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Current Medical Research and Opinion
Vol. 3, No. 5, 1975
Simultaneous pharmacokinetics of alclofenac in plasma and synovial fluid in patients with rheumatoid arthritis
G. M. Thomas, B. Pharm., B.Sc., P. Rees, J. E. Dippy, B.Pharm., M.B.,
Curr. med. Res. Opin., (1975), 3,264.
B.S., M.R.C.P., and J. Maddock, M.Sc., A.R.I.C.
Paper read: 6th June 1975
Summary The simultaneous pharmacokinetics of alclofenac in the plasma and synovial fluid of I0 patients with rheumatoid arthritis were studied after a single I g. oral dose. A gasliquid chromatographic method was used for assaying alclofenac in both plasma and synovialfluid. Alclofenac readily appears in the plasma and synovialfluid. Key words: Alclofenac - pharmacokinetics
Introduction The purpose of the present study was to measure alclofenac concentrations in plasma and synovial fluid of patients with rheumatoid arthritis following oral administration of alclofenac in its commercially available encapsulated form. t The metabolism of aklofenac, (4-allyloxy-3-chlorophenylaceticacid) a nonsteroidal anti-inflammatory/analgesic drug, has been extensively investigated in man and in 7 different animal species.5-7Three major metabolites in plasma and urine have been identified : alclofenac itself, 3-chloro-4-hydroxyphenylaceticacid, and racemic 3-chloro-4-(y, p, dihydroxy)-propyloxyphenylacetic acid. Dramatic interspecies differences have been observed, however, when amounts of these endproducts in theurine werecompared. Manand monkey excrete very large amounts of alclofenac whereas in the other species investigated, the dihydroxy derivative and the dealkylated compounds are the major metabolites. Alclofenac is well-absorbed from the gastro-intestinal tract, dose-related peak plasma concentrations occurring during the second hour after oral intake, and more than 90 % being excreted in the urine within 48 hours. In vitro experiments with bovine serum albumin indicate a substantial binding of alclofenac and its main metabolites with this protein fraction.’ At concentrations of alclofenac up to 200 pg./ml., more than 99 % is bound to human serum albumin in vitro and in vivo. The proliferative and destructive changes of rheumatoid arthritis are most probably consequent to synovial immune complex deposition, followed by the release of leucocyte lysosomal enzymes into the synovial membrane and synovial fluid.14 Since the efficacy of most drugs is related to their concentration at the target receptor cells,g it follows that the measurement of synovial fluid drug levels might be t‘Prinalgin’, trade mark Berk Pharmaceuticals Ltd. 264
G. M. Thomas, P. Rees, J. E. Dippy and J. Maddock
Curr Med Res Opin Downloaded from informahealthcare.com by University of Melbourne on 10/28/14 For personal use only.
of greater relevance in establishing optimal anti-inflammatory drug regimens, considering the evidence for there bejng a local pathogenic process within the rheumatoid joint.
Materials and methods Ten out-patients with active ‘definite’ or ‘classical’ rheumatoid arthritis8 and chronic knee joint effusions were studied. None of the patients exhibited clinical or laboratory evidence of renal or hepatic dysfunction. The nature, design, and aims of the study were explained to each patient prior to obtaining their consent to enter the study. All patients were fasted for at least 8 hours prior to and 1 hour after receiving 2 capsules (1.O g.) of alclofenac by mouth with a small amount of water. All received 500 ml. of water 2 hours before drug ingestion and 250 ml. every 2 hours to ensure adequate urine production. Samples of venous blood (5 ml.) and synovial fluid (5 ml.) were drawn at 30, 60, 90, 120, 360 and 540-minute intervals following administration of the drug. Samples of venous blood were also drawn at 150 and 180 minutes. The blood was quickly transferred to lithium heparin tubes and the plasma separated by centrifugation. Samples of separated plasma and of synovial fluid were rapidly frozen and stored at -4°C until analysed within 2 weeks. Several analyses of aliquots of both plasma and synovial fluid alclofenac concentrations throughout 2 months storage at -4°C indicated no significant change in drug levels. Alclofenac assays on both plasma and synovial fluid were performed using a modification of the method of Roncucci et a1.5 which employs a gas-liquid chromatographic technique. The sensitivity of the assays in this procedure under isothermal as well as under programmed conditions is better than 0.25 pg./injection for alclofenac.
