Clinical pharmacokinetics of non-steroidal anti-inflammatory drugs

The number of non-steroidal anti-inflammatory drugs (NSAIDs) available for clinical use has dramatically increased during the last decade. As a general rule, NSAIDs are well absorbed from the gastrointestinal tract, with the exception of aspirin (and possibly diclofenac, tolfenamic acid and fenbufen) which undergoes presystemic hydrolysis to form salicylic acid. Concomitant administration of NSAIDs with food or antacids may in some cases lead to delayed or even reduced absorption. The NSAIDs are highly bound to plasma proteins (mainly albumin), which limits their body distribution to the extracellular spaces. Apparent volumes of distribution of NSAIDs are, therefore, very low and usually less than 0.2 L/kg. The elimination of these drugs depends largely on hepatic biotransformation; renal excretion of unchanged drugs is usually small (less than 5% of the dose). Total body clearance is low and for most NSAIDs is less than 200 ml/min. The effect of age and disease on the disposition of NSAIDs has not been extensively studied. Due to the central role of the liver in the overall elimination of the majority of these compounds, hepatic disease will most likely lead to a significant alteration in their pharmacokinetic behaviour. NSAIDs have been reported to be involved in numerous pharmacokinetic drug interactions. Aspirin decreases the plasma concentrations of many other NSAIDs, although the clinical significance of this is uncertain. Due to the extremely high plasma protein binding of NSAIDs (around 99% in many cases), competition for the same binding sites on plasma proteins may be at least partly responsible for some interactions of NSAIDs with other highly bound drugs; however, another mechanism such as decreased metabolism or decreased urinary elimination is usually involved as well. The most important interactions with NSAIDs are those involving the oral anticoagulants and oral hypoglycaemic agents, though not all NSAIDs have been found to interact with these drugs. In clinical practice, there appear to be no clear-cut guidelines to assist the clinician in the selection of the most appropriate drug for an individual patient. The selection of an anti-inflammatory drug should be based on clinical experience, patient convenience (e.g. once or twice daily dosage schedule), side effects and cost. Since a marked interindividual variability exists in the clinical response to a given NSAID, clinicians prescribing these agents may try several of them sequentially until an adequate response is obtained.     

The pharmacokinetics of non-steroidal anti-inflammatory drugs in the elderly

The elderly often suffer from chronic musculoskeletal disease, and non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to control symptoms. The aged have been shown to be particularly at risk of adverse effects from these drugs, of which gastrointestinal irritation and bleeding are both common and potentially serious. Because of this, a comparison of NSAID pharmacokinetics in young and elderly subjects is of particular importance. In general, protein binding tends to decrease with age; volumes of distribution may undergo a small increase; and clearance, especially of renally eliminated drugs, may fall. However, these changes are relatively minor, and the increased propensity of the elderly to suffer adverse reactions to NSAIDs cannot readily be explained on a pharmacokinetic basis.     

Protein binding of non-steroidal anti-inflammatory drugs in plasma and synovial fluid of arthritic patients

1 The protein binding of seven non-steroidal anti-inflammatory drugs (indomethacin, tolmetin, salicylic acid, ibuprofen, flurbiprofen, naproxen and GP53,633) and warfarin was investigated by equilibrium dialysis in simultaneous samples of synovial fluid and plasma from 12 arthritic patients. 2 The protein binding of all drugs studied except warfarin and flurbiprofen was significantly lower in synovial fluid than in plasma. 3 The decreased protein binding of these drugs is likely to explain the lower total drug concentrations found in synovial fluid in comparison to plasma. 4 The lower albumin concentration plays an important role in determination of reduced drug binding in synovial fluid compared to plasma and the fatty acid concentration in synovial fluid may also influence the protein binding of some of these drugs.     

A comparison of synovial fluid concentrations of non-steroidal anti-inflammatory drugs with their in vitro activity

For NSAIDs it has been widely accepted that prostaglandin inhibition is their mechanism of action in clinical use. Yet many other actions have been described, although it is unclear to what extent these may contribute to clinical activity. This review attempts to relate some of the experimental activities of NSAIDs to concentrations of drugs which occur in clinical use. Since it is assumed that to be effective a drug must reach its target site of action, synovial fluid concentrations for NSAIDs are considered. The resulting analysis suggests that prostaglandin inhibition is a viable mode of action for most, if not all, NSAIDs. However, some NSAIDS may rely as much, if not more, on other actions for their anti-inflammatory effect.     

