Abstract
Grapefruit juice (GFJ) and naringin when consumed previously or together with medications may alter their bioavailavility and consequently the clinical effect. Ifosfamide (IF) is an antitumoral agent prescribed against various types of cancer. Nevertheless, there is no information regarding its interaction with the ingestion of GFJ or naringin. The aims of the present report were validating a method for the quantitation of IF in the plasma of mouse, and determine if mice pretreated with GFJ or naringin may modify the IF pharmacokinetics. Our HPLC results to quantify IF showed adequate intra and inter-day precision (RSD < 15%) and accuracy (RE < 15%) indicating reliability. Also, the administration of GFJ or naringin increased Cmax of IF 22.9% and 17.8%, respectively, and decreased Tmax of IF 19.2 and 53.8%, respectively. The concentration of IF was higher when GFJ (71.35 ± 3.5 µg/mL) was administered with respect to that obtained in the combination naringin with IF (64.12 ± µg/mL); however, the time required to reach such concentration was significantly lower when naringin was administered (p < 0.5). We concluded that pre-administering GFJ and naringin to mice increased the Tmax and decreased the Cmax of IF.
Highlights
Grapefruit juice (GFJ) and naringin when consumed previously or together with medications may alter their bioavailavility and the clinical effect
Both agents (GFJ and naringin) have shown the capacity to modify the pharmacokinetic parameters of numerous medications when ingested together with, or close to the consumption of the juice or of the flavanone
For the present report it seems pertinent to mention that in mouse it has been described the expression of the enzyme CYP3A11, which correspond to the human CYP3A4 representative[27], and that even though the metabolic differences, pharmacokinetic studies in mouse have human clinical relevance, because mouse most closely approximates the determination of pharmacokinetic measures in humans than other in vivo or in vitro model, showing a linearity response greater than 0.94% respect to human studies[28,29]
Summary
Grapefruit juice (GFJ) and naringin when consumed previously or together with medications may alter their bioavailavility and the clinical effect. The intervention of GFJ and naringin in such processes has been found in various in vitro and in vivo assays, as well as in computational modeling studies These studies have suggested at least two mechanisms involved to explain the observed effects: the inhibition of intestinal enzymes (mainly CYP3A) to decrease the rate of pre-systemic metabolism, and to increase the bioavailability of the involved drug[20,21], and alterations in molecular transporters, such as the organic anion-transporting polypeptide 2B1 (OATP2B1), the multidrug-resistant protein sulfotransferases 1 and 3, and the P-glycoprotein transporter[22,23]. For the present report it seems pertinent to mention that in mouse it has been described the expression of the enzyme CYP3A11, which correspond to the human CYP3A4 representative[27], and that even though the metabolic differences, pharmacokinetic studies in mouse have human clinical relevance, because mouse most closely approximates the determination of pharmacokinetic measures in humans than other in vivo or in vitro model, showing a linearity response greater than 0.94% respect to human studies[28,29]
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