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Analyzing Potential Intestinal Transporter Drug-Drug Interactions: Reevaluating Ticagrelor Interaction Studies

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Abstract

Purpose

Previous studies evaluating ticagrelor drug-drug interactions have not differentiated intestinal versus systemic mechanisms, which we do here.

Methods

Using recently published methodologies from our laboratory to differentiate metabolic- from transporter-mediated drug-drug interactions, a critical evaluation of five published ticagrelor drug-drug interactions was carried out to investigate the purported clinical significance of enzymes and transporters in ticagrelor disposition.

Results

The suggested CYP3A4 inhibitors, ketoconazole and diltiazem, displayed unchanged mean absorption time (MAT) and time of maximum concentration (Tmax) values as was expected, i.e., the interactions were mainly mediated by metabolic enzymes. The potential CYP3A4/P-gp inhibitor cyclosporine also showed an unchanged MAT value. Further analysis assuming there was no P-gp effect suggested that the increased AUC and unchanged t1/2 for ticagrelor after cyclosporine administration were attributed to the inhibition of intestinal CYP3A4 rather than P-gp. Rifampin, an inducer of CYP3As after multiple dosing, unexpectedly showed decreased MAT and Tmax values, which cannot be completely explained. In contrast, grapefruit juice, an intestinal CYP3A/P-gp/OATP inhibitor, significantly increased MAT and Tmax values for ticagrelor, which may be due to activation of P-gp or inhibition of OATPs expressed in intestine.

Conclusions

This study provides new insight into the role of transporter pathways in ticagrelor intestinal absorption by examining potential MAT and Tmax changes mediated by drug-drug interactions.

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Abbreviations

AUC :

Area under the curve

AUMC :

Area under the moment curve

BCRP:

Breast cancer resistance protein

BCS:

Biopharmaceutics Classification System

BDDCS:

Biopharmaceutics Drug Disposition Classification System

CL/F :

Apparent clearance

CYP:

Cytochrome P450

DDIs:

Drug-drug interactions

ER :

Extraction ratio

F :

Oral bioavailability

MAT :

Mean absorption time

MRT :

Mean residence time

OATP:

Organic anion transport protein

P-gp:

P-glycoprotein

T max :

Time of maximum concentration

t ½,z :

Terminal half-life

V ss /F :

Apparent volume of distribution steady-state

References

  1. Teng R, Oliver S, Hayes MA, Butler K. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos. 2010;38(9):1514–21.

    Article  CAS  Google Scholar 

  2. Teng R. Ticagrelor: Pharmacokinetic, pharmacodynamic and pharmacogenetic profile: An update. Clin Pharmacokinet. 2015;54(11):1125–38.

    Article  CAS  Google Scholar 

  3. Zhou D, Andersson TB, Grimm SW. In vitro evaluation of potential drug-drug interactions with ticagrelor: cytochrome P450 reaction phenotyping, inhibition, induction, and differential kinetics. Drug Metab Dispos. 2011;39(4):703–10.

    Article  CAS  Google Scholar 

  4. Hosey CM, Chan R, Benet LZ. BDDCS predictions, self-correcting aspects of BDDCS assignments, BDDCS assignment corrections, and classification for more than 175 additional drugs. AAPS J. 2016;18(1):251–60.

    Article  CAS  Google Scholar 

  5. FDA. ticagrelor approved pacakage. [cited; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022433Orig1s000ChemR.pdf. 2011

  6. Marsousi N, Doffey-Lazeyras F, Rudaz S, Desmeules JA, Daali Y. Intestinal permeability and P-glycoprotein-mediated efflux transport of ticagrelor in Caco-2 monolayer cells. Fundam Clin Pharmacol. 2016;30(6):577–84.

    Article  CAS  Google Scholar 

  7. Liu S, Wang Z, Hou L, Tian X, Zhang X, Cai W. Predicting the effect of tea polyphenols on ticagrelor by incorporating transporter-enzyme interplay mechanism Chem Biol Interact. 2020;330:109228.

  8. Varenhorst C, Eriksson N, Johansson A, Barratt BJ, Hagstrom E, Akerblom A, et al. Effect of genetic variations on ticagrelor plasma levels and clinical outcomes. Eur Heart J. 2015;36(29):1901–12.

    Article  CAS  Google Scholar 

  9. Sodhi JK, Benet LZ. The necessity of using changes in absorption time to implicate intestinal transporter involvement in oral drug-drug interactions. AAPS J. 2020;22:111.

    Article  CAS  Google Scholar 

  10. Sodhi JK, Liu S, Benet LZ. Intestinal efflux transporters P-gp and BCRP are not clinically relevant in apixiban disposition. Pharm Res. 2020;37(10):208.

    Article  CAS  Google Scholar 

  11. Kou W, Sodhi JK, Wu X, Benet LZ. Investigating intestinal transporter involvement in rivaroxaban disposition through examination of changes in absorption. Pharm Res. 2021;38(5):795–801.

    Article  CAS  Google Scholar 

  12. Sodhi JK, Huang CA, Benet LZ. Volume of distribution is unaffected by metabolic drug-drug interactions. Clin Pharmacokinet. 2021;60:205–22.

    Article  CAS  Google Scholar 

  13. Grover A, Benet LZ. Effects of drug transporters on volume of distribution. AAPS J. 2009;11:250-61.

  14. Benet LZ, Galeazzi RL. Noncompartmental determination of the steady-state volume of distribution. J Pharm Sci. 1979;68:1071–4.

