Time-dependent inhibition of platelet cyclo-oxygenase by indomethacin is slowly reversible |
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Authors: | Ronald W Walenga Susan F Wall BNY Setty Marie J Stuart |
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Institution: | 1. Department of Cardiology, University Hospital Tübingen, Tübingen, Germany;2. Dr. Margarete‐Fischer‐Bosch Institute of Clinical Pharmacology, Stuttgart, Germany;3. University of Tübingen, Tübingen, Germany;4. Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany;5. Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany;6. Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany;7. Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany |
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Abstract: | Indomethacin has been charterized
as a time-dependent, irreversible inhibitor of cyclo-oxygenase, yet its effects on human platelets have been found to be reversible
. To understand this apparent contradiction, we have investigated the kinetics of recovery of platelet thromboxane production after a single dose of indomethacin. The inhibition of platelet thromboxane production was greater than would be expected from the levels of indomethacin found in the plasma suggesting that the time-dependent inhibition occurs
. Yet recovery of platelet thromboxane production was faster than expected for the irreversible inhibitor, with 50% of control values being regained within 24 hours after ingestion of the drug. When platelets were isolated and resuspended in homologous drug-free plasma, slow recovery of thromboxane production was seen to occur with 50% of control activity regained in 100 minutes. This recovery was much slower than that seen from a competitive inhibitor of cyclo-oxygenase, ibuprofen. Ibuprofen-treated platelets recovered nearly completely immediately on being resuspended in drug-free plasma. When microsomes were isolated from platelets, then treated with indomethacin, no time-dependent recovery of activity was seen. The recovery of cyclo-oxygenase after indomethacin inhibition appears to be limited to the unperturbed enzyme in this natural milieu. |
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