Modelling circadian variation in the pharmacokinetics of non-steroidal anti-inflammatory drugs

Summary A one-compartment model with first-order absorption has provided good fits to five sets of indomethacin data and four sets of ketoprofen data taken at different times of day. There was substantial variation in the model parameters with time of administration and most of the features of this variation applied equally to both drugs. From the data examined, the source of variation appears to be mainly in the absorption phase and this was confirmed using a chronokinetic analysis, in which simultaneous fits were obtained with time-variant rate parameters. However, there may also be circadian variation in protein binding.The danger of quoting parameter values for either of these two drugs based on administration at a single time of day has been illustrated, and this may well be true for other drugs.     

Pharmacokinetics of nonsteroidal anti-inflammatory drugs in synovial fluid

The major site of action for nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of rheumatic diseases is probably within the synovial compartment. There has been little work on the disposition of NSAIDs in the synovium and most studies have involved the measurement of their concentrations in synovial fluid. The concentrations of NSAIDs are more sustained in synovial fluid than in plasma, the difference being particularly noted with NSAIDs with short elimination half-lives. The more sustained concentrations may contribute to the prolonged effect of the short half-life NSAIDs, which are usually administered at intervals longer than their half-lives in plasma. The most widely used method of kinetic analysis of NSAIDs in synovial fluid is a compartmental model in which synovial fluid is a peripheral compartment of distribution of the drug. Repeated samples of synovial fluid from individual patients are difficult to collect, but even 1 sample of synovial fluid and plasma from each patient can provide useful data when analysed using the population approach to pharmacokinetic analysis. According to the compartmental model, the mean half-lives of efflux of the NSAIDs from synovial fluid range from 1.5 to 7 hours. The mean partition coefficient of most NSAIDs between synovial fluid and plasma is approximately 0.6. The NSAIDs are highly protein-bound, and the lower mean concentrations in synovial fluid are largely because of the lower concentrations of the binding protein, albumin. The NSAIDs diffuse into and out of synovial fluid in their unbound forms, but there is some diffusion in the protein-bound forms, particularly out of synovial fluid. The mean rates of diffusion of NSAIDs into and out of skin blisters in humans are similar to the rates of influx and efflux in the synovial fluid of the knee, but there is considerable variation between the pharmacokinetics of transfer at the 2 sites in individual patients. NSAIDs decrease the synthesis of prostaglandins in synovial fluid, but there are few data on the relationship between the kinetics of NSAIDs in synovial fluid and the effects on prostaglandin synthesis.     

Effects of non-steroidal anti-inflammatory drugs on the pharmacokinetics and elimination of aciclovir in rats

This study aims to investigate the effect of commonly used non-steroidal anti-inflammatory drugs (NSAIDs) on the pharmacokinetics and the renal elimination of aciclovir in rats. Pharmacokinetic parameters were determined following an intravenous administration of aciclovir (5 mg kg(-1)) to rats in the presence and absence of ketoprofen or naproxen (25 mg kg(-1)). Compared with the control (given aciclovir alone), pre-treatment with ketoprofen or naproxen 30 min before aciclovir administration significantly altered the pharmacokinetics of aciclovir. Renal clearance of aciclovir was reduced by approximately two fold in the presence of ketoprofen or naproxen. Consequently, the systemic exposure (AUC) to aciclovir in the rats pre-treated with ketoprofen or naproxen was significantly (P < 0.05) higher than that from the control group given aciclovir alone. Furthermore, the mean terminal plasma half-life of aciclovir was enhanced by 4-5 fold by pre-treatment with ketoprofen or naproxen. These results suggest that NSAIDs, such as ketoprofen and naproxen, are effective in altering the pharmacokinetics of aciclovir by inhibiting the organic anion transporter-mediated tubular secretion of aciclovir. Therefore, concomitant use of ketoprofen or naproxen with aciclovir should require close monitoring for clinical consequence of potential drug interaction.     

