cultures incubated in solutions containing high bupivacaine concentrations for long durations. The aim of this study was to measure the actual synovial fluid bupivacaine concentrations after intra-articular injection. Eight healthy beagles with normal stifles and 22 large and giant-breed dogs with stifle osteoarthritis (OA) were treated with a single intra-articular injection of bupivacaine (1 mg/kg) into a stifle. Joint fluid samples were taken from the treated stifle immediately after injection and 30 min after injection and analyzed for bupivacaine concentrations. Immediately after injection, the median bupivacaine concentrations in normal and OA stifles were 3.6 and 2.5 mg/mL, respectively. Thirty minutes after injection, bupivacaine concentrations in normal and OA stifles were 0.4 and 0.6 mg/mL, respectively. These results provide insight into the pharmacokinetics of bupivacaine after injection into a joint. Given its immediate dilution and rapid drop in synovial fluid concentration, bupivacaine is unlikely to damage chondrocytes when administered as a single intra-articular injection.

DHEA and response to antidepressant treatment: A Mendelian Randomization analysis.

Treatment response is hard to predict and detailed mechanisms unknown. Lower levels of the dehydroepiandrosterone sulphate (DHEA(S)) - a precursor to testosterone and estrogen - have been associated to depression and to response to antidepressant treatment. Previous studies however may have been ridden by confounding and reverse causation. The aim of this study is to evaluate whether higher levels of DHEA(S) are causally linked to response to antidepressants using mendelian randomization (MR). We performed a Two-sample MR analysis using data the largest publicly available GWAS of DHEA(S) levels (n = 14,846) using eight common genetic variants associated to DHEA(S) (seven single nucleotide polymorphisms and one variant rs2497306) and the largest GWAS of antidepressant response (n = 5218) using various MR methods (IVW, MR Egger, Weighted mean, weighted mode, MR-PRESSO) and single SNP analysis. We further investigated for pleiotropy conducting a look up on PhenoScanner and GWAS Catalog. Results show no evidence for DHEA(S) gene risk score from any of MR methods, however, we found a significant association on individual variant analysis for rs11761538, rs17277546, and rs2497306. There was some evidence for heterogeneity and pleiotropy. This is the first paper to show some evidence for a causal association of genetically-predicted DHEA and improvement of depressive symptoms. The effect is not a simple linear effect, and we were unable to dissect whether the effect was direct effect of DHEA(S), mediated by DHEA(S) or on the pathway is not yet clear. Further studies using more refined instrumental variables will help clarify this association.

Pharmacokinetics of oral rufinamide in dogs.

The objective of this study was to determine the pharmacokinetic properties and short-term adverse effect profile of single-dose oral rufinamide in healthy dogs. Six healthy adult dogs were included in the study. The pharmacokinetics of rufinamide were calculated following administration of a single mean oral dose of 20.0 mg/kg (range 18.6-20.8 mg/kg). Plasma rufinamide concentrations were determined using high-performance liquid chromatography, and pharmacokinetic data were analyzed using commercial software. No adverse effects were observed. The mean terminal half-life was 9.86 ± 4.77 h. The mean maximum plasma concentration was 19.6 ± 5.8 µg/mL, and the mean time to maximum plasma concentration was 9.33 ± 4.68 h. Mean clearance was 1.45 ± 0.70 L/h. The area under the curve (to infinity) was 411 ± 176 µg · h/mL. Results of this study suggest that rufinamide given orally at 20 mg/kg every 12 h in healthy dogs should result in a plasma concentration and half-life sufficient to achieve the therapeutic level extrapolated from humans without short-term adverse effects. Further investigation into the efficacy and long-term safety of rufinamide in the treatment of canine epilepsy is warranted.

Systemic delivery of E6/7 siRNA using novel lipidic particles and its application with cisplatin in cervical cancer mouse models.

