Persistence of NSAIDs at Effect Sites and Rapid Disappearance From Side-Effect Compartments Contributes to Tolerability

By Brune, Kay

Key words: COX-2 – Diclofenac – Ibuprofen – Mode of action – Pharmacokinetics – Tissue accumulation ABSTRACT

Background: Non-steroidal, anti-inflammatory drugs (NSAIDs) are still the most widely used drugs worldwide. The introduction of selective cyclooxygenase (COX)-2 inhibitors has led to compounds which appear less damaging to the gastrointestinal tract, but possibly more risky to the cardiovascular system than older drugs. None has as yet reached OTC-status.

Objective: This situation necessitates an analysis of the characteristics of those older ones which – due to their relative safety – have achieved over-the-counter (OTC) status.

Design: The pharmacodynamic and pharmacokinetic characteristics of non-selective COX inhibitors in OTC use were obtained from the literature by systematic search, examined and used to construct a coherent hypothesis why they achieved OTC status, i.e. effectiveness and relative safety at low doses.

Results: Pharmacodynamic (COX-2 preferential, but not selective inhibition) and, more importantly, pharmacokinetic characteristics of some of the older compounds may make them particularly safe drugs if used at low (OTC) doses with treatment limited to a few days of intake. The reason why some NSAIOs are particularly active while being relatively free from side-effects may be due to their specific biodistribution and metabolism, leading to drug accumulation and persistence in inflamed tissue (effect compartment) together with fast clearance from the central compartment, including blood, vascular wall, heart and kidney, i.e., possible side-effect compartments.

Conclusion: This specific pharmacokinetic behavior of some non- selective COX inhibitors, such as diclofenac and ibuprofen, may explain why these widely used, non-steroidal, anti-inflammatory compounds are relatively well suited for OTC use and why some are more appropriate for the therapy of certain pain conditions than others.

Introduction

Non-steroidal, anti-inflammatory drugs (NSAIDs) are frequently and widely used to treat pain and inflammation. They are available in various formulations (oral, rectal parenteral or topical) for prescription and over-the-counter (OTC) use. Systematic review of the literature has confirmed that NSAIDs are more effective than placebo in providing analgesia and reducing inflammation1-5.

There is one main mechanism by which NSAIDs exert their anti- inflammatory and analgesic effects: Inhibition of cyclooxygenase (COX), an enzyme that converts arachidonic acid into prostaglandins (PGs), thromboxanes and prostacyclins (Figure 1)6-8. NSAIDs work by inhibiting both COX isoenzymes. COX-1 is expressed in all tissues9 and is thought to lead to production of PGs (e.g., PGE^sub 2^, PGI^sub 2^, and TXA^sub 2^) involved in ‘housekeeping’, such as protection of the stomach wall (PGE^sub 2^), platelet aggregation (TXA^sub 2^) and kidney function (PGI^sub 2^). By contrast, COX-2 is almost undetectable in most tissues under normal physiological conditions10-12 (although it has been found to be expressed in some tissues such as the brain13, kidney14 and the cardiovascular [CV] system15,16). However, it can be rapidly and transiently induced in inflamed tissue (by as much as 10-80 fold)16. In some areas of the CNS, it is involved in pain and fever development. Upregulation leads to the production of PGs that mediate pain, fever and inflammation (in particular PGE^sub 2^(15) via EP, and EP^sub 2^ receptors17).

Figure 1. Mechanism of action of NSAIDs

Some of the most widely used NSAIDs inhibit COX-1 and COX-2 to a similar degree at clinical doses6. For example, ibuprofen, naproxen and piroxicam belong to a group of compounds that can produce full inhibition of both COX-1 and COX-2 with relatively poor selectivity (< 5-fold COX-2 selective)18. This would explain why these drugs (especially in the oral form) have anti-inflammatory and pain- relieving effects, but also unwanted side-effects, such as gastrointestinal (GI) bleeding and gastric ulcerations19. Certain NSAIDs (e.g., diclofenac) have a slight specificity for COX-2 and preferentially inhibit COX-2 which is thought to result in a lower incidence of GI side-effects than other non-selective NSAIDs, such as naproxen619. Very recent NSAIDs (e.g., etoricoxib, lumiracoxib and valdecoxib/parecoxib) inhibit COX-2 exclusively and are therefore thought to be even less gastrotoxic20-22. However, considerable uncertainty now surrounds the long-term risks associated with COX-2 selective inhibitors23, in particular with respect to CV toxicity24.

