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Title: Identification of the human liver cytochrome P450 isozymes responsible for the metabolism of non-steroidal anti-inflammatory drugs
Author: Newlands, Alan J.
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1994
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A human liver microsomal bank was established and assessed for P450 drug metabolising activity. Formation of dehydrofelodipine and dieldrin by human liver microsomes correlated significantly, suggesting that common P450 isozymes were involved. Both activities also correlated with immunochemically determined P4503A concentrations. It was concluded that aldrin and felodipine represent excellent in vitro probes for P4503A activity in man. Three NSAIDs: naproxen, ibuprofen and diclofenac, exhibiting different routes of oxidative metabolism, were selected to investigate the major cytochrome P450 isozymes involved in their metabolism. The rates of formation of O-desmethylnaproxen, 4'-hydroxydiclofenac and hydroxy-/carboxyibuprofen were measured in human liver microsomes. Activities (with the exception of carboxylation of (S)- and (R)-ibuprofen) showed significant correlations with the P4502C-mediated hydroxylation of tolbutamide and did not correlate with P4503A, P4502D, P4501A and P4502C (mephenytoin hydroxylase forms) activities. Sulphaphenazole was found to inhibit the formation of metabolites of the NSAIDs. It was concluded that P4502C is the major P450 subfamily responsible for the metabolism of NSAIDs. Molecular modelling suggests that the distance of a H-bond from the site of metabolism of a substrate and the angle created between the H-bond and site of metabolism are relatively constrained, thus suggesting a tightly fitting P4502C active site. These findings aid prediction of drug substrates of P4502C in man.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available