Small interfering RNA (siRNA) shows great promise in cancer therapy, but its effectiveness in vivo still remains a crucial issue for its transition into the clinics. Although the successful use of polyethylene glycol (PEG)ylated lipidic delivery systems have already been reported, most of the formulation procedures used are labour intensive and also result in unstable end products. We have previously developed a simple yet efficient hydration-of-freeze-dried-matrix (HFDM) method to entrap siRNA within lipid particles, in which the products exhibited superior stability. Here, we show that these HFDM-formulated particles are stable in the presence of serum and can deliver siRNA efficiently to tumours after intravenous administration. Using these particles, around 50% knockdown of the target gene expression was observed in tumours. With the use of siRNA targeting the E6/7 oncogenes expressed in cervical cancer, we showed a 50% reduction in tumour size. This level of tumour growth suppression was comparable to that achieved from cisplatin at the clinically used dose. Overall, our results demonstrate the feasibility of using HFDM-formulated particles to systematically administer E6/7-targeted siRNA for cervical cancer treatment. The simplicity of preparation procedure along with superior product stability obtained from our method offers an innovative approach for the in vivo delivery of siRNA.

Enhancing absorption of fluorescein and LHRH across hindgut epithelia in a marsupial, the common brushtail possum Trichosurus vulpecula.

We have identified differences in transport properties of intestinal epithelia in the marsupial brushtail possum, compared to eutherian mammals. To determine whether differences in its permeability to hydrophilic compounds also occur, the absorption of sodium fluorescein and luteinizing hormone releasing hormone (LHRH) was assessed in vitro and the ability of chemical enhancers and a metabolic inhibitor to promote their absorption investigated. The apparent permeability of colonic and caecal tissues to fluorescein and LHRH and transepithelial resistance (Rt) in the absence or presence of ethylenediamine tetra-acetic acid (EDTA), sodium deoxycholic acid (SDA), dithiothreitol (DTT), polyacrylic acids (PAA), or the inhibitor bacitracin were determined. The effects of SDA and/or DTT on adherent mucus and the release of lactate dehydrogenase (LDH) were also assessed. In the absence of treatment, both tissues had comparable amounts of adherent mucus, Rt and low permeabilities to fluorescein and LHRH. All chemical enhancers increased fluorescein permeability, but SDA at concentrations >0.5 mM also induced LDH release. DTT alone and in combination with SDA reduced the amount of adherent mucus. Bacitracin inhibited LHRH metabolism and increased LHRH permeability. These data indicate that the possum hindgut epithelium represents a significant barrier to the uptake of hydrophilic compounds, similar to that in eutherians.

W/O microemulsions for ocular delivery: evaluation of ocular irritation and precorneal retention.

Water-in-oil microemulsions (w/o ME) capable of undergoing a phase-transition to lamellar liquid crystals (LC) or bicontinuous ME upon aqueous dilution were formulated using Crodamol EO, Crill 1 and Crillet 4, an alkanol or alkanediol as cosurfactant and water. The hypothesis that phase-transition of ME to LC may be induced by tears and serve to prolong precorneal retention was tested. The ocular irritation potential of components and formulations was assessed using a modified hen's egg chorioallantoic membrane test (HET-CAM) and the preocular retention of selected formulations was investigated in rabbit eye using gamma scintigraphy. Results showed that Crill 1, Crillet 4 and Crodamol EO were non-irritant. However, all other cosurfactants investigated were irritant and their irritation was dependent on their carbon chain length. A w/o ME formulated without cosurfactant showed a protective effect when a strong irritant (0.1 M NaOH) was used as the aqueous phase. Precorneal clearance studies revealed that the retention of colloidal and coarse dispersed systems was significantly greater than an aqueous solution with no significant difference between ME systems (containing 5% and 10% water) as well as o/w emulsion containing 85% water. Conversely, a LC system formulated without cosurfactant displayed a significantly greater retention compared to other formulations.

Preparation of immuno-stimulating complexes (ISCOMs) by ether injection.

