Effects of pomegranate juice on human cytochrome P450 2C9 and tolbutamide pharmacokinetics in rats.
In this study, we investigated whether pomegranate juice could inhibit CYP2C9 activity. The ability of pomegranate juice to inhibit the diclofenac 4'-hydroxylase activity of human CYP2C9 was examined using human liver microsomes. Pomegranate juice was shown to be a potent inhibitor of human CYP2C9. The addition of 25 microl (5% v/v) of pomegranate juice resulted in almost complete inhibition of human CYP2C9 activity. In addition, we investigated the effect of pomegranate juice on the pharmacokinetics of tolbutamide (substrate for CYP2C9) in rats. Relative to the control group, the area under the concentration-time curve was approximately 1.2-fold greater when pomegranate juice (3 ml) was injected p.o. 1 h before the p.o. administration of the tolbutamide (20 mg/kg). The elimination half-life of tolbutamide was not altered by pomegranate juice administration. These results suggest pomegranate juice ingestion inhibits the intestinal metabolism of tolbutamide without inhibiting the hepatic metabolism in rats. Thus, we discovered that pomegranate juice inhibited human CYP2C9 activity and furthermore increased tolbutamide bioavailability in rats.
Nagata
Masashi
M
School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka City, Miyazaki, 882-8508, Japan. m-nagata@phoenix.ac.jp
Hidaka
Muneaki
M
Sekiya
Hiroshi
H
Kawano
Yohei
Y
Yamasaki
Keishi
K
Okumura
Manabu
M
Arimori
Kazuhiko
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D001628:Beverages; D001682:Biological Availability; D065729:Cytochrome P-450 CYP2C9; D018565:Food-Drug Interactions; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D029561:Lythraceae; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014044:Tolbutamide / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007004:Hypoglycemic Agents; D014044:Tolbutamide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases