RT Journal Article
SR Electronic
T1 Involvement of CYP2J2 on the Intestinal First-Pass Metabolism of Antihistamine Drug, Astemizole
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1240
OP 1245
DO 10.1124/dmd.30.11.1240
VO 30
IS 11
A1 Shigeki Matsumoto
A1 Tomoe Hirama
A1 Tsutomu Matsubara
A1 Kiyoshi Nagata
A1 Yasushi Yamazoe
YR 2002
UL http://dmd.aspetjournals.org/content/30/11/1240.abstract
AB Orally administered astemizole is well absorbed but undergoes an extensive first-pass metabolism toO-desmethylastemizole. Desmethylastemizole is formed in the human microsomal systems of the small intestine as well as the liver, which suggests the role of cytochromes P450 (P450s) in the first-pass metabolism of astemizole. Human P450s involved in theO-demethylation of astemizole have, however, not been identified, and the involvement of twelve known drug-metabolizing P450s were denied. During the course of the P450 identification study, higher activities of the astemizole O-demethylation in the rabbit small intestine than in the liver (about 3-fold) were found. These data suggest the possible involvement of CYP2J, since P450 included in this subfamily is dominantly expressed in the small intestine of rabbits. Therefore, CYP2J2 cDNA has been isolated from the human cDNA library and expressed in COS-1 cells. A clear activity of astemizole O-demethylation was detected in recombinant CYP2J2 with Km = 0.65 μM and Vmax = 1129 pmol/nmol P450/min. Expression of the immunoreactive protein with CYP2J2 antibody was detected in the small intestine and liver. Expression levels of the immunoreactive protein with the CYP2J2 antibody in the small intestine were well correlated with the activities of the astemizoleO-demethylation (r = 0.901,n = 5, p < 0.05). The CYP2J2 substrates, arachidonic acid and ebastine, strongly inhibited the microsomal astemizole O-demethylation in the human small intestines and recombinant CYP2J2. These results indicate the involvement of CYP2J2 in the presystemic elimination of astemizole in the human small intestine. The American Society for Pharmacology and Experimental Therapeutics