This study investigated the application of the solvent dispersion technique, specifically ether injection, which has been successfully used in the preparation of liposomes, as a new, continuous and potentially scaleable method for the preparation of ISCOMs. Phosphatidylcholine (PC) and cholesterol (Chol) were dissolved in ether, which was injected into an aqueous solution, maintained at 55 degrees C, containing Quil A. The influences of the following variables on ISCOM formation were investigated: ratio of PC:Quil A:Chol used, pumping rate, total lipid mass and concentration of buffer salts and Quil A in the aqueous phase. All samples were characterized by negative stain transmission electron microscopy, photon correlation spectroscopy and sucrose ultracentrifugation gradient. It was demonstrated that ISCOMs could be produced by this method but the homogeneity of the preparation was influenced by the conditions used. Homogeneous ISCOM preparations were consistently produced only when the weight ratio of PC:Quil A:Chol was 5:3:2 with a total lipid mass of 20 mg, the Quil A dissolved in a 0.01 M phosphate buffer at a concentration of 6 mg in 4 ml, and the ether solution injected into the warmed buffer solution at a rate of 0.2 ml/min. Changing any of these variables resulted in more heterogeneous preparations in which ISCOMs typically co-existed with other colloidal structures such as worm-like and helical micelles, liposomes, lamellae and lipidic particles.

Using different structure types of microemulsions for the preparation of poly(alkylcyanoacrylate) nanoparticles by interfacial polymerization.

A phase diagram of the pseudoternary system ethyloleate, polyoxyethylene 20 sorbitan mono-oleate/sorbitan monolaurate and water with butanol as a cosurfactant was prepared. Areas containing optically isotropic, low viscosity one-phase systems were identified and systems therein designated as w/o droplet-, bicontinuous- or solution-type microemulsions using conductivity, viscosity, cryo-field emission scanning electron microscopy and self-diffusion NMR. Nanoparticles were prepared by interfacial polymerization of selected w/o droplet, bicontinuous- or solution-type microemulsions with ethyl-2-cyanoacrylate. Morphology of the particles and entrapment of the water-soluble model protein ovalbumin were investigated. Addition of monomer to the different types of microemulsions (w/o droplet, bicontinuous, solution) led to the formation of nanoparticles, which were similar in size ( approximately 250 nm), polydispersity index ( approximately 0.13), zeta-potential ( approximately -17 mV) and morphology. The entrapment of the protein within these particles was up to 95%, depending on the amount of monomer used for polymerization and the type of microemulsion used as a polymerization template. The formation of particles with similar characteristics from templates having different microstructure is surprising, particularly considering that polymerization is expected to occur at the water-oil interface by base-catalysed polymerization. Dynamics within the template (stirring, viscosity) or indeed interfacial phenomena relating to the solid-liquid interface appear to be more important for the determination of nanoparticle morphology and characteristics than the microstructure of the template system.

Gastrointestinal transit in the common brushtail possum measured by gamma scintigraphy.

This paper reports an example of the application of pharmaceutical technology to wildlife management, specifically the design of an oral delivery system for the common brushtail possum in New Zealand. Designing an oral delivery system requires a knowledge of the time taken for particulates to reach target sites within the gastrointestinal tract (GIT). The transit time for fluid and indigestible particles of two different size ranges was determined in the common brushtail possum (Trichosurus vulpecula). Technetium-labelled (99mTc) anion exchange resin particles (75-125 or 500-700 microm diameter) or solution (99mTc-labelled diethylenetriamine pentaacetic acid, 99mTc-DTPA) was administered orally. At predetermined times after dosing (3, 6, 12, 24 or 32 h), the distribution of radioactivity throughout excised gastrointestinal tracts was determined by gamma scintigraphy. The transit profile was similar for the three formulations investigated. Unlike other closely related hindgut fermenting marsupials, there was no evidence to support the presence of a colonic separating mechanism in the common brushtail possum. Gastrointestinal transit was independent of body mass, gender and time of day that the dose is given. To target the hindgut for oral delivery of protein and peptide biocontrol agents, the formulation would need to protect the bioactive for approximately 12 h prior to release.

