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The Necessity of Using Changes in Absorption Time to Implicate Intestinal Transporter Involvement in Oral Drug-Drug Interactions

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Abstract

Introduction

In drug discovery and development, it is of high interest to characterize the potential for intestinal drug-drug interactions to alter bioavailability of a victim drug. For drugs that are substrates of both intestinal transporters and enzymes, estimating the relative contribution of each process has proved challenging, especially since the susceptibility of drug to uptake or efflux transporters in vitro does not always translate to clinically significant in vivo involvement. Here we introduce a powerful methodology to implicate intestinal transporters in drug-drug interactions based on the theory that clinically relevant intestinal transporter interactions will result in altered rate of absorption of victim drugs.

Methods and Materials

We present exemplary clinical drug-drug interaction studies that utilize well-characterized clinical substrates and perpetrators to demonstrate how mean absorption time (MAT) and time to maximum concentration (tmax) are expected to change (or remain unchanged) when either intestinal transporters or metabolic enzymes were/are altered. Apixaban was also selected to demonstrate the utility of the methodology, as the purported involvement of both intestinal enzymes and transporters has been suggested in its FDA package insert.

Results and Discussion

Acute inhibition of gut efflux transporters resulted in decreased MAT and tmaxvalues, induction increased these values, while inhibition of intestinal metabolic enzymes did not result in altered MAT or tmax. Involvement of intestinal efflux transporters in apixaban disposition is unlikely.

Conclusion

Utilization of this simple but powerful methodology to implicate intestinal transporter involvement will have significant impact on how drug-drug interactions are interpreted.

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Abbreviations

AUC :

area under the curve

AUC 0 → ∞ :

area under the curve extrapolated to infinity for a single dose

AUC 0 → τ :

area under the curve during a dosing interval at steady-state

AUC τ → ∞ :

area under the curve extrapolated from the end of the dosing interval to infinity at steady-state

AUMC :

area under the moment curve

AUMC 0 → ∞ :

area under the moment curve extrapolated to infinity for a single dose

AUMC 0 → τ :

area under the moment curve during a dosing interval at steady-state

BCRP:

breast cancer resistance protein

BDDCS:

Biopharmaceutics Drug Disposition Classification System

CL :

clearance

CL/F :

apparent clearance

CYP:

cytochrome P450

DDI:

drug-drug interaction

F :

bioavailability

F A :

fraction absorbed

F G :

fraction escaping intestinal elimination

F H :

fraction escaping hepatic elimination

I gut :

maximum perpetrator concentration in the gut

k a :

absorption rate constant

k e :

elimination rate constant

MAT :

mean absorption time

MRT :

mean residence time

OATP:

organic anion transporting polypeptide

P-gp:

P-glycoprotein

τ :

dosing interval

t max :

time at which maximal concentration is observed

t 1/2, z :

terminal half-life

V ss :

volume of distribution at steady state

V ss /F :

apparent volume of distribution at steady state

References

  1. Benet LZ, Cummins CL, Wu CY. Transporter-enzyme interactions: implications for predicting drug-drug interactions from in vitro data. Curr Drug Metab. 2003;4:393–8.

    CAS  PubMed  Google Scholar 

  2. Shugarts S, Benet LZ. The role of transporters in the pharmacokinetics of orally administered drugs. Pharm Res. 2009;26:2039–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. van de Waterbeemd H, Jones BC. Predicting oral absorption and bioavailability. Prog Med Chem. 2003;41:1–59.

    PubMed  Google Scholar 

  4. Yoshida K, Maeda K, Sugiyama Y. Hepatic and intestinal transporters: prediction of pharmacokinetic effects caused by drug-drug interactions and genetic polymorphisms. Annu Rev Pharmacol Toxicol. 2013;53:581–612.

    CAS  PubMed  Google Scholar 

  5. 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;108:306–315.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Sodhi JK, Huang CH, Benet LZ. Volume of distribution is unaffected by metabolic drug–drug interactions. Clin Pharmacokinet. 2020. https://doi.org/10.1007/s40262-020-00926-7.