As all NSAIDs have the same mode of action (inhibition of pro- algesic and tissue-protective prostaglandins), it is implicit that the pharmacokinetic characteristics of each NSAID may contribute substantially to the overall pharmacological/toxicological profile25,26. In particular, the efficacy of an NSAID is influenced by whether the drug can achieve therapeutic concentrations in inflamed (effect) tissues at the same time as low concentrations in possible side-effect compartments (i.e., the kidneys). A high and persistent concentration of NSAIDs in inflamed tissue is central to the anti-inflammatory action, whereas high concentrations in the GI tract, kidneys, blood (including the vascular wall) and liver (side- effect compartments) may be contributing factors to the incidence and severity of side-effects.

This paper examines the time course of tissue distribution, with specific reference to diclofenac. Diclofenac has been selected because it is one of the most extensively studied NSAIDs, is often used as the reference drug in clinical trials, and during the last decade it has been given OTC status in several European countries (although several NSAIDs have been available OTC in the USA for many years). Where data are available, diclofenac is compared with other widely-used non-selective NSAIDs (e.g., ibuprofen, naproxen).

All publications available on PubMed and dealing with the tissue distribution of diclofenac, ibuprofen and naproxen were evaluated in the context of their importance to the concept elaborated in this manuscript.

Diclofenac and other NSAIDs in OTC use

Diclofenac is an effective and relatively well tolerated NSAID that is available in systemic and topical formulations and has been used for over 30 years to reduce inflammation and relieve pain, tenderness and stiffness in conditions such as arthritis (e.g., osteoarthritis), soft tissue injuries (e.g., sprains, strains, bruises, sports injuries), back pain and soft tissue rheumatic syndromes (e.g., tendonitis, bursitis)1-5,27-30. Systemic diclofenac can also be used to relieve posttraumatic or menstrual pain as well as common headache. In addition, it has an antipyretic action. Oral formulations are the most widely used formulations and are associated with one of the lowest relative risks (RR) for GI adverse events19. Nevertheless, some patients may experience GI complications, including bleeding and perforation which necessitate discontinuation of treatment. Topical formulations were developed to enable targeted delivery to the site of tissue damage (where possible), allowing patients to benefit from a reduction of pain and inflammation while reducing the risk of GI complications and other side-effects31.

Diclofenac is a member of the heteroaryl acetic NSAIDs32,33 and is usually formulated as either the sodium (Na) or potassium (K) salt; both salts have the same mechanisms of action, are absorbed to the same extent following oral administration and have similar pharmacodynamic effects34. Diclofenac is a weak acid (with a pKa value of around 4)35 and is thus hydrophilic/lipophilic, i.e., an amphiphilic molecule that can access all tissues.

Figure 2. Structure of non-acidic (a+b) and acidic (c-f) NSAIDs.* Asymmetrical C-atom resulting in two enantiomers with different pharmacodynamic and pharmacokinetic behaviors; the drug formulation of naproxen is marketed as the S-enantiomer only