Stereospecific quantitation of 6-prenylnaringenin in commercially available H. lupulus-containing natural health products and dietary supplements.

6-Prenylnaringenin (6PN) is a chiral prenylflavonoid found most prevalently in hops (Humulus lupulus) and present in hops and hop products. It is an isomer of the potent phytoestrogen, 8-prenylnaringenin. An enantiospecific method for quantitation 6PN by LC-ESI-MS has been developed. Baseline enantiomeric resolution of 6PN was attained on a Chiralpak(®) AD-RH column with an isocratic mobile phase consisting of acetonitrile and 10 mM ammonium formate (pH 8.5) (39:61, v/v) and a flow rate of 1.25 mL/min. Quantitative MS data were obtained by selected ion monitoring of the [M-H](-)-ion of both enantiomers of 6PN (m/z 339.10) and the internal standard, 4-acetamidobenzoic acid (m/z 178.05). The method was found to be accurate and precise for enantiospecific quantification of 6PN. The method was successfully applied to the content analysis of 39 commercially available natural health products and dietary supplements reported to contain H. lupulus plant material, extracts and label claims of 6PN. 6PN was present in 25 of 34 products containing plant material or extracts of H. lupulus. Of the five products with claimed amounts of 6PN, all were found to possess <50% of label claims. Results of the content analysis indicated a lack of uniformity in botanical nutraceuticals claiming 6PN content.

Clinical pharmacokinetics of flurbiprofen and its enantiomers.

Flurbiprofen is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid class. Although it possesses a chiral centre, with the S-(+)-enantiomer possessing most of the beneficial anti-inflammatory activity, both enantiomers may possess analgesic activity and all flurbiprofen preparations to date are marketed as the racemate. Flurbiprofen exhibits stereoselectivity in its pharmacokinetics. Stereoselectivity is exhibited at the level of protein binding and metabolite formation. Hence, the data generated using nonstereoselective assays may not be used to explain the pharmacokinetics of individual enantiomers. The absorption of flurbiprofen is rapid and almost complete when given orally. The area under the plasma concentration-time curve of flurbiprofen is proportional to the dose administered to patients. Sustained release dosage forms are available, which may be beneficial due to the short terminal phase elimination half-life of conventional immediate release flurbiprofen (3 to 6 hours). They may also decrease local gastrointestinal adverse effects. Although with these preparations the peak plasma drug concentration is reduced and time taken to achieve peak concentrations is prolonged, the bioavailability is the same as that with regular release counterparts. Flurbiprofen binds extensively to plasma albumin, apparently in a stereoselective manner. Substantial concentrations of the drug are attained in synovial fluid, which is the proposed site of action of NSAIDs. There is negligible R to S inversion after oral administration. Flurbiprofen is eliminated following extensive biotransformation to glucuro-conjugated metabolites. Conjugates are excreted in urine, and approximately 20% of flurbiprofen is eliminated unchanged. The excretion of conjugates may be tied to renal function as accumulation of conjugates occurs in end-stage renal disease, but not in young individuals or elderly patients. Although flurbiprofen is excreted into breast milk, the amount of drug transferred comprises only a small fraction of the maternal exposure. Significant drug interactions have been demonstrated for aspirin (acetylsalicylic acid), coumarins and propranolol. The relationship between concentration and anti-inflammatory and analgesic effect has yet to be elucidated for this drug.

Clinical pharmacokinetics of ibuprofen. The first 30 years.

