Effects of morin pretreatment on the pharmacokinetics of diltiazem and its major metabolite, desacetyldiltiazem in rats.
The purpose of this study was to investigate the effect of morin, a flavonoid, on the pharmacokinetics of diltiazem and one of its metabolites, desacetyldiltiazem in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined after oral administration of diltiazem (15 mg/kg) in rats pretreated with morin (1.5, 7.5, and 15 mg/kg). Compared with the control group (given diltiazem alone), pretreatment of morin significantly increased the absorption rate constant (Ka) and peak concentration (Cmax) of diltiazem (p<0.05, p<0.01). Area under the plasma concentration-time curve (AUC) of diltiazem in rats pretreated with morin were significantly higher than that in the control group (p<0.05, p<0.01), hence the absolute bioavailability (AB%) of diltiazem was significantly higher than that of the control group (p<0.05, p<0.01). Relative bioavailability (RB%) of diltiazem in rats pretreated with morin was increased by 1.36- to 2.03-fold. The terminal half-life (t1/2) and time to reach the peak concentration (Tmax) of diltiazem were not altered significantly with morin pretreatment. AUC of desacetyldiltiazem was increased significantly (p<0.05) in rats pretreated with morin at doses of 7.5 and 15 mg/ kg, but metabolite-parent ratio (MR) of desacetyldiltiazem was decreased significantly (p<0.05), implying that pretreatment of morin could be effective to inhibit the CYP 3A4-mediated metabolism of diltiazem. There were no apparent changes of Tmax and t1/2 of desacetyldiltiazem with morin pretreatment. Collectively, the pretreatment of morin significantly altered pharmacokinetics of diltiazem, which can be attributed to increased intestinal absorption as well as reduced first-pass metabolism. Based on these results, dose modification should be taken into consideration when diltiazem is used concomitantly with morin or morin-containing dietary supplements in clinical setting.
Choi
Hyun Jin
HJ
College of Pharmacy, Chosun University, 375 Seosuk-Dong, Dong-Gu, Gwangju 501-759, Korea.
Choi
Jun-Shik
JS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics*; D065607:Cytochrome P-450 Enzyme Inhibitors; D019587:Dietary Supplements; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology*; D007408:Intestinal Absorption; D008297:Male; D023421:Models, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D047309:Flavones
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D065607:Cytochrome P-450 Enzyme Inhibitors; D004110:Diltiazem; D005419:Flavonoids; C037769:deacetyldiltiazem; C008548:morin; D047309:Flavones