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Title: Pharmacokinetic studies with piroxicam
Author: Milligan, Peter A.
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1991
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Abstract:
When one examines the scientific literature pertaining to the NANSAID, piroxicam, it is clear that controversy of one type or another has not been far away. Perhaps the most serious threat to the drugs existence concerned its reputed potential to induce a range of gastrointestinal toxicity, including perforation and haemorrhage. After intense investigation by the regulatory authorities, however, it was concluded that the data cited were flawed due to reliance on spontaneous Adverse Drug Reaction reports. This controversy, together with the withdrawals of Opren and Osmosin during the 1980's, focused attention on prophylactic remedies for the potentially serious gastrointestinal toxicity exhibited, not only with piroxicam, but with all the NANSAIDs. Initial therapy was confined to the coadministration of H2 receptor antagonists but now other treatments are available. Little interest, however, has been placed on the theoretical interaction between NANSAIDs and cimetidine, an H2 receptor antagonist known to reduce the clearance of drugs that are metabolised via cytochrome P450 hepatic enzymes. Of the two studies that have examined this phenomenon, both have been of such a poor design that definite conclusions have been impossible. Before addressing the question of an interaction, therefore, simulation work was performed to design a study which would ensure the right degree of statistical confidence. The technique known as the Jackknife was introduced, its theory explained and its application to study design optimisation described. A prospective power calculation was performed to determine the number of subjects required to detect a 20% difference in the steady state AUC of piroxicam. The 20% value was chosen because it was considered that any alteration in the AUC, as a result of H2 receptor antagonist coadministration, greater than this value would be clinically significant The interaction study was a randomised crossover design comparing the coadministration of cimetidine and nizatidine in patients receiving chronic piroxicam therapy. No clinically significant interaction was found. There was no statistically significant alteration in the plasma AUCs of piroxicam and its metabolite 5-hydroxypiroxicam. However, the ratio of the two (5-hydroxypiroxicam:piroxicam) showed a statistically significant decrease in combination with either cimetidine or nizatidine. This indicated that a mild inhibition of piroxicam metabolism occurred. It is known that cimetidine binds to all isoenzymes of cytochrome P450 with low affinity, but to only a few with high affinity, resulting in a significant clearance alteration. Nizatidine has been shown to cause mild in vitro inhibition of cytochrome P450. The conclusion must therefore be that the H2 receptor antagonists bind to the isoenzyme responsible for piroxicam metabolism with low affinity, and as a consequence no clinically significant interaction will occur as a result of this combination. Another controversy, but by no means as crucial to the drugs continued availability for prescribing, was the question of whether piroxicam entered the bile and underwent enterohepatic circulation. Only one previous study has attempted to examine this, but it was flawed in its design, which made investigation of this phenomenon compelling. Piroxicam's biliary excretion was examined in one patient with a naso-biliary drain which allowed complete collection of the biliary output. The patient received 80mg of piroxicam over 3 days and samples of bile, urine and plasma were collected over a 24 hour period and quantitated for piroxicam, 5-hydroxypiroxicam, and 5-hydroxypiroxicam glucuronide (after development of a suitable assay technique). Neither piroxicam nor 5-hydroxypiroxicam entered the bile in sufficient quantities to undergo significant enterohepatic circulation. However, 5-hydroxypiroxicam glucuronide was present in the bile in large amounts, but this is likely to become important only if reverse metabolism to reform parent drug takes place. It can be concluded that the "multiple peak" phenomenon in piroxicam plasma concentration/time curves was not a result of enterohepatic circulation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.796616  DOI: Not available
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