Ibuprofen is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2 arylpropionic acid (2-APA) class. A common structural feature of 2-APANSAIDs is a sp3-hybridised tetrahedral chiral carbon atom within the propionic acid side chain moiety with the S-(+)-enantiomer possessing most of the beneficial anti-inflammatory activity. Ibuprofen demonstrates marked stereoselectivity in its pharmacokinetics. Substantial unidirectional inversion of the R-(-) to the S-(+) enantiomer occurs and thus, data generated using nonstereospecific assays may not be extrapolated to explain the disposition of the individual enantiomers. The absorption of ibuprofen is rapid and complete when given orally. The area under the plasma concentration-time curve (AUC) of ibuprofen is dose-dependent. Ibuprofen binds extensively, in a concentration-dependent manner, to plasma albumin. At doses greater than 600mg there is an increase in the unbound fraction of the drug, leading to an increased clearance of ibuprofen and a reduced AUC of the total drug. Substantial concentrations of ibuprofen are attained in synovial fluid, which is a proposed site of action for nonsteroidal anti-inflammatory drugs. Ibuprofen is eliminated following biotransformation to glucuronide conjugate metabolites that are excreted in urine, with little of the drug being eliminated unchanged. The excretion of conjugates may be tied to renal function and the accumulation of conjugates occurs in end-stage renal disease. Hepatic disease and cystic fibrosis can alter the disposition kinetics of ibuprofen. Ibuprofen is not excreted in substantial concentrations into breast milk. Significant drug interactions have been demonstrated for aspirin (acetylsalicylic acid), cholestyramine and methotrexate. A relationship between ibuprofen plasma concentrations and analgesic and antipyretic effects has been elucidated.

Clinical pharmacokinetics of oxaprozin.

Oxaprozin is a nonsteroidal anti-inflammatory drug which reaches peak plasma concentrations 2 to 6 hours after oral administration. Oxaprozin binds extensively, in a concentration-dependent manner, to plasma albumin. The area under the plasma concentration-time curve (AUC) of oxaprozin is linearly proportional to the dose for oral doses up to 1200 mg. At doses greater than 1200 mg there is an increase in the unbound fraction of drug, leading to an increased clearance and volume of distribution (Vd) of total oxaprozin. Accumulation of the drug at steady state is between 40 and 58% lower than predicted by single dose data. After administration of multiple doses, the apparent oral clearance (CL/F) and Vd of total oxaprozin increased while those of the unbound drug decreased significantly. Substantial concentrations of oxaprozin are attained in synovial fluid, which is a proposed site of action for nonsteroidal anti-inflammatory drugs. Relationships between total plasma, unbound plasma and synovial concentrations, and therapeutic and toxicological effects have yet to be established. Oxaprozin is eliminated following biotransformation to glucuroconjugated metabolites which are excreted in urine and bile, with little drug being eliminated unchanged. Two hydroxylated metabolites have been shown to possess anti-inflammatory activity. Hepatic disease and rheumatoid arthritis do not significantly alter the disposition of oxaprozin. Patients with renal impairment demonstrate an increase in unbound plasma concentrations of oxaprozin. A significant drug interaction has been demonstrated between oxaprozin and aspirin (acetylsalicylic acid).

Clinical pharmacokinetics of tiaprofenic acid and its enantiomers.

Tiaprofenic acid is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid (2-APA) class. A common structural feature of 2-APA NSAIDs is a sp3-hybridised tetrahedral chiral carbon heteroatom within the propionic acid side chain moiety, with the S-enantiomer possessing most of the beneficial anti-inflammatory activity. However, all tiaprofenic acid preparations to date are marketed as the racemate. Tiaprofenic acid has been suggested to exhibit limited pharmacokinetic stereoselectivity. The synovium is the proposed site of action of NSAIDs when used for musculoskeletal disorders, and substantial concentrations of tiaprofenic acid are attained in synovial fluid. Recent data suggested that possibility of stereoselective distribution of tiaprofenic acid into synovium and cartilage. Hence, data generated using non-stereospecific assays may not always be extrapolated to explain the disposition of the individual enantiomers. Tiaprofenic acid is rapidly and almost completely absorbed when given orally. The area under the plasma concentration-time curve (AUC) of tiaprofenic acid is proportional to the oral dose administered. A sustained release dosage form is available, which may be beneficial due to the short terminal phase half-life of tiaprofenic acid (3 to 6 hours). The bioavailability is the same as that with conventional rapid release preparations, although the peak plasma drug concentration is reduced and time peak is prolonged. Tiaprofenic acid binds extensively to plasma albumin. These is negligible R to S inversion upon oral administration. Tiaprofenic acid is eliminated following extensive biotransformation to glucuronide-conjugated metabolites. Approximately 60% is eliminated as conjugates excreted in urine, and little drug is eliminated unchanged. The rate of excretion of tiaprofenic acid and its conjugates may be related to renal function; accumulation of conjugates occurs in end-stage renal disease, but not in young individuals or elderly patients. Potentially clinically important drug interactions with tiaprofenic acid have been demonstrated for some anticoagulants and probenecid. Relationships between tiaprofenic acid concentrations in biological matrices and therapeutic or toxic effects have not yet been elucidated for this drug.