Results A mean peak plasma level of 136 pg./ml. (S.E.M.f20.7) occurred at 1 hour following the oral administration of a single 1.0 g. dose of alclofenac, (Figure 1). The mean peak drug level in synovial fluid was 32.6 pg./ml. (S.E.M.f 16.3) and occurred 2 hours after drug ingestion. Plasma levels declined rapidly after reaching peak values and when measured 6 hours after the dose, they were significantly less than synovial fluid levels. At 9 hours, there was no significant difference between the levels of the drug in synovial fluid and in plasma. In the period between peak values at 1 hour and 2* hours, the half-time of drug disappearance from the plasma ranged from 45 to 110 minutes, (mean 75 minutes). During the same time period the half-time of drug appearance into the synovial fluid ranged from 60 to 120 minutes, (mean 75). 265
Simultaneous pharmacokinetics of alclofenac in plasma and synovial fluid in patients with rheumatoid arthritis
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Figure 1. Plasma and synovial fluid concentrationsafter a single 1 g. oral dose of alclofenac: mean va1ueshS.E.M. from 10 patients
d, Plasma
-++-
4
1
14
2
2!
3
4
5
Synovial fluid
6
7
8
9
Time (hours)
Discussion Following oral administration of alclofenac capsules (1 g.) to patients with rheumatoid arthritis the drug readily enters the synovial fluid. However, peak synovial fluid concentrations of the drug occur 1 hour later than the plasma peak levels, and are approximately 25 % as great. During the initial phase of equilibration, the half-time for disappearance of alclofenac from plasma was 75 minutes, which is identical to the mean half-time for appearance in synovial fluid during the same period. It is notable that alclofenac concentrations in synovial fluid were significantly greater than those in plasma at 6 hours. The present pharmacokinetic findings with regard to alclofenac are qualitatively similar to the serum and synovial fluid pharmacokinetics reported for acetylsalicylic acid,' 1 although the reported half-time for disappearance of acetylsalicylic acid is more rapid. They certainly differ from those of salicylate10 and gold3 for which the drug concentration in synovial fluid is substantially lower than that in the serum after equilibration. The present findings are most similar to the serum and synovial fluid pharmacokinetics reported for indomethacin.2 The lower synovial salicylate concentrations have been explained by Soren12 by the lower albumin concentrations available for drug binding in synovial fluid. This would not explain, however, the reportedly higher synovial fluid concentrations of indomethacin, acetylsalicylic acid, and alclofenac, all of which are highly bound to 266
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G. M. Thomas, P. Rees, J. E. Dippy and J. Maddock
albumin. Were it possible that active transport is required for these drugs to cross the synovial membrane, then a delay in equilibration would be expected. It would follow that, after equilibration, these drugs are less rapidly metabolised in the joint space than they are in the plasma. Duggan and others’ f 4 suggest the presence of a hypothetical organ or body compartment in which certain drugs gradually reach peak levels with the subsequent gradual decline in drug levels. These kinetics in such a compartment have been used to explain the previously observed onset and duration of the therapeutic response to indomethacin.2 The data given in the present study would also suggest that the kinetics observed for this synovial space would be compatible with the therapeutic response observed in clinical practice with alclofenac. It has been demonstrated that 6 hours after a single 1 g. oral dose of alclofenac capsules, plasma and synovial fluid drug concentrations are closely approximated and remain approximated thereafter. It may be argued that it is possible to infer synovial fluid concentrations from those of plasma specimens if obtained at least 5 hours after drug ingestion. References 1. Duggan, D. E., Hogans, A. F., Kwan, K. D., and McMahon, F. G., (1972). The metabolism of indomethacin in man. J . Pharm. exp. Ther., 181,563. 2. Emori, H. W., Champion, G. D., Bluestone, R., and Paulus, H. E., (1973). Simultaneous pharmacokinetics of indomethacin in serum and synovial fluid. Ann. rheum. Dis., 32,433. 3. Gerber, R. C., Paulus, H. E., Bluestone, R., and Lederer, M., (1972). Kinetics of aurothiomalate in serum and synovial fluid. Arthr. Rheum., 15,625. 4. Koch-Weser, J., (1972). Serum drug concentrations as therapeutic guides. New Eng. J. Med., 287,227. 5. Roncucci, R., Simon, M.