The Pharmacokinetics of Raloxifene and Its Interaction with Apigenin in Rat

Abstract

Purpose: Raloxifene is a selective estrogen receptor modulator which is structurally similar to tamoxifen. As flavonoids can interact with raloxifene in vitro, we evaluated the in vivo pharmacokinetics of raloxifene in rats when co-administered with apigenin. Methods: The pharmacokinetics of raloxifene in the absence or presence of apigenin was investigated in rats after different dosage regimens. The plasma concentrations before and after enzymatic hydrolysis were analyzed by HPLC, and the pharmacokinetic profiles of raloxifene administered alone and in combination with apigenin were compared. Results: Co-administration of apigenin with raloxifene in a 1:2 ratio by weight resulted in a 55% and 37% increase in the Cmax and AUC of intact raloxifene, respectively. When equal proportions of raloxifene and apigenin (1:1) were administered, the Cmax and AUC of intact raloxifene were increased by 173% and 97% respectively. This increase in intact raloxifene was not associated with an increase in total raloxifene (intact plus conjugated raloxifene) because AUC and Cmax of total raloxifene when administered alone or in combination with apigenin were found to be similar. The results indicated that apigenin inhibited the glucuronidation and sulfation of raloxifene in the intestine bringing about an increased bioavailability of the drug. Conclusions: The results showed that apigenin decreased the first-pass metabolism of raloxifene but did not increase its absorption from the gastrointestinal tract.

LC-UV method to assay raloxifene hydrochloride in rat plasma and its application to a pharmacokinetic study

“…Yang et al (2007) validated a LC-UV method to determine raloxifene in rat plasma in a pharmacokinetic study, reporting a limit of quantification of 0.20 µg.mL -1 iD using 23 ºC as column temperature. On the other hand, Chen et al (2010) conducted a RH pharmacokinetic study in rats based on a LC-UV method using a gradient elution of the mobile phase and a limit of quantification of 0.56 µg.mL -1 . However, to the best of our knowledge, simple and inexpensive pharmacokinetic analytical methods with low limits of quantification and excellent accuracy for the analysis of RH in biological samples have not been designed.…”

“…In addition, Ravi, Aditya and Vats (2012) developed a LC-UV method to estimate RH levels in rabbit plasma with a limit of quantification of 0.05 µg.mL -1 . It is important to highlight that these methods (Yang et al, 2007;Chen et al, 2010;Ravi, Aditya, Vats, 2012) were based on a protein precipitation technique to extract the drug from rat or rabbit plasma.…”

Quantitative prediction and clinical evaluation of an unexplored herb–drug interaction mechanism in healthy volunteers

“…This framework has been applied to interactions mediated via inhibition of cytochrome P450 enzymes, but investigation of alternate mechanisms that underlie herb–drug interactions remain relatively unexplored. Inhibition of intestinal UDP‐glucuronosyl transferases (UGTs) represents one such potential mechanism based on in vitro and animal studies . Taken together, a PBPK modeling and simulation approach was expanded by applying to a an herb–drug interaction mediated via inhibition of intestinal glucuronidation, a mechanism not previously evaluated in humans.…”

“…Inhibition of intestinal UDP-glucuronosyl transferases (UGTs) represents one such potential mechanism 3,4 based on in vitro and animal studies. 3,[5][6][7][8][9][10][11][12][13][14][15] Taken together, a PBPK modeling and simulation approach 2 was expanded by applying to a an herb-drug interaction mediated via inhibition of intestinal glucuronidation, a mechanism not previously evaluated in humans.…”

Nanoemulsion liquid preconcentrates for raloxifene hydrochloride: optimization and in vivo appraisal

“…Due to the absorption and disposition of flavonoids being similar to that of RLX in enterocytes, apigenin competitively inhibited the formation of RLX glucuronide and RLX sulfate in the gut; therefore, apigenin could improve the absorption fraction of intact RLX from intestine during transport across monolayer enterocyte. 13 Metabolic inhibition and kinetic RLX by bioactive excipients have been investigated by Kim et al 14 Their study aimed at modulating poorly bioavailable drugs via decreasing the first-pass metabolism in gastrointestinal tract and liver and inhibition of P-gp efflux transporters. Nonionic surfactants such as Cremophor EL and Tween 80 have demonstrated significant inhibition of RLX metabolism with different mechanisms of action.…”