Clinical pharmacokinetics of nabumetone. The dawn of selective cyclo-oxygenase-2 inhibition?

Nabumetone is a nonsteroidal anti-inflammatory drug (NSAID) of the 2,6-disubstituted naphthyl-alkanone class. Nabumetone is metabolised to an active metabolite 6-methoxy-2-napthylacetic acid (6-MNA) which is a relatively selective cyclo-oxygenase-2 inhibitor that has anti-inflammatory and analgesic properties. Nabumetone and its metabolites bind extensively to plasma albumin. Nabumetone is eliminated following biotransformation to 6-MNA, which does not undergo enterohepatic circulation and the respective glucoroconjugated metabolites are excreted in urine. Substantial concentrations of 6-MNA are attained in synovial fluid, which is he proposed site of action in chronic inflammatory arthropathies. A smaller area under the plasma concentration-time curve (AUC) is evident at steady state as compared with a single dose; this is possibly due to an increase in the volume of distribution and saturation of protein binding. Relationships between 6-MNA concentrations and the therapeutic and toxicological effects have yet to be elucidated for this NSAID. Renal failure significantly reduces 6-MNA elimination but steady-state concentrations of 6-MNA are not increased, possibly because of nonlinear protein binding. Elderly patients with osteoarthritis demonstrate decreased elimination and increased plasma concentrations of nabumetone as compared with young healthy volunteers. Rheumatic disease activity also influences 6-MNA plasma concentrations, as patients with more active disease and lower serum albumin concentrations demonstrate a lower area under the plasma concentration versus time curve. A reduced bioavailability of 6-MNA in patients with severe hepatic impairment is also evident. Dosage adjustment may be required in the elderly, patients with active rheumatic disease and those with hepatic impairment, but not in patients with mild-to-moderate renal failure.

Clinical pharmacokinetics of sulindac. A dynamic old drug.

Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) of the indene acetic acid class. The absorption of sulindac is rapid when given orally. Sulindac is reversibly metabolised to sulindac sulphide which has anti-inflammatory and analgesic properties and is irreversibly metabolised to sulindac sulphone which has been suggested to possess antiproliferative effects against tumours. Sulindac and its sulphide and sulphone metabolites bind extensively to plasma albumin. Sulindac is eliminated following bio-transformation; sulindac and sulindac sulphone and their respective glucurooconjugated metabolites are excreted in urine; however only a small amount of the sulindac sulphide metabolite is eliminated in urine. Following long term twice daily administration both sulindac and its metabolites accumulate in plasma. Both patients with cirrhosis and the elderly demonstrate elevated concentrations of all species upon long term sulindac administration as compared with a single dose. The disposition of sulindac and its metabolites may be tied to renal function. In end-stage renal disease, increased free fractions of all species and accumulation of the sulphide and sulphone metabolites, and to a lesser extent sulindac, occurs. Significant drug interactions have been demonstrated for dimethylsulphoxide, cyclosporin, furosemide (frusemide), hydrochlorothiazide, methotrexate and cholestyramine.

Choosing the right nonsteroidal anti-inflammatory drug for the right patient: a pharmacokinetic approach.