-J., and Lambelin, G., (1971). Gas chromatographic determination of 4-allyloxy-3-chlorophenylacetic acid (alclofenac) and its metabolites. J . Chromatography, 62, 135. 6 Roncucci, R , Simon, M.-J., Lambelin, G., Gillet, C., Staquet, M., and Buu-Hoi, N. P., (1970). Metabolic patterns of 4-allyloxy-3-chlorophenylaceticacid in rat, rabbit, dog, monkey and man. Arzneim.-forsch., 20,631. 7. Roncucci, R., Simon, M.-J., Lambelin, G., Staquet, M., Gillet, C., Van Cauwenberge, H., Lefebvre, P., Daubresse, J. C., and Buu-Hoi, N. P., (1971). Kinetic studies on the absorption and acid in man. Europ. J. Pharmacol., 3, 176. excretion of 4-allyloxy-3-chlorophenylacetic 8. Ropes, M. W., Bennett, G. A., Cobb, S., Jacox, R., and Jessar, R. A., (1959). Diagnostic criteria for rheumatoid arthritis, 1958 Revision. Ann. rheum. Dis., 18,49. 9. Rosenoer, V. M., and Gill, G. M., (1972). Drug interactions in clinical medicine. Med. Clin. N . Amer., 56,585. 10. Rosenthal, R. K., Bayles, T. B., and Fremont-Smith, K., (1964). Simultaneous salicylate concentrations in synovial fluid and plasma in rheumatoid arthritis. Arthr. Rheum., 7,103. 11. Sholkoff, S. D., Eyring, E. J., Rowland, M., and Riegelman, S., (1967). Plasma and synovial fluid concentrations of acetylsalicylic acid in patients with rheumatoid arthritis. Arthr. Rheum., 10,348. 12. Soren, A., (1970). Salicylates in blood and joint fluid after ingestion of buffered aspirin. Clin. Orthopaed., 68,322. 13. Strolin-Benedetti, M., Strolin, P., Roncucci, R., Simon, M.-J., Lambelin, G., and Negand Deuxchaisnes, C., (1973). Evaluation of alclofenac treatment regimes in man. Europ. J. clin. Pharmacol., 6,261. 14. Zvaifler, N. J., (1970). Further speculation on the pathogenesis of joint inflammation in rheumatoid arthritis. Arthr. Rheum., 13,895. 267
Current Medical Research and Opinion
Vol. 3, No. 5, 1975
Simultaneous pharmacokinetics of alclofenac in plasma and synovial fluid in patients with rheumatoid arthritis
G. M. Thomas, B. Pharm., B.Sc., P. Rees, J. E. Dippy, B.Pharm., M.B.,
Curr. med. Res. Opin., (1975), 3,264.
B.S., M.R.C.P., and J. Maddock, M.Sc., A.R.I.C.
Paper read: 6th June 1975
Summary The simultaneous pharmacokinetics of alclofenac in the plasma and synovial fluid of I0 patients with rheumatoid arthritis were studied after a single I g. oral dose. A gasliquid chromatographic method was used for assaying alclofenac in both plasma and synovialfluid. Alclofenac readily appears in the plasma and synovialfluid. Key words: Alclofenac - pharmacokinetics
Introduction The purpose of the present study was to measure alclofenac concentrations in plasma and synovial fluid of patients with rheumatoid arthritis following oral administration of alclofenac in its commercially available encapsulated form. t The metabolism of aklofenac, (4-allyloxy-3-chlorophenylaceticacid) a nonsteroidal anti-inflammatory/analgesic drug, has been extensively investigated in man and in 7 different animal species.5-7Three major metabolites in plasma and urine have been identified : alclofenac itself, 3-chloro-4-hydroxyphenylaceticacid, and racemic 3-chloro-4-(y, p, dihydroxy)-propyloxyphenylacetic acid. Dramatic interspecies differences have been observed, however, when amounts of these endproducts in theurine werecompared. Manand monkey excrete very large amounts of alclofenac whereas in the other species investigated, the dihydroxy derivative and the dealkylated compounds are the major metabolites. Alclofenac is well-absorbed from the gastro-intestinal tract, dose-related peak plasma concentrations occurring during the second hour after oral intake, and more than 90 % being excreted in the urine within 48 hours. In vitro experiments with bovine serum albumin indicate a substantial binding of alclofenac and its main metabolites with this protein fraction.’ At concentrations of alclofenac up to 200 pg./ml., more than 99 % is bound to human serum albumin in vitro and in vivo. The proliferative and destructive changes of rheumatoid arthritis are most probably consequent to synovial immune complex deposition, followed by the release of leucocyte lysosomal enzymes into the synovial membrane and synovial fluid.14 Since the efficacy of most drugs is related to their concentration at the target receptor cells,g it follows that the measurement of synovial fluid drug levels might be t‘Prinalgin’, trade mark Berk Pharmaceuticals Ltd. 264
G. M. Thomas, P. Rees, J. E. Dippy and J. Maddock
Curr Med Res Opin Downloaded from informahealthcare.com by University of Melbourne on 10/28/14 For personal use only.
of greater relevance in establishing optimal anti-inflammatory drug regimens, considering the evidence for there bejng a local pathogenic process within the rheumatoid joint.