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

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Alluri RV, Li R, Varma MVS. Transporter-enzyme interplay and the hepatic drug clearance: what have we learned so far? Expert Opin Drug Metab Toxicol. 2020;16:287–401.

  11. Varma MV, Pang KS, Isoherranen N, Zhao P. Dealing with complex drug-drug interactions: towards mechanistic models. Biopharm Drug Dispos. 2015;36:71–92.

    CAS  PubMed  Google Scholar 

  12. Wagner JG, Northam JI, Alway CD, Carpenter OS. Blood levels of drug at the equilibrium state after multiple dosing. Nature. 1965;207:1301–2.

    CAS  PubMed  Google Scholar 

  13. Greenberg HE, England MJ, Hellriegel ET, Bjornsson TD. Time of peak drug concentration after a single dose and a dose at steady state. J Clin Pharmacol. 1997;27:480–5.

    Google Scholar 

  14. Sahin S, Benet LZ. The operational multiple dosing half-life: a key to defining drug accumulation in patients and to designing extended release dosage forms. Pharm Res. 2008;25:2869–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Lau YY, Huang Y, Frassetto L, Benet LZ. Effect of OATP1B1 transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther. 2007;81:194–204.

    CAS  PubMed  Google Scholar 

  16. Cheng H, Jusko WJ. Noncompartmental determination of the mean residence time and steady-state volume of distribution during multiple dosing. J Pharm Sci. 1991;80:202–4.

    CAS  PubMed  Google Scholar 

  17. Pfeffer M. Estimation of mean residence time from data obtained when multiple-dosing steady state has been reached. J Pharm Sci. 1984;73:854–6.

    CAS  PubMed  Google Scholar 

  18. Rohatagi S, Kan S, Derendorf H. Non-compartmental analysis of pharmacokinetic data after multiple intravenous and oral administration. Pharmazie. 1997;52:529–32.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  20. Tornio A, Filppula AM, Niemi M, Backman JT. Clinical studies on drug-drug interactions involving metabolism and transport: methodology, pitfalls and interpretation. Clin Pharmacol Ther. 2019;105:1345–61.

    PubMed  PubMed Central  Google Scholar 

  21. Wu HF, Hristeva N, Chang J, Liang X, Li R, Frassetto L, et al. Rosuvastatin pharmacokinetics in Asian and White subjects wild type for both OATP1B1 and BCRP under control and inhibited conditions. J Pharm Sci. 2017;106:2751–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Westphal K, Weinbrenner A, Zschiesche M, Franke G, Knoke M, Oertel R, et al. Induction of P-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: a new type of drug/drug interaction. Clin Pharmacol Ther. 2000;68:345–55.

    CAS  PubMed  Google Scholar 

  23. Varhe A, Olkkola KT, Neuvonen PJ. Fluconazole, but not terbinafine, enhances the effects of triazolam by inhibiting its metabolism. Br J Clin Pharmacol. 1996;41:319–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Gustavson LE, Kaiser JF, Edmonds AL, Locke CS, DeBartolo ML, Schneck DW. Effect of omeprazole on concentrations of clarithromycin in plasma and gastric tissue at steady state. Antimicrob Agents Chemother. 1995;39:2078–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Vakkalagadda B, Frost C, Byon W, Boyd RA, Wang J, Zhang D, et al. Effect of rifampin on the pharmacokinetics of apixaban, an oral direct inhibitor of factor Xa. Am J Cardiovasc Drugs. 2016;16:119–27.

    CAS  PubMed  Google Scholar 

  26. ELIQUIS (apixaban) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2012.

  27. Jacqueroux E, Mercier C, Margelidon-Cozzolino V, Hodin S, Bertoletti L, Delavenne X. In vitro assessment of P-gp and BCRP transporter-mediated drug-drug interactions of riociguