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Effect of Ginkgo Leaf Tablets on the Pharmacokinetics of Amlodipine in Rats

  • Original Research Article
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Abstract

Background and Objective

Ginkgo leaf tablet (GLT) is an effective traditional Chinese multi-herbal formula, which is often combined with amlodipine for treating senile hypertension in clinic. The aim of this study was to study the pharmacokinetics of amlodipine after oral administration of amlodipine and GLT and to investigate the potential for pharmacokinetic herb–drug interactions between GLT and amlodipine in rats.

Methods

A liquid chromatography-tandem mass spectrometry (LC–MS/MS) analytical method was developed for quantification of amlodipine in rat plasma. The accuracy, precision, linearity, selectivity and recovery were all within an acceptable range. Male Sprague–Dawley rats were randomly assigned to two groups: amlodipine group and amlodipine + GLT group. Plasma concentrations of amlodipine were determined at the designated time points after oral administration by using the developed LC–MS/MS method, and the main pharmacokinetic parameters were calculated and compared. As ginkgolides A, ginkgolides B, bilobalide, quercetin and kaempferol were the main components of GLT, the effects of these ingredients in GLT on metabolism of amlodipine were further investigated in rat liver microsomes.

Results

The pharmacokinetic parameters, maximum plasma concentration (C max), time to reach C max (T max), area under the concentration-time curve (AUC), area under the first moment plasma concentration–time curve (AUMC) and elimination half-life (t 1/2), of amlodipine were significantly increased in amlodipine + GLT group, which suggested that GLT may influence the pharmacokinetic behavior after oral co-administration with amlodipine. Amlodipine is metabolized by cytochrome P450 (CYP) 3A4, so it was speculated that GLT may change the pharmacokinetic parameters of amlodipine through modulating the metabolism of CYP3A4 enzymes. When ginkgolides B, bilobalide, or quercetin and amlodipine were co-incubated in the rat liver microsomes, the metabolic rate of amlodipine was prolonged to 533.1, 216.1 and 407.6 min, respectively, from 73.7 min.

Conclusions

These results suggested that these components in GLT inhibit the metabolism of amlodipine. So it can be speculated that the herb–drug interactions between GLT and amlodipine resulted from inhibiting the metabolism of amlodipine by GLT when they were co-administered.

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References

  1. Adake P, Somashekar HS, Mohammed-Rafeeq PK, Umar D, Basheer B, Baroudi K. Comparison of amlodipine with cilnidipine on antihypertensive efficacy and incidence of pedal edema in mild to moderate hypertensive individuals: a prospective study. J Adv Pharm Technol Res. 2015;6(2):81–5.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Agrawal H, Aggarwal K, Littrell R, Velagapudi P, Turagam MK, Mittal M, et al. Pharmacological and non pharmacological strategies in the management of coronary artery disease and chronic kidney disease. Curr Cardiol Rev. 2015;11(3):261–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Fraser LA, Shariff SZ, McArthur E, Naylor KL, Garg AX. Calcium channel blocker-clarithromycin drug interaction did not increase the risk of nonvertebral fracture: a population-based study. Ann Pharmacother. 2015;49(2):185–8.

    Article  CAS  PubMed  Google Scholar 

  4. Zhu Y, Wang F, Li Q, Zhu M, Du A, Tang W, et al. Amlodipine metabolism in human liver microsomes and roles of CYP3A4/5 in the dihydropyridine dehydrogenation. Drug Metab Dispos: Biol Fate Chem. 2014;42(2):245–9.

    Article  CAS  Google Scholar 

  5. Zuo XC, Zhou YN, Zhang BK, Yang GP, Cheng ZN, Yuan H, et al. Effect of CYP3A5*3 polymorphism on pharmacokinetic drug interaction between tacrolimus and amlodipine. Drug Metab Pharmacokinet. 2013;28(5):398–405.

