Evaluation of Drug-diet interaction between Psidium guajava (Guava) fruit and Metoclopramide
Abstract
Studies have showed that phytochemicals present in fruit juices alter the oral bioavailability of drugs by inhibition of metabolising enzymes and transport proteins. The present study aimed to investigate the effect of Psidium guajava on the oral exposure of metoclopramide in rabbits. Pharmacokinetic parameters of metoclopramide were determined in rabbits following an oral (0.5mg/kg) administration of metoclopramide in the presence and absence of Psidium guajava (5mL/kg, given orally). Compared to the control group given metoclopramide alone, the combined use of Psidium guajava increased the oral exposure (AUC) of metoclopramide by 13% with a corresponding 177 % increase in Cmax and half-life (71%). Furthermore, Tmax decreased from 2h to 1h which might have contributed to the elevated plasma drug concentration in the first two hours in the presence of Psidium guajava. There was a significant increase in Cmax (177%) and Ka (207%) which could be attributed to enhanced absorption via inhibition of P-gp resulting to increased bioavailability of the drug. In contrast, there was a significant decrease in elimination rate (88%) and a decrease in clearance rate (17%) attributable to inhibitor of P450 enzymes (CYP2D6) by the phytochemical constituents. Psidium guajava enhanced the oral exposure of metoclopramide in rabbits likely by the inhibition of P-glycoprotein-mediated efflux during the intestinal absorption and inhibition of P450 enzyme system during metabolism, suggesting that the combined use of Psidium guajava or Psidium guajava-containing diet with metoclopramide may require close monitoring for potential drug–diet interactions.
Keywords: metoclopramide, Psidium guajava, diet–drug interaction, P-glycoprotein, P450 enzymes.
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References
2. Evans AM: Influence of dietary components on the gastrointestinal metabolism and transport of drugs. Ther Drug Monit 2000; 22:131–136.
3. Mallhi TH, Sarriff A, Adnan AS, Khan YH, Qadir MI, Hamza AA, Khan AH: Effect of Fruit/Vegetable-Drug Interactions on CYP450, OATP and p-Glycoprotein: A Systematic Review. Tropical Journal of Pharmaceutical Research 2015; 14:1927-1935.
4. Rodríguez‐Fragoso L, Martínez‐Arismendi JL, Orozco‐Bustos D, Reyes‐Esparza J, Torres E, Burchiel SW: Potential Risks Resulting from Fruit/Vegetable– Drug Interactions: Effects on Drug‐Metabolizing Enzymes and Drug Transporters. J Food Sci 2011; 76:R112-R124.
5. Radwan AM, Determination of metoclopramide in serum by HPLC assay and its application to pharmacokinetic study in rats. Analytical letters 1998; 31:2397-2410.
6. Jouad H, Haloui M, Rhiouani H, El Hilaly J, Eddouks M: Ethnobotanical survey of medicinal plants used for the treatment of diabetes, cardiac and renal diseases in the North centre region of Morocco (Fez-Boulemane). J Ethnopharmacol 2001; 77:175–82.
7. de Wet H, Nkwanyana MN, van Vuuren SF: Medicinal plants used for the treatment of diarrhoea in northern Maputaland, KwaZulu-Natal Province, South Africa. J Ethnopharmacol 2010; 130:284–289.
8. Qian H, Nihorimbere V: Antioxidant power of phytochemicals from Psidium guajava leaf. J Zhejiang Univ Sci 2004; 5:676–683.
9. Junyaprasert VB, Soonthornchareonnon N, Thongpraditchote S, Murakami T, Takano M: Inhibitory effect of Thai plant extracts on P-glycoprotein mediated efflux. Phytother Res 2006; 20:79–81.
10. Nwafor SV, Esimone CO, Amadi CA, Nworu CS: In vivo interaction between ciprofloxacin hydrochloride and the pulp of unripe plantain (Musa paradisiaca). Eur J Drug Metab Pharmacokinet 2003; 28:253-258.
11. Cossu M, Sanna V, Gavin E, Rassu G, Giunchedi PA: New Sensitive Reversed-phase High- performance Liquid Chromatography Method for the Quantitative Determination of Metoclopramide in Canine Plasma. Analytical Letters 2008; 41:767–778.
12. Kunta JR, Sinko, PJ: Intestinal drug transporters: In vivo function and clinical importance. Current Drug Metabolism, 2004; 5:109–124.
13. Kim RB: Organic anion-transporting polypeptide (OATP) transporter family and drug disposition. European Journal of Clinical Investigation 2003; 33:1–5.
14. Greenblatt DJ: Analysis of drug interactions involving fruit beverages and organic anion transporting polypeptides. Journal of Clinical Pharmacology 2009; 49:1403–1407.
15. Kamath AV, Yao M, Zhang Y, Chong S: Effect of Fruit Juices on the Oral Bioavailability of Fexofenadine in Rats. Journal of Pharmaceutical Science 2004; 94:233–239.
16. Bailey DG, Malcolm J, Arnold O, Spence JD: Grapefruit juice – drug interactions. Br J Clin Pharmacol 1998; 46:101–110.
17. Dresser GK, Bailey DG: The effects of fruit juices on drug disposition: A new model for drug interactions. Eur J Clin Invest 2003; 33:10–16.
18. Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA, Brown MB, Guo W, Watkins PB: Grapefruit Juice increases felodipine oral availability in humans by decreas- ing intestinal CYP3A4 protein expression. J Clin Invest 1997; 99:2545–2553.
19. Desta Z, Wu GM, Morocho AM, Flockhart DA: The gastroprokinetic and antiemetic drug metoclopramide is a substrate and inhibitor of cytochrome P450 2D6. Drug metab Dispos 2002; 30:336-343.
20. Pottier, G., Marie, S., Goutal, S., Auvity, S., Peyronneau, M.A., Stute, S., Boisgard, R., Dolle, F., Buvat, I., Caile, F., Tournier, N:Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide. Journal of Nuclear Medicine 2016, 57:309-314.
21. Livezey MR, Briggs ED, Bolles AK, Nagy LD, Fujiwara R, Furge LL: Metoclopramide is metabolized by CYP2D6 and is a reversible inhibitor, but not inactivator, of CYP2D6. Xenobiotica 2014; 44:309-319.

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