Ibuprofen and naproxen are also available OTC, and the clinical experience with these compounds is similar to that with diclofenac. However, these propionic acid derivatives differ from diclofenac not only chemically (see Figure 2), but also with regard to certain pharmacological aspects. While only the active form (S-enantiomer) of naproxen is provided, ibuprofen is given as a racemic mixture, i.e., containing the active S-ibuprofen as well as the inactive R- ibuprofen. The inactive R-ibuprofen is metabolically transformed into the S-form in the human body, but to a variable degree. Whether some of the ibuprofen is retained as thio-ester in body lipids36 and what the consequences of this might be, is still an open question. Similar to diclofenac, the elimination half-life of ibuprofen (S- enantiomer) is in the range of 2 h. By contrast, naproxen is eliminated slowly with an elimination half-life of about 12-14 h. Diclofenac, ibuprofen, and naproxen inhibit both COX-1 and -2, with ibuprofen and naproxen presenting some slight preference for COX-1 inhibition and diclofenac demonstrating some preference for COX-2 inhibition18. These pharmacological differences may explain some of the particular therapeutic pros and cons of diclofenac, ibuprofen and naproxen, which are referred to below.

Mechanism of action

As with all NSAIDs, the primary mode of action of diclofenac (Figure 1) is decreased PG synthesis via inhibition of the COX-1 and COX-2 isoenzymes6; diclofenac is considered a non-selective NSAID, although it has been shown to present a slight preferential inhibitory activity at COX-2(18,37,38). The reduction of PG synthesis in inflamed tissue and the CNS is directly responsible for the anti-inflammatory activity of diclofenac and other NSAIDs (Figure 3a). Diclofenac does not directly affect existing hyperalgesia or the pain threshold. Instead, the analgesic effect is indirect and results from inhibition of further production of the PGs (specifically E^sub 2^) that are responsible for sensitizing the pain receptors (nociceptors) and for the anti-hyperalgesic effects exerted via glycinergic hyperpolarization of post-synaptic (pain- mediating) neurons (Figure 3b). The antipyretic action of diclofenac indicates that diclofenac suppresses PG synthesis (specifically PGE^sub 2^) in the hypothalamus. Absorption

Following oral administration (unless enteric coating is used), diclofenac (Na or K salts) tablets rapidly disintegrate in the stomach and facilitate complete absorption of the active drug from the GI tract and rapid onset of analgesic action. First pass metabolism of oral diclofenac results in a bioavailability of around 60%(39,40). Maximum plasma concentrations are achieved some 30 minutes after administration, and a single dose of 50 mg results in plasma concentrations that are between 50 and 100 times higher than the concentrations achieved after a repeated or single topical administration respectively41. The time to onset of action of ibuprofen depends considerably on the galenic formulation. Ibuprofen salts act faster than ibuprofen acid formulations42. Naproxen is also available as a salt. Both ibuprofen and naproxen are fully bioavailable.

Topical diclofenac preparations are applied directly to the site of pain and/or inflammation and thus avoid first-pass metabolism. Diclofenac is a small, relatively lipophilic molecule, allowing rapid diffusion through the skin with the highest transdermal penetration compared to other NSAIDs (indomethacin, ketoprofen, piroxicam, tenoxicam, ketorolac, aceclofenac)43. It is absorbed into the underlying dermis and subcutaneous tissue to a depth of at least 3-4 mm44. At that level, uptake of the drug from the dermal microcirculation into the systemic circulation occurs, but systemic exposure to the drug is low35,41. The skin may act as a reservoir from which there is a sustained release of drug into surrounding tissues45,46. There is little scientific information on the topical administration of ibuprofen and naproxen, mainly due to the lack of evidence assessing the clinical effects of topical formulations.

Preferential distribution and action in areas of inflammation

For a drug to be effective, it must reach the target tissues in a sufficient concentration to produce a clinically relevant effect. Plasma concentrations of NSAIDs do not always appear to parallel clinical efficacy, and the importance of finding significant concentrations of drug at the site of inflammation is widely recognized. In fact, it has been suggested that synovial fluid concentrations may be a more reliable indicator of clinical efficacy than plasma concentrations47. Thus, preferential distribution of the drug to the effect areas (e.g., inflamed tissue, synovial area) rather than plasma, is important (Figure 4). Conversely, high concentrations in plasma, and hence the vascular wall and the kidney, may result in unwanted CV drug effects48. Several factors can have an effect on the distribution of NSAIDs to effect as well as side-effect compartments, as discussed below.