Materials and methods Ten out-patients with active ‘definite’ or ‘classical’ rheumatoid arthritis8 and chronic knee joint effusions were studied. None of the patients exhibited clinical or laboratory evidence of renal or hepatic dysfunction. The nature, design, and aims of the study were explained to each patient prior to obtaining their consent to enter the study. All patients were fasted for at least 8 hours prior to and 1 hour after receiving 2 capsules (1.O g.) of alclofenac by mouth with a small amount of water. All received 500 ml. of water 2 hours before drug ingestion and 250 ml. every 2 hours to ensure adequate urine production. Samples of venous blood (5 ml.) and synovial fluid (5 ml.) were drawn at 30, 60, 90, 120, 360 and 540-minute intervals following administration of the drug. Samples of venous blood were also drawn at 150 and 180 minutes. The blood was quickly transferred to lithium heparin tubes and the plasma separated by centrifugation. Samples of separated plasma and of synovial fluid were rapidly frozen and stored at -4°C until analysed within 2 weeks. Several analyses of aliquots of both plasma and synovial fluid alclofenac concentrations throughout 2 months storage at -4°C indicated no significant change in drug levels. Alclofenac assays on both plasma and synovial fluid were performed using a modification of the method of Roncucci et a1.5 which employs a gas-liquid chromatographic technique. The sensitivity of the assays in this procedure under isothermal as well as under programmed conditions is better than 0.25 pg./injection for alclofenac.
Results A mean peak plasma level of 136 pg./ml. (S.E.M.f20.7) occurred at 1 hour following the oral administration of a single 1.0 g. dose of alclofenac, (Figure 1). The mean peak drug level in synovial fluid was 32.6 pg./ml. (S.E.M.f 16.3) and occurred 2 hours after drug ingestion. Plasma levels declined rapidly after reaching peak values and when measured 6 hours after the dose, they were significantly less than synovial fluid levels. At 9 hours, there was no significant difference between the levels of the drug in synovial fluid and in plasma. In the period between peak values at 1 hour and 2* hours, the half-time of drug disappearance from the plasma ranged from 45 to 110 minutes, (mean 75 minutes). During the same time period the half-time of drug appearance into the synovial fluid ranged from 60 to 120 minutes, (mean 75). 265
Simultaneous pharmacokinetics of alclofenac in plasma and synovial fluid in patients with rheumatoid arthritis
Curr Med Res Opin Downloaded from informahealthcare.com by University of Melbourne on 10/28/14 For personal use only.
Figure 1. Plasma and synovial fluid concentrationsafter a single 1 g. oral dose of alclofenac: mean va1ueshS.E.M. from 10 patients
d, Plasma
-++-
4
1
14
2
2!
3
4
5
Synovial fluid
6
7
8
9
Time (hours)
Discussion Following oral administration of alclofenac capsules (1 g.) to patients with rheumatoid arthritis the drug readily enters the synovial fluid. However, peak synovial fluid concentrations of the drug occur 1 hour later than the plasma peak levels, and are approximately 25 % as great. During the initial phase of equilibration, the half-time for disappearance of alclofenac from plasma was 75 minutes, which is identical to the mean half-time for appearance in synovial fluid during the same period. It is notable that alclofenac concentrations in synovial fluid were significantly greater than those in plasma at 6 hours. The present pharmacokinetic findings with regard to alclofenac are qualitatively similar to the serum and synovial fluid pharmacokinetics reported for acetylsalicylic acid,' 1 although the reported half-time for disappearance of acetylsalicylic acid is more rapid. They certainly differ from those of salicylate10 and gold3 for which the drug concentration in synovial fluid is substantially lower than that in the serum after equilibration. The present findings are most similar to the serum and synovial fluid pharmacokinetics reported for indomethacin.2 The lower synovial salicylate concentrations have been explained by Soren12 by the lower albumin concentrations available for drug binding in synovial fluid. This would not explain, however, the reportedly higher synovial fluid concentrations of indomethacin, acetylsalicylic acid, and alclofenac, all of which are highly bound to 266
Curr Med Res Opin Downloaded from informahealthcare.com by University of Melbourne on 10/28/14 For personal use only.