Effective use of the growing number of nonsteroidal anti-inflammatory drugs (NSAIDs), a group that has recently been augmented by the introduction of the selective cyclo-oxygenase-2 inhibitors, requires adequate knowledge of their pharmacokinetics. After oral administration, the absorption of NSAIDs is generally rapid and complete. NSAIDs are highly bound to plasma proteins, specifically to albumin (>90%). The volume of distribution of NSAIDs is low, ranging from 0.1 to 0.3 L/kg, suggesting minimal tissue binding. NSAID binding in plasma can be saturated when the concentration of the NSAID exceeds that of albumin. Most NSAIDs are metabolised by the liver, with subsequent excretion into urine or bile. Enterohepatic recirculation occurs when a significant amount of an NSAID or its conjugated metabolites are excreted into the bile and then reabsorbed in the distal intestine. NSAID elimination is not dependent on hepatic blood flow. Hepatic NSAID elimination is dependent on the free fraction of NSAID within the plasma and the intrinsic enzyme activities of the liver. Renal elimination is not an important elimination pathway for NSAIDs, except for azapropazone. The plasma half-life of NSAIDs ranges from 0.25 to >70 hours, indicating wide differences in clearance rates. Hepatic or renal disease can alter NSAID protein binding and metabolism. Some NSAIDs with elimination predominantly via acylglucuronidation can have significantly altered disposition. Pharmacokinetics are also influenced by chronobiology, and many NSAIDs exhibit stereoselectivity. There appear to be relationships between NSAID concentration and effects. At therapeutically equivalent doses, NSAIDs appear to be equally efficacious. The major differences between NSAIDs are their therapeutic half-lives and safety profiles. NSAIDs undergo drug interactions through protein binding displacement and competition for active renal tubular secretion with other organic acids. When choosing the right NSAID for the right patient, individual patient-specific and NSAID-specific pharmacokinetic principles should be considered.

Clinical pharmacokinetics of diclofenac. Therapeutic insights and pitfalls.

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) of the phenylacetic acid class. When given orally the absorption of diclofenac is rapid and complete. Diclofenac binds extensively to plasma albumin. The area under the plasma concentration-time curve (AUC) of diclofenac is proportional to the dose for oral doses between 25 to 150 mg. Substantial concentrations of drug are attained in synovial fluid, which is the proposed site of action for NSAIDs. Concentration-effect relationships have been established for total bound, unbound and synovial fluid diclofenac concentrations. Diclofenac is eliminated following biotransformation to glucoroconjugated and sulphate metabolites which are excreted in urine, very little drug is eliminated unchanged. The excretion of conjugates may be related to renal function. Conjugate accumulation occurs in end-stage renal disease; however, no accumulation is apparent upon comparison of young and elderly individuals. Dosage adjustments for the elderly, children or for patients with various disease states (such as hepatic disease or rheumatoid arthritis) may not be required. Significant drug interactions have been demonstrated for aspirin (acetylsalicylic acid), lithium, digoxin, methotrexate, cyclosporin, cholestyramine and colestipol.

Clinical pharmacokinetics and pharmacodynamics of bromfenac.

Bromfenac is a nonsteroidal anti-inflammatory drug whose peak plasma concentration is reached 0.5 hours after oral administration. Bromfenac binds extensively to plasma albumin. The area under the plasma concentration-time curve is linearly proportional to the dose for oral doses up to 150 mg. The relationship between the total plasma and analgesic effect has been established. Only small amounts of bromfenac are eliminated unchanged, with the remaining drug being biotransformed into glucuronide metabolites which are excreted in urine and bile. Rapid elimination occurs in healthy individuals (half-life 0.5 to 4.0 h). Renal disease, hepatic disease and aging alter the disposition kinetics of bromfenac, and dosage adjustment may be advisable. Bromfenac modestly decreases free phenytoin concentrations. Bromfenac can cause idiosyncratic hepatic toxicity and has been withdrawn by its manufacturer pending further investigation of these case reports.