Protein binding

One of the factors that affects distribution is the protein binding of the NSAID26. All NSAIDs are highly bound to plasma proteins, predominantly albumin26. For example, the protein binding of diclofenac to albumin in plasma has been shown to be 99.4%50. As a result of extensive protein binding, the mean concentrations of NSAIDs in plasma or in synovial fluid are largely controlled by the concentration of albumin in these areas. In a healthy joint, for example, the concentration of albumin in the synovial fluid is generally lower than in plasma. Consequently, the mean concentrations of most NSAIDs in the synovial fluid of a healthy joint at steady state are also lower than in plasma. However, during inflammation the concentrations of albumin in inflamed tissue and synovial fluid are greatly increased; accordingly, the mean concentrations of NSAIDs in the synovial fluid are also increased by inflammation. Furthermore, the acidic microenvironment of the inflamed tissue results in lower protein binding of acidic NSAIDs such as diclofenac, allowing for more drug to diffuse into the intracellular space where the therapeutic effect takes place51. The preferential distribution of NSAIDs to the effect compartment has been confirmed in several studies with diclofenac and other acidic NSAIDs, which show that the drug rapidly penetrates into (inflamed) synovial fluid and that over time greater concentrations are found in the synovial fluid and tissue than in plasma35,41,47,52-58. The higher concentrations found in synovial fluid seem to translate to a specific pharmacodynamic effect for several widely used NSAIDs (including diclofenac and ibuprofen) that is sufficient to decrease the synthesis of PGs47,59-62 and is associated with decreased concentrations of PGE^sub 2^ in synovial fluid47,63-68.

Figure 3. Hyperalgesia as a result of inflammation (a); glycinergic kyperpolarization of postsynaptic (pain-mediating) neurons (b)

Figure 4. NSAIDs are preferentially distributed to the effect areas (e.g., inflamed tissue, synovial fluid) rather than plasma, which is important for a clinical effect49

Volume of distribution

Another important characteristic that reflects the distribution and retention of a NSAID to (and in) the inflamed tissues is the volume of distribution (V^sub D^). The strong protein binding seen with most NSAIDs, which is facilitated by the lipophylic/ hydrophilic polarity of the acid NSAID molecules (e.g., the carboxylic acid group in diclofenac), results in a low V^sub D^69,70. Coupled with a short plasma half-life (1-2 h), a low V^sub D^ helps to establish a high plasma/tissue gradient that favors movement of the drug into the inflamed tissue when the conditions are right, facilitated by particular forces that affect the properties of blood movements (hemodynamics), such greater capillary permeability resulting in an increased blood flow to the inflamed tissues. Furthermore, the fenestrated endothelium of normal connective tissue does not allow the passage of proteins and drugs, and accumulation does not take place; however, in inflamed tissue the gaps in the endothelium are much wider and do allow proteins and drugs to permeate through. In other words, a low V^sub D^ and short plasma half-life result in a higher distribution coefficient (K^sub S^) (Figure 5), a value that predicts the ability of a compound to penetrate lipophilic biological membranes26,71. Thus, the low V^sub D^ and short plasma half-life of diclofenac, for example, allows it to preferentially distribute to synovial fluid, leading to persisting therapeutic concentrations of the drug in inflamed tissues (effect compartment) and fast decline of concentrations in side-effect compartments (CV-renal system).

Acidity of the molecule

Both acidic and non-acidic NSAIDs (e.g., Figure 2, Table 1) are able to inhibit PG synthesis72. However, non-acidic NSAIDs (e.g., acetaminophen [paracetamol], propyphenazone, celecoxib, etoricoxib) distribute almost equally throughout the body or are sequestered in body fat because of their lipophilicity (celecoxib)73. In contrast, acidic NSAIDs with a pKa value of around 4 (e.g., diclofenac, ibuprofen, and naproxen) show a hydrophilic/lipophilic polarity and > 99% protein binding, causing distribution and persistence in blood, kidneys, liver and synovial fluid. Consequently, acidic NSAIDs are found in significantly higher concentrations in inflamed tissues compared with non-inflamed tissues, but also in undesirable areas such as the vasculature (endothelium) and kidneys72,74,75. The local acidic microenvironment caused by inflammation might further promote uptake and retention of the drug; the relatively acidic pH values in the extracellular space of inflamed tissues in comparison to neutral intracellular pH values are likely to cause a considerable shift of acidic compounds into cell membranes and intracellular space (Table 2)72,74. Such a shift (ion trapping) would cause higher concentrations of acidic NSAID at the site of possible pharmacodynamic actions (i.e., the cell membranes or the intracellular space containing the COX-2 enzymes of, for example, nociceptors).