    Article  CAS  PubMed  Google Scholar 

  6. Atalay Y, Bozkurt MF, Gonul Y, Cakmak O, Agacayak KS, Kose I, et al. The effects of amlodipine and platelet rich plasma on bone healing in rats. Drug Des Devel Ther. 2015;7(9):1973–81.

    Article  Google Scholar 

  7. Mancia G. Comparison of single-pill strategies first line in hypertension: perindopril/amlodipine versus valsartan/amlodipine. J Hypertens. 2015;33(5):1115–6.

    Article  CAS  PubMed  Google Scholar 

  8. Yun CH, Lee HS, Lee H, Rho JK, Jeong HG, Guengerich FP. Oxidation of the angiotensin II receptor antagonist losartan (DuP 753) in human liver microsomes. Role of cytochrome P4503A(4) in formation of the active metabolite EXP3174. Drug Metab Dispos: Biol Fate Chem. 1995;23(2):285–9.

    CAS  Google Scholar 

  9. Zhang XF, Liu J, Ye F, Ji SG, Zhang N, Cao RS, et al. Effects of triptolide on the pharmacokinetics of cyclophosphamide in rats: a possible role of cytochromeP3A4 inhibition. Chin J Integr Med. 2014;20(7):534–9.

    Article  CAS  PubMed  Google Scholar 

  10. Zaidenstein R, Soback S, Gips M, Avni B, Dishi V, Weissgarten Y, et al. Effect of grapefruit juice on the pharmacokinetics of losartan and its active metabolite E3174 in healthy volunteers. Ther Drug Monit. 2001;23(4):369–73.

    Article  CAS  PubMed  Google Scholar 

  11. Li J, Wu XL, Chen Y, Tang Z, Xu YH, Jiang JM, et al. Antidiarrheal properties of different extracts of Chinese herbal medicine formula Bao-Xie-Ning. J Integr Med. 2013;11(2):125–34.

    Article  PubMed  Google Scholar 

  12. Li XS, Zheng WY, Lou SX, Lu XW, Ye SH. Effect of Ginkgo leaf extract on vascular endothelial function in patients with early stage diabetic nephropathy. Chin J Integr Med. 2009;15(1):26–9.

    Article  PubMed  Google Scholar 

  13. Mi XS, Zhong JX, Chang RCC, So KF. Research advances on the usage of traditional Chinese medicine for neuroprotection in glaucoma. J Integr Med. 2013;11(4):233–40.

    Article  PubMed  Google Scholar 

  14. Song J, Fang G, Zhang Y, Deng Q, Wang S. Fingerprint analysis of Ginkgo biloba leaves and related health foods by high-performance liquid chromatography/electrospray ionization-mass spectrometry. J AOAC Int. 2010;93(6):1798–805.

    CAS  PubMed  Google Scholar 

  15. Li XN, Yang JY, Pan X, Zhao S, Zhang CY, Zhu DY, et al. Influence of extract of Ginkgo biloba leaves tablets on the aquaporin-1 expression in isolated lung ischemia reperfusion. Chin Med J. 2013;126(24):4720–3.

    CAS  PubMed  Google Scholar 

  16. Shi YB, Li HL, Wang HQ, Yang YB, Zhang XY, Wang H, et al. Simultaneous determination of five anthraquinones in a Chinese traditional preparation by RP-HPLC using an improved extraction procedure. J Integr Med. 2014;12(5):455–62.

    Article  PubMed  Google Scholar 

  17. He Y, Si D, Yang C, Ni L, Li B, Ding M, et al. The effects of amlodipine and S(−)-amlodipine on vascular endothelial function in patients with hypertension. Am J Hypertens. 2014;27(1):27–31.

    Article  CAS  PubMed  Google Scholar 

  18. Witte S, Anadere I, Walitza E. Improvement of hemorheology with ginkgo biloba extract. Decreasing a cardiovascular risk factor. Fortschr Med. 1992;110(13):247–50.