G. M. Thomas, P. Rees, J. E. Dippy and J. Maddock
albumin. Were it possible that active transport is required for these drugs to cross the synovial membrane, then a delay in equilibration would be expected. It would follow that, after equilibration, these drugs are less rapidly metabolised in the joint space than they are in the plasma. Duggan and others’ f 4 suggest the presence of a hypothetical organ or body compartment in which certain drugs gradually reach peak levels with the subsequent gradual decline in drug levels. These kinetics in such a compartment have been used to explain the previously observed onset and duration of the therapeutic response to indomethacin.2 The data given in the present study would also suggest that the kinetics observed for this synovial space would be compatible with the therapeutic response observed in clinical practice with alclofenac. It has been demonstrated that 6 hours after a single 1 g. oral dose of alclofenac capsules, plasma and synovial fluid drug concentrations are closely approximated and remain approximated thereafter. It may be argued that it is possible to infer synovial fluid concentrations from those of plasma specimens if obtained at least 5 hours after drug ingestion. References 1. Duggan, D. E., Hogans, A. F., Kwan, K. D., and McMahon, F. G., (1972). The metabolism of indomethacin in man. J . Pharm. exp. Ther., 181,563. 2. Emori, H. W., Champion, G. D., Bluestone, R., and Paulus, H. E., (1973). Simultaneous pharmacokinetics of indomethacin in serum and synovial fluid. Ann. rheum. Dis., 32,433. 3. Gerber, R. C., Paulus, H. E., Bluestone, R., and Lederer, M., (1972). Kinetics of aurothiomalate in serum and synovial fluid. Arthr. Rheum., 15,625. 4. Koch-Weser, J., (1972). Serum drug concentrations as therapeutic guides. New Eng. J. Med., 287,227. 5. Roncucci, R., Simon, M.-J., and Lambelin, G., (1971). Gas chromatographic determination of 4-allyloxy-3-chlorophenylacetic acid (alclofenac) and its metabolites. J . Chromatography, 62, 135. 6 Roncucci, R , Simon, M.-J., Lambelin, G., Gillet, C., Staquet, M., and Buu-Hoi, N. P., (1970). Metabolic patterns of 4-allyloxy-3-chlorophenylaceticacid in rat, rabbit, dog, monkey and man. Arzneim.-forsch., 20,631. 7. Roncucci, R., Simon, M.-J., Lambelin, G., Staquet, M., Gillet, C., Van Cauwenberge, H., Lefebvre, P., Daubresse, J. C., and Buu-Hoi, N. P., (1971). Kinetic studies on the absorption and acid in man. Europ. J. Pharmacol., 3, 176. excretion of 4-allyloxy-3-chlorophenylacetic 8. Ropes, M. W., Bennett, G. A., Cobb, S., Jacox, R., and Jessar, R. A., (1959). Diagnostic criteria for rheumatoid arthritis, 1958 Revision. Ann. rheum. Dis., 18,49. 9. Rosenoer, V. M., and Gill, G. M., (1972). Drug interactions in clinical medicine. Med. Clin. N . Amer., 56,585. 10. Rosenthal, R. K., Bayles, T. B., and Fremont-Smith, K., (1964). Simultaneous salicylate concentrations in synovial fluid and plasma in rheumatoid arthritis. Arthr. Rheum., 7,103. 11. Sholkoff, S. D., Eyring, E. J., Rowland, M., and Riegelman, S., (1967). Plasma and synovial fluid concentrations of acetylsalicylic acid in patients with rheumatoid arthritis. Arthr. Rheum., 10,348. 12. Soren, A., (1970). Salicylates in blood and joint fluid after ingestion of buffered aspirin. Clin. Orthopaed., 68,322. 13. Strolin-Benedetti, M., Strolin, P., Roncucci, R., Simon, M.-J., Lambelin, G., and Negand Deuxchaisnes, C., (1973). Evaluation of alclofenac treatment regimes in man. Europ. J. clin. Pharmacol., 6,261. 14. Zvaifler, N. J., (1970). Further speculation on the pathogenesis of joint inflammation in rheumatoid arthritis. Arthr. Rheum., 13,895. 267