Figure 5. Distribution coefficients (K^sub S^) between synovial fluid and plasma for some common NSAIDs26. The partition coefficient between synovial fluid and plasma, describes the rate of entry and loss of nonsteroidal anti-inflammatory drugs from synovial fluid. Samples were collected during multiple doses. The parameters are presented as means. Half-lives are categorized as short (1-4h), medium (7-14 h) and long (> 24h)

Table 1. Pharmacokinetic characteristics of NSAIDs32,75

Table 2. Influence of variation of pH on the relative concentrations of an acidic drug (phenylbutazone) in neighboring compartments*74

Hemodynamics of inflamed tissues

Changes in the hemodynamics of tissue (changes in the vascular system leading to modification of the blood flow properties) during inflammation further contribute to an increased concentration of (acidic) NSAID in the synovial fluid, including increased localized blood flow and capillary ‘leakiness’55. Inflammation causes vasodilation, resulting in increased blood flow to the affected area and allowing the NSAID to reach the synovial fluid more quickly. In addition, there is also an increase in synovial (capillary) membrane permeability to proteins such as albumin26. The capillaries in the synovial membrane provide a continuous flow of plasma ‘filtrate’ to the joint and a supply of nutrients (and drugs) to the tissue. The capillaries are fenestrated, which allows for limited access of both albumin-bound drug as well as unbound drug to the tissue. During inflammation the capillaries become ‘open’ or discontinuous, enabling proteins to have free access to the joint tissue and fluid. Therefore, the concentrations of plasma protein and drug bound to it increases in the synovial fluid. Concentrations in areas of inflammation

The combined influences of strong protein binding, a short plasma half life, a low volume of distribution, weak acidity of the molecule, and changes in the hemodynamics of inflamed tissues ensure that diclofenac and other short half-life acidic NSAIDs preferentially distribute to areas of inflammation where they are retained, causing prolonged COX inhibition and hence analgesia. Pharmacokinetic analysis shows that the concentrations of topicallyapplied diclofenac in synovial fluid (119-3320ng/ ml) and tissue (131-1740 ng/g) are up to 20 times higher than in plasma (6- 52 ng/ml)41 at later times (Figure 6), while other studies confirm that diclofenac is present in sufficient concentrations in the synovial fluid52,54-58 to exert a therapeutic response58,77-80. Similar drug persistence has been observed with ibuprofen26. Naproxen differs in its pharmacokinetic behavior (see below); due to its slow elimination, naproxen persists in both the central (cardiovascular/renal) compartment as well as in the inflamed tissue.

Persistence in synovial fluid

Despite a relatively fast elimination from plasma, diclofenac has a long persistence at the site of inflammation which might explain the duration of its therapeutic effect35,47. The plasma half-lives of NSAIDs have a profound effect on the pharmacokinetics of these drugs in synovial fluid26. NSAIDs diffuse into and out of synovial fluid relatively slowly, which leads to more sustained concentrations of NSAIDs in synovial fluid than in plasma if the elimination half-life of the NSAID is short. Thus, NSAIDs such as diclofenac, ibuprofen, and ketoprofen have short plasma halflives of approximately 2 h, with slow elimination from the synovial fluid. After a single dose of these short half-life NSAIDs, the concentrations in synovial fluid increase more slowly and attain lower peaks than in plasma. At later times, there is a crossover, and the concentrations in synovial fluid exceed those in plasma. After administration of multiple doses, the trough concentrations are lower in plasma than in synovial fluid, but there is a similar crossover pattern. Overall, the concentrations in synovial fluid are more sustained than in plasma (Figure 6). This situation allows the central compartment (i.e., blood, vessel wall, kidney) to recover. In the effect compartment active COX inhibition and by that inhibition of nociception persists. Clearly, high doses, frequent dosing intervals and long elimination half life of the NSAID will eliminate these pharmacokinetic advantages (Figure 7).