    CAS  PubMed  Google Scholar 

  19. Yang SH, Cho YA, Choi JS. Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in rats. Acta Pharmacol Sin. 2011;32(7):967–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yang SH, Choi JS, Choi DH. Effects of HMG-CoA reductase inhibitors on the pharmacokinetics of losartan and its main metabolite EXP-3174 in rats: possible role of CYP3A4 and P-gp inhibition by HMG-CoA reductase inhibitors. Pharmacology. 2011;88(1–2):1–9.

    Article  CAS  PubMed  Google Scholar 

  21. Yang XX, Hu ZP, Duan W, Zhu YZ, Zhou SF. Drug–herb interactions: eliminating toxicity with hard drug design. Curr Pharm Des. 2006;12(35):4649–64.

    Article  CAS  PubMed  Google Scholar 

  22. Wrighton SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol. 1992;22(1):1–21.

    Article  CAS  PubMed  Google Scholar 

  23. Zhang JW, Liu Y, Cheng J, Li W, Ma H, Liu HT, et al. Inhibition of human liver cytochrome P450 by star fruit juice. J Pharm Pharm Sci. 2007;10(4):496–503.

    Article  PubMed  Google Scholar 

  24. Manda VK, Avula B, Ali Z, Wong YH, Smillie TJ, Khan IA, et al. Characterization of in vitro ADME properties of diosgenin and dioscin from Dioscorea villosa. Planta Med. 2013;79(15):1421–8.

    Article  CAS  PubMed  Google Scholar 

  25. Zhou S, Chan E, Li SC, Huang M, Chen X, Li X, et al. Predicting pharmacokinetic herb–drug interactions. Drug Metabol Drug Interact. 2004;20(3):143–58.

    Article  CAS  PubMed  Google Scholar 

  26. Li AP. Screening for human ADME/Tox drug properties in drug discovery. Drug Discov Today. 2001;6(7):357–66.

    Article  CAS  PubMed  Google Scholar 

  27. Qi XY, Liang SC, Ge GB, Liu Y, Dong PP, Zhang JW, et al. Inhibitory effects of sanguinarine on human liver cytochrome P450 enzymes. Food Chem Toxicol. 2013;56:392–7.

    Article  CAS  PubMed  Google Scholar 

  28. Qin CZ, Ren X, Tan ZR, Chen Y, Yin JY, Yu J, et al. A high-throughput inhibition screening of major human cytochrome P450 enzymes using an in vitro cocktail and liquid chromatography-tandem mass spectrometry. Biomed Chromatogr. 2014;28(2):197–203.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This project was supported by the Foundation of Shanghai Municipal Commission of Health and Family Planning (Grant No. 20144Y0239), and the Foundation of Shanghai Jiao Tong University School of Medicine (Grant No. 14XJ10067).

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Author notes

    Authors and Affiliations

    1. Department of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Rd, Shanghai, 200011, China

      Rong Wang, Yuanyuan Wang & Yongfang Yuan

    2. Department of Pharmacy, Eastern Hepatobiliary Surgery Hospital, School of Pharmacy, Second Military Medical University, Shanghai, 200438, China

      Hai Zhang & Sen Sun

    3. Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China

      Yifeng Chai

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    1. Rong Wang
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    2. Hai Zhang
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    Correspondence to Yongfang Yuan.

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    RW, HZ, SS, YW, YC and YY declare no conflict of interest.

    Ethical approval

    This animal experimental protocol was approved by the Animal Ethics Committee of the Second Military Medical University (Shanghai, China).

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    R. Wang and Hai Zhang have contributed equally to this work.

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    Wang, R., Zhang, H., Sun, S. et al. Effect of Ginkgo Leaf Tablets on the Pharmacokinetics of Amlodipine in Rats. Eur J Drug Metab Pharmacokinet 41, 825–833 (2016). https://doi.org/10.1007/s13318-015-0312-3

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