Interaction between apigenin and sodium deoxycholate with raloxifene: A potential risk for clinical practice

Abstract

Apigenin (API) and sodium deoxycholate (NaDC) have different pharmacodynamic properties and can affect pharmacokinetics of drugs without causing significant toxicity. The aim of our study was to investigate the effect of API and NaDC on raloxifene pharmacokinetics in rats as well as on hemostasis parameters after applying the raloxifene therapeutic dose. Rats were treated daily with oral single dose of saline solution (1 ml/kg), API (10 mg/kg) and/or NaDC (4 mg/kg) for 7 days. Raloxifene was given orally or intravenously in a single dose (6 mg/kg) and during period of 24 h blood samples, feces and urine samples were collected. Blood samples were collected at the 15th, 30th, 45th, 60th, 90th minute and 2, 3, 4, 6, 8, 10, 12 and 24 h after raloxifene administration. Urine and feces samples were collected in the 3th, 6^h, 12th and 24th hour of the experiment. Rats were divided into 10 groups each of which contained 6 animals. Differences were considered statistically significant if p<0.05. Pretreatment with NaDC and API affected raloxifene pharmacokinetic profile after intravenous application. NaDC lead to statistically significant decrease in raloxifene serum concentration and increased volume of distribution and clearance as well as halftime of elimination, while API has also decreased also raloxifene serum concentrations and increased volume of distribution but not as profoundly as NaDC alone. Difference was also noticed in clearance where it was significantly increased in group pretreated with NaDC and slightly decreased in group pretreated with API. NaDC and API increased raloxifene amount in feces, both after peroral (p<0.05) and intravenous application. However, peroral application of raloxifene did not produce measurable raloxifene serum concentration in neither of investigated groups. NaDC shortened activated partial thromboplastin time (aPTT) and prothrombin time (PT). API reduced aPTT, PT and d-dimer level. Fibrinogen level was significantly increased in all experimental groups. Both NaDC and apigenin had significant influence on raloxifene pharmacokinetics and can potentiate the raloxifene effects on hemostasis parameters, by increasing its bioavailability. These substances may be the subject of further investigation into the formulation of raloxifene and other medicines as depot preparations, which could prolong the dosing interval and thus improve patient compliance and quality of life.

Keywords: Apigenin; Hemostasis parameters; Raloxifene; Sodium deoxycholate.