Metabolism of tiaramide in vitro. I. Oxidative metabolism of tiaramide by human and rat liver microsomes.
1. N-Dealkylation and N-oxidation of tiaramide and of its major metabolite, TRAA, by human and rat liver microsomes were investigated. 2. With human liver microsomes, N-oxidation of tiaramide was 1.5-8.0 times faster than N-dealkylation. N-Oxidation of the metabolite, TRAA, by human liver microsomes was much slower than that of tiaramide. The high recovery of tertiary amine N-oxides in human urine after tiaramide dosing reflects the high activity of N-oxidation of tiaramide by human liver microsomes. 3. Phenobarbital treatment of rats caused an increase in the liver microsomal N-dealkylation of tiaramide in vitro, but had little effect on N-oxidation. 3-Methylcholanthrene treatment of rats caused decrease of both reactions. 4. Metyrapone added to rat liver microsomes inhibited N-dealkylation more strongly than N-oxidation. Tetrahydrofuran and 7,8-benzoflavone inhibited N-dealkylation but had little effect on N-oxidation. Addition to the microsomal incubations of antisera against NADPH-cytochrome c reductase caused marked inhibition of N-dealkylation and slight inhibition of N-oxidation.
D000818:Animals; D052160:Benzothiazoles; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D052160:Benzothiazoles; D010879:Piperazines; D008748:Methylcholanthrene; C003468:tiaramide; D006899:Mixed Function Oxygenases; D010634:Phenobarbital