NSAIDs抗炎作用机制研究进展

NSAIDs的抗炎作用机制被认为主要是抑制COX2的活性。NSAIDs还可以抑制COX2的表达,并可通过COX非依赖性的途径产生抗炎作用,包括抑制转录因子NFκB与AP1,作用于蛋白激酶如Erk、p38MAPK、及核糖体S6激酶2等,激活PPARγ及热休克转录因子1,抑制诱导型NO合酶及前列腺素转运等。     

非甾体抗炎药的合理应用

1899年阿司匹林问世开创了人类用合成抗炎药的历史.百余年来,以其为代表相继开发的一大批具有独特药理作用的抗炎药在临床上占有重要治疗地位,成为一日不可或缺的药品.为此临床医师应了解并合理地应用.     

Assessment of topical non-steroidal anti-inflammatory drugs

A new non-invasive technique for assessing the efficacy of topical non-steroidal anti-inflammatory drugs (NSAID) in man is proposed. The NSAID are initially applied to the skin under occlusion before inflammation is induced by a methyl nicotinate solution. The inflammatory response is quantified in terms of cutaneous blood flow by a laser Doppler velocimeter (LDV). The efficacy of NSAID preparations is calculated by comparing the responses of the LDV to the methyl nicotinate challenge on the pretreated and the non-treated skin sites. This protocol has been used to investigate the effect of three different NSAID preparations (indomethacin, niflumic acid, palmitoyl collagenic acid) and the influence of the vehicle on the efficacy of indomethacin. The three preparations tested gave positive results but with different amplitudes in response. The efficacy of indomethacin varied with the vehicle used.     

Effects of non-steroidal anti-inflammatory drugs on lymphocyte activation

Guinea-pig lymph node lymphocytes were stimulated with mitogen (phytohaemagglutinin) in vitro and lymphocyte activation was measured by tritiated thymidine incorporation (DNA synthesis). Inclusion of non-steroidal anti-inflammatory drugs (NSAIDs) in the culture medium at therapeutic concentrations, frequently exerted an inhibitory effect. Such inhibition could not be attributed to the ability of these drugs to inhibit cyclo-oxygenase or lipoxygenase enzymes. Inhibition by salicylates was not associated with cytotoxic or cytopathic effects, since inhibition was only evident when the drugs were included in the early phase of culture. Other NSAIDs exhibited varying degrees of toxicity, which in some instances may account for observed inhibition. The effects on lymphocyte activation of selective inhibitors of pathways of arachidonic acid metabolism, do not support the proposition that the generation of prostaglandins, thromboxanes, leukotrienes or related compounds is an obligatory step during lymphocyte activation.     

Cardiovascular hazard and non-steroidal anti-inflammatory drugs

Selective inhibitors of cyclooxygenase (COX)-2 depress prostacyclin (PGI(2)) without a concomitant inhibition of platelet COX-1-derived thromboxane (Tx)A(2). Experiments in gene-deleted mice have shown that ablation of the PGI(2) receptor (the IP) predisposes to an exaggerated response to agonists which elevate blood pressure, accelerate atherogenesis and induce thrombosis. Such a class-based effect would be expected to be modulated by the underlying risk of cardiovascular disease in patients, elements of drug exposure, such as dose, duration of action and duration of dosing, and inter-individual variability of drug response. Five placebo-controlled trials of three structurally distinct selective inhibitors of COX-2 have revealed an increased hazard of myocardial infarction and stroke consistent with a mechanism-based class-specific cardiovascular hazard. Sustained inhibition of platelet TxA(2) by aspirin affords cardiovascular benefit, despite concomitant inhibition of PGI(2). Although there is no information from randomized placebo-controlled trials, traditional non-steroidal anti-inflammatory drugs, such as naproxen, dicofenac and ibuprofen, might differ in their effects of cardiovascular biology.     