With NSAIDs that have a medium half-life (e.g., naproxen, which has a mean half-life of 14 h), the plasma concentrations fluctuate over nearly a two-fold range during the usual administration interval of 12 h26. As with the short half-life NSAIDs, the concentrations in synovial fluid do not fluctuate as much as the plasma concentrations; however, they are consistently lower than the total plasma concentrations during long-term administration. Even more, the concentrations of the long half-life NSAIDs (e.g., tenoxicam) are consistently lower in synovial fluid than in plasma26. The concentrations of tenoxicam (for example) in synovial fluid increase more slowly than in plasma during the absorption phase, and the total concentrations in synovial fluid are, like naproxen, consistently lower than in plasma26. Consequently, even with low doses and long dosing intervals (once or twice daily) of these NSAIDs, sufficiently low concentrations are not seen in side- effect compartments, such as blood (vasculature) and kidney.

Figure 6. Concentration of diclofenac in plasma and synovial fluid over time; diclofenac preferentially distributes to the synovial fluid compared with plasma53. Diclofenac was administered as an enteric-coated oral tablet. Plasma (solid circles) and synovial fluid (open circles) concentrations of diclofenac (ng/ml) over time (up to 12h) in a patient with osteoarthritis of the knee. The patient received 75 mg of diclofenac every 12 h for 1 week. The data presented here reflect the concentration of diclofenac in blood and synovial fluid samples, collected at 0, 2, 4, 8 and 12 h post- dose on day 8

Figure 7. Typical concentration profile of acidic NSAIDs such as diclofenac and ibuprofen (short elimination half-life)

Conclusions

From the information presented here it can be concluded that certain pharmacokinetic properties (i.e., strong protein-binding, a short half-life, a low volume of distribution, and weak acidity) of some NSAIDs, such as diclofenac, in combination with changes in the vascular properties of inflamed tissues (increased blood flow and capillary permeability), favor their preferential distribution and persistent presence in areas of inflammation. The concentrations reached in the target areas have been shown to be adequate to exert a therapeutic response. On the other hand, clearance of these drugs from the central compartment may allow for recovery of tissue- protective prostaglandins therein, provided that low doses are given (systemically or topically).

Acknowledgments

Declaration of interest: The author would like to thank Deborah Nock, a professional medical writer with DPP-Cordell Ltd, for editorial support during the final stages of the manuscript. This support to the medical writer was funded by Novartis.

K. Brune has collaborated with Bayer, Merck, Novartis, Pfizer and other research-oriented pharmaceutical companies in order to develop new anti-inflammatory/analgesic drugs, to improve the use of the existing compounds and promote knowledge of these drugs in order to increase the awareness of the treating physicians of their advantages and disadvantages. He has been an invited speaker at sponsored symposia and has received research grants from the companies mentioned.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-4154_5, Accepted for publication: 19 September 2007

Published Online: 18 October 2007

doi:10.1185/030079907X242584

Kay Brune

Department of Experimental and Clinical Pharmacology and Toxicology, FAU Erlangen-Nuremberg, Germany

Address for correspondence: Kay Brune, Doerenkamp Professor, Department of Experimental and Clinical Pharmacology and Toxicology, FAU Erlangen-Nuremberg, Fahrstrasse 17, D-91054 Erlangen, Germany. Tel: +49 9131 85 22292; Fax: +49 9131 206119; brune@pharmakologie.med.uni-erlangen.de

Copyright Librapharm Dec 2007

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