PT  - JOURNAL ARTICLE
AU  - Surapaneni, Sekhar S.
AU  - Clay, Michael P.
AU  - Spangle, Larry A.
AU  - Paschal, Jonathan W.
AU  - Lindstrom, Terry D.
TI  - <em>In Vitro</em> Biotransformation and Identification of Human Cytochrome P450 Isozyme-Dependent Metabolism of Tazofelone
DP  - 1997 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 1383--1388
VI  - 25
IP  - 12
4099  - http://dmd.aspetjournals.org/content/25/12/1383.short
4100  - http://dmd.aspetjournals.org/content/25/12/1383.full
SO  - Drug Metab Dispos1997 Dec 01; 25
AB  - Tazofelone is a new inflammatory bowel disease agent. The biotransformation of tazofelone in human livers and the cytochrome P450 responsible for the biotransformation has been studied. Two metabolites of tazofelone were formed in vitro. A sulfoxide metabolite was identified by cochromatography with authentic standards, and a quinol metabolite of tazofelone was identified by mass spectrometry and proton NMR. Sulfoxidation was catalyzed by a single enzyme system while formation of the quinol metabolite was catalyzed by a two enzyme system. The Km andVmax values for sulfoxidation were 12.4 μM and 0.27 nmol/min/mg protein, respectively. The high affinityKm and Vmaxvalues for the formation of the quinol metabolite were 7.5 μM and 0.17 nmol/min/mg protein, respectively. Tazofelone was incubated at 20 μM concentration with human microsomes to determine which of the cytochrome P450 isozyme(s) is involved in the oxidation of tazofelone. A strong correlation was found between the immunoquantified concentrations of CYP3A and the rates of formation of the sulfoxide and quinol metabolites of tazofelone. Similarly, significant correlations were observed between the formation of midazolam 1′-hydroxylation and the rates of formation of both metabolites of tazofelone. Inhibition studies have indicated that triacetyloleandomycin, a CYP3A specific inhibitor, almost completely inhibited the formation of both of these tazofelone metabolites. Incubations with specific cDNA expressed microsomes indicated that the formation of both the sulfoxide and quinol metabolites was highest with CYP3A4 containing microsomes. The correlation data was confirmed by inhibition studies and cDNA expressed cytochrome P450 systems demonstrating that the biotransformation of tazofelone to its metabolites is primarily mediated by CYP3A. The American Society for Pharmacology and Experimental Therapeutics