2001 Volume 16 Issue supplement Pages 82-83
Human intestinal microsomes were found to catalyze dealkylation and hydroxylation of an antihistamine ebastine and the former was shown to be mediated by intestinal CYP3A. Ebastine hydroxylase was purified from monkey intestinal microsomes and it was identified as a CYP4F isoform by the amino acid sequence. CYP4F cDNAs were then cloned from human intestine and expressed in yeast. A novel CYP4F (4F12) only exhibited the high activity of the hydroxylation, however, its actual contribution in human microsomes was only partial (about 20%) when judged by immunoinhibition study using anti-CYP4F antibody. From a marked inhibition of ebastine hydroxylation by arachidonic acid, CYP2J2 was speculated to involve in the hydroxylation. In fact, anti-CYP2J antibody inhibited 70% of ebastine hydroxylation. The finding above that human intestinal CYP2J and CYP4F as well as CYP3A play an important role in the drug metabolism extends the concept of studies of the drug metabolism in the intestine, the organ being enrolled in the first pass effect.
