Effects of morin pretreatment on the pharmacokinetics of diltiazem and its major metabolite, desacetyldiltiazem in rats

Abstract

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.

Effects of morin on the pharmacokinetics of etoposide in rats

“…Epidemiologic studies in the USA, Europe and Asia estimated that the daily dietary intake of the isomer of morin, quercetin, is 4-68 mg [16][17][18][19], but there are no reports on the ingestion of morin. Since 3-20 mg/ kg of morin was chosen in several papers for pharmacokinetic studies in rodents [20][21][22], doses of 5 and 15 mg/kg of morin were selected in this paper.…”

Effects of morin on the pharmacokinetics of docetaxel in rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors

“…It has also been reported that morin could be a fairly potent P-gp inhibitor (Zhang and Morris, 2003). Morin altered the total areas under the plasma concentration-time curve from time zero to infinity (AUC) of oral diltiazem (Choi and Choi, 2005), etoposide (Li et al, 2007;Suh, 2011), nicardipine , paclitaxel (Choi et al, 2006), talinolol (Pathak and Udupa, 2010), and tamoxifen (Shin et al, 2008) in rats. Thus, it could be expected that morin could also affect the pharmacokinetics of above drugs in tumor rat model.…”

Pre‐clinical evidence of enhanced oral bioavailability of the P‐glycoprotein substrate talinolol in combination with morin

“…Morin (3,5,7,2 0 ,4 0 -pentahydroxyflavone) is found in the fig and other Moraceae that are used as herbal medicines and exhibits various biological activities including anti-oxidation, anti-mutagenesis and anti-inflammation [3][4][5]. In recent years various articles have been published, in which a modulating effect of morin on drug kinetics was described [6][7][8][9]. In human liver microsomes, the formation of paclitaxel metabolite, 6a-hydroxypaclitaxel (formed by CYP2C8), C3 0 -hydroxypaclitaxel and C2-hydroxypaclitaxel (formed by CYP3A4) were inhibited by morin.…”