*3.4. Pharmacokinetic Study*

The mean arterial plasma concentration–time profiles of fexofenadine after the pharmacokinetic study of fexofenadine in a rat drug interaction model, are shown in Figure 5. The pharmacokinetic parameters of fexofenadine after oral coadministration of vehicle, emodin and *R. acetosa* extract are shown in Table 1. The area under the plasma concentration–time curve (AUC) values of fexofenadine were 222.0 ± 85.5 ng·h/mL in the control group and 411.9 ± 189.1 ng·h/mL in the emodin coadministered group. In the emodin group, the absorption of fexofenadine was significantly higher, with a larger fexofenadine AUC and no di fference in Tmax. However, the fexofenadine AUC was lower, with a value of 132.0 ± 50.5 ng·h/mL, in the 2 g/kg *R. acetosa* extract coadministered group. Because fexofenadine is characterized by limited metabolism, it is probable that the lower fexofenadine AUC is due to the inhibitory e ffect of *R. acetosa* extract on absorption. Consequently, *R. acetosa* extract could inhibit the absorption of fexofenadine. Together with the results of the in vitro assay, this suggests that *R. acetosa* extract inhibits the intracellular uptake of fexofenadine via an intervention in OATP1A2.

**Figure 5.** Mean plasma concentration–time profiles of fexofenadine (ng/mL) after oral coadministration of fexofenadine (10 mg/kg) with vehicle (•; *n* = 6), emodin (11 mg/ kg, -; *n* = 6) and *R. acetosa* extract (2 g/kg, -; *n* = 6) to rats. Bars represent standard deviations.

**Table 1.** Pharmacokinetic parameters of fexofenadine after oral coadministration of fexofenadine (10 mg/kg) with vehicle (control), emodin and *R. acetosa* extract to rats. Values represent means ± standard deviations for AUC0-24 h and Cmax (ng/mL), median (range) for Tmax.


AUC0-24 h, total area under the plasma concentration–time curve from time zero to 24 h; Cmax—maximum plasma concentration; Tmax—time to reach Cmax; \*—*p* < 0.05 compared to vehicle only control group.

#### *3.5. Physicochemical Interaction Study*

To evaluate the possible physicochemical interactions between *R. acetosa* extract and fexofenadine, FT-IR spectra of extract, fexofenadine and mixture were measured and are shown in Figure 6. The FT-IR spectrum of fexofenadine HCl showed the characteristic absorption bands at 3291.03 (OH stretching), 2936.14 (CH stretching), 2639.82 (OH of carboxylate), 1698.68 (CO stretching), 1448.00, 1403.11 (C=C stretching of aromatic ring), 1167.57 (CO stretching of tertiary alcohol) and 1067.94 (CO stretching of secondary alcohol) [38,39]. According to Figure 6, the mixture of *R. acetosa* extract and fexofenadine HCl showed the same bands compared to the pure fexofenadine HCl. It suggests that there is no significant physical interaction between fexofenadine molecule and *R. acetosa* extract component on fexofenadine functional groups.

**Figure 6.** FT-IR spectra of (**A**) fexofenadine, (**B**) a mixture of fexofenadine and *R. acetosa* extract and (**C**) *R. acetosa* extract.

However, there was significant di fference on the solubility of fexofenadine after incubation with the extract (Table 2). The average solubilities of fexofenadine in SIF were 1.03 ± 0.04 mg/mL and 0.83 ± 0.10 mg/mL without and with *R. acetosa* extract, respectively. This result indicates that *R. acetosa* extract could alter the solubility of fexofenadine and lead to precipitation in gastro-intestinal tract.

**Table 2.** The solubility of fexofenadine HCl in simulated intestinal fluid (SIF) with and without *R. acetosa* extract.

