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The Metabolism of Aminotetralins in vitro and in vivo.

Martin, Iain J. (1996) The Metabolism of Aminotetralins in vitro and in vivo. Doctoral thesis, University of Surrey (United Kingdom)..

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Abstract

A study was undertaken on the metabolism of a series of 14 aminotetralins displaying activity at the 5-HT1A receptor. All of the compounds possessed a 2-(N,N-di-n-propylamino)tetralin (DPAT) nucleus and varying substituents at either the 5- or 8- positions (or both). The objectives of the study were (i) to investigate the effects of the substituents on routes and rates of metabolism in rat isolated hepatocytes (ii) to investigate the enzymology of the metabolism and whether it was affected by the various substitutions and (iii) to see whether information obtained from hepatocytes was predictive of in vivo metabolism. For 13 of the compounds, the major route of metabolism in hepatocytes was N-dealkylation as determined by LC/MS and LC/MS/MS. For 5-F-8-OH-DPAT, direct glucuronide conjugation was the major metabolic route although N-dealkylation (followed by glucuronidation) was again important. Minor routes of metabolism were hydroxylation in the aromatic ring, saturated ring or on the propyl side-chains. The presence of electron withdrawing substituents on the aromatic ring tended to protect against aromatic hydroxylation. The rate of metabolism (intrinsic clearance relative to that of DPAT) varied approximately 10-fold across the series. This 'relative metabolic stability' correlated with experimentally determined values of log D indicating that lipophilicity was a major determinant of the rate of metabolism. The metabolism of 5-F-8-OH-DPAT was much faster than was predicted by the correlation as a result of rapid glucuronidation. P450 2B1 was the major isoform responsible for metabolism of the aminotetralins in hepatic microsomes from phenobarbital pretreated rats, with a smaller contribution from P450 3A. Inhibition studies in hepatocytes from control animals indicated the involvement of 2C6 and 3A. Hepatocytes were generally predictive of the urinary metabolites of the aminotetralins following single oral administration to rats.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors : Martin, Iain J.
Date : 1996
Additional Information : Thesis (Ph.D.)--University of Surrey (United Kingdom), 1996.
Depositing User : EPrints Services
Date Deposited : 06 May 2020 13:07
Last Modified : 06 May 2020 13:11
URI: http://epubs.surrey.ac.uk/id/eprint/855929

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