RT Journal Article
SR Electronic
T1 INHIBITORY EFFECTS OF POMELO ON THE METABOLISM OF TACROLIMUS AND THE ACTIVITIES OF CYP3A4 AND P-GLYCOPROTEIN
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 828
OP 833
DO 10.1124/dmd.32.8.828
VO 32
IS 8
A1 Kanoko Egashira
A1 Hisakazu Ohtani
A1 Suwako Itoh
A1 Noriko Koyabu
A1 Masayuki Tsujimoto
A1 Hideyasu Murakami
A1 Yasufumi Sawada
YR 2004
UL http://dmd.aspetjournals.org/content/32/8/828.abstract
AB We recently reported a case of increase in the blood level of tacrolimus following intake of pomelo in a renal transplant recipient. To clarify the mechanism of this increase in the blood level of tacrolimus, we investigated the effect of pomelo juice extract on the activities of CYP3A4 and P-glycoprotein, in comparison with that of extract of grapefruit juice (GFJ). The 10% ethyl acetate extracts of the juice of three pomelos of different origins (Banpeiyu, pomelo I; Hirado Buntan, pomelo II; and Tosa Buntan, pomelo III) and GFJ significantly inhibited 6β-hydroxylation of testosterone in human liver microsomes by 76.4, 67.2, 37.5, and 83.9%, respectively. The extract of pomelo I was as potent as that of GFJ. The metabolism of tacrolimus itself was also inhibited by the extract of pomelo I, as well as that of GFJ. Furthermore, the inhibition of both 6β-hydroxylation of testosterone and metabolism of tacrolimus by pomelo I and GFJ was preincubation time-dependent. On the other hand, the extract of pomelo I had little effect on the transcellular transport of tacrolimus or [3H]digoxin across a monolayer of LLC-GA5-COL150 cells (a porcine kidney epithelial cell line, LLC-PK1, transfected with human MDR1 cDNA and overexpressing human P-glycoprotein). In conclusion, pomelo constituents inhibit the activity of CYP3A4 and may thereby produce an increase in the blood level of tacrolimus. The American Society for Pharmacology and Experimental Therapeutics