Cutaneous reactions to non-steroidal anti-inflammatory drugs

We retrospectively reviewed the records of 195 patients with suspected cutaneous reactions from NSAIDs. Two hundred and six different non-steroidal anti-inflammatory drugs (NSAIDs) were suspected of causing cutaneous reactions, and the most frequent suspected causative NSAID was ibuprofen (25.7%). Angioedema and/or urticaria were the most frequent cutaneous reactions (54.4%), and the foremost suspected causative drug for these reactions was ibuprofen. The second most frequently found cutaneous reaction was maculopapular eruption (26.2%), and celecoxib was the most commonly suspected causative NSAID for it. The primary suspected NSAIDs causing fixed drug eruption were in enolic acid group. Furthermore, drug hypersensitivity syndrome was diagnosed in five patients, and Stevens-Johnson syndrome and toxic epidermal necrolysis were detected in five patients.     

结肠直肠癌和非甾类消炎药(英文)

Non-steroidal anti-inflammatory drugs ( NSAIDs) can prevent or reduce the occurrence of colorectal cancers . Anti-carcinogenic properties of NSAIDs have been demonstrated in epidemiological studies of humans and experimental animals. In addition, clinical studies of familial adenomatous polyposis and sporadic adenomas have demonstrated that NSAIDs induce regression of colorectal adenomas and prevent formation of these tumors. NSAIDs thus induce early disruption of the adenoma-carcinoma sequence and may mainly suppress subsequent cancer formation at adenoma stage. The mechanism of the anti-carcinogenic effect of these drugs is not known, but results of most studies support that cyclooxygenase-2 (an inducible isoform of prostaglandin synthetase, COX-2) is a major target of NSAIDs in this effect. Recent immunohistochemical studies have revealed that COX-2 is expressed not in tumor cells but in interstitial cells of colonic adenomas. Accordingly, NSAIDs may exhibit anti-carcinogenic property through the inh     

非甾体抗炎药物在骨性关节炎中的应用

骨性关节炎是老年人中常见、多发的慢性进行性骨关节疾病,主要临床表现为缓慢发展的可使活动受限的关节疼痛、僵硬和肿胀,严重的能导致关节功能障碍.非甾体抗炎药物是目前治疗骨性关节炎等关节炎性疾病的最常用药物,作用机制为抑制环氧化酶活性、阻断该酶催化花生四烯酸转化为炎性物质前列腺素,从而发挥止痛、消炎作用.非甾体抗炎药物分为非选择性环氧化酶抑制剂和选择性环氧化酶-2抑制剂两类,应用广泛,但也存在多种不良反应,故选择用药时要严格掌握适应证,合理用药.     

Influence of molecular lipophilicity on the diffusion of arylpropionate non-steroidal anti-inflammatory drugs into the cerebrospinal fluid.

The diffusion of seven arylpropionic acid non-steroidal anti-inflammatory drugs (NSAIDs) into the cerebrospinal fluid (CSF) has been investigated in male Wistar rats by means of quantitative structure-activity relationship (QSAR) study. After intraperitoneal administration of each drug (5 mg/kg), blood and CSF samples were collected at different times (0.5, 1, 3, and 6 h). The fraction bound to plasma proteins (fb) was determined using ultracentrifugation. The total (CT) and free (CF) plasma concentrations and the concentrations in CSF (CCSF) were measured by a reversed-phase high performance liquid chromatographic (RP-HPLC) method. The areas under the curve of the free plasma (AUCF) and CSF (AUCCSF) concentrations were calculated according to the trapezoidal rule. The overall drug transit into CSF was estimated by the ratio RAUC (AUCCSF: AUCF). The lipophilicity of the compounds was expressed as their polycratic capacity factors (log k'w) measured in a RP-HPLC system. The RAUC ranged from 0.24 to 6.58 and fb from 91.4 to 99.8%. The compounds with an intermediate lipophilicity value (3 < logk'w < 3.6) easily entered the CSF (RAUC > 1). A parabolic relationship was found between log k'w and log RAUC, emphasizing the role of molecular lipophilicity in the diffusion into CSF. Considering the fb value of each drug in regard to this non-linear relationship, it can be hypothesized that the diffusion rate of NSAIDs into the CSF depends primarily on the lipophilicity.