    Article  CAS  Google Scholar 

  15. Teng R, Butler K. Effect of the CYP3A inhibitors, diltiazem and ketoconazole, on ticagrelor pharmacokinetics in healthy volunteers. J Drug Assess. 2013;2(1):30–9.

    Article  Google Scholar 

  16. Teng R, Mitchell P, Butler K. Effect of rifampicin on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy subjects. Eur J Clin Pharmacol. 2013;69(4):877–83.

    Article  Google Scholar 

  17. Teng R, Kujacic M, Hsia J. Pharmacokinetic interaction study of ticagrelor and cyclosporine in healthy volunteers. Clin Drug Invest. 2014;34(8):529–36.

    Article  CAS  Google Scholar 

  18. Holmberg MT, Tornio A, Joutsi-Korhonen L, Neuvonen M, Neuvonen PJ, Lassila R, et al. Grapefruit juice markedly increases the plasma concentrations and antiplatelet effects of ticagrelor in healthy subjects. Br J Clin Pharmacol. 2013;75(6):1488–96.

    Article  CAS  Google Scholar 

  19. Sodhi JK, Benet LZ. A simple methodology to differentiate changes in bioavailability from changes in clearance following oral dosing of metabolized drugs. Clin Pharmacol Ther. 2020;108(2):306–15.

    Article  CAS  Google Scholar 

  20. Benet LZ, Bowman CM, Koleske ML, Rinaldi CL, Sodhi JK. Understanding drug-drug interaction and pharmacogenomic changes in pharmacokinetics for metabolized drugs. J Pharmacokinet Pharmacodynam. 2019;46:155–63.

    Article  CAS  Google Scholar 

  21. Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivistö KT. Pharmacokinetic interactions with rifampicin. Clin Pharmacokinet. 2003;42(9):819–50.

    Article  CAS  Google Scholar 

  22. Reitman M, Chu X, Cai X, Yabut J, Venkatasubramanian R, Zajic S, et al. Rifampin’s acute inhibitory and chronic inductive drug interactions: experimental and model-based approaches to drug–drug interaction trial design. Clin Pharmacol Ther. 2011;89(2):234–42.

    Article  CAS  Google Scholar 

  23. Zheng HX, Huang Y, Frassetto LA, Benet LZ. Elucidating rifampin’s inducing and inhibiting effects on glyburide pharmacokinetics and blood glucose in healthy volunteers: Unmasking the differential effects of enzyme induction and transporter inhibition for a drug and its primary metabolite. Clin Pharmacol Ther. 2009;85:78–85.

    Article  CAS  Google Scholar 

  24. Benet LZ, Bowman CM, Sodhi JK. How transporters have changed basic pharmacokinetic understanding. AAPS J. 2019;21:103.

    Article  Google Scholar 

  25. Soldner A, Christians U, Susanto M, Wacher VJ, Silverman JA, Benet LZ. Grapefruit juice activates P-glycoprotein-mediated drug transport. 1999;16(4):478–85.

    CAS  Google Scholar 

  26. Satoh H, Yamashita F, Tsujimoto M, Murakami H, Koyabu N, Ohtani H, Sawada Y. Citrus juices inhibit the function of human organic anion-transporting polypeptide OATP-B. Drug Metab Dispos. 2005;33:518–23.

    Article  CAS  Google Scholar 

  27. Bailey DG, Dresser GK, Leake BF, Kim RB. Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice. Clin Pharmacol Ther. 2007;81:495–502.

    Article  CAS  Google Scholar 

  28. Wang Z-T, Xue Y, Sun H, Zhang Z, Tang Z-J, Liu S-B, Cai W-M. Effect of tea polyphenols on the oral and intravenous pharmacokinetics of ticagrelor in rats and its in vitro metabolism. J Food Sci. 2020;85:1285–91.

    Article  CAS  Google Scholar 

Download references

ACKNOWLEDGEMENTS AND DISCLOSURES

Mr. Liu was supported by a grant from the National Natural Science Foundation of China (grant number 81603204) and a grant from Overseas Training Project for Health Science and Technology Talents of Henan Province (grant number 2018035). Dr. Sodhi was supported in part by an American Foundation for Pharmaceutical Education Predoctoral Fellowship, NIH grant R25 GM56847 and a Louis Zeh Fellowship. Dr. Benet is a member of the UCSF Liver Center supported by NIH grant P30 DK026743. The work in Dr. Benet’s laboratory was supported by the UCSF Benet Fund for Excellence generated from individual contributions and Dr. Benet’s consultation, expert witness and board of director fees that are made payable to the Regents of the University of California. All authors contributed to the writing and analysis of this manuscript. The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Bioengineering and Therapeutics Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, California, 94143-0912, San Francisco, USA

    Shuaibing Liu, Jasleen K. Sodhi & Leslie Z. Benet

  2. Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Shuaibing Liu

  3. Department of Drug Metabolism and Pharmacokinetics, Plexxikon Inc, South San Francisco, California, USA

    Jasleen K. Sodhi

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  1. Shuaibing Liu
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Correspondence to Leslie Z. Benet.

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Liu, S., Sodhi, J.K. & Benet, L.Z. Analyzing Potential Intestinal Transporter Drug-Drug Interactions: Reevaluating Ticagrelor Interaction Studies. Pharm Res 38, 1639–1644 (2021). https://doi.org/10.1007/s11095-021-03105-w

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  • DOI: https://doi.org/10.1007/s11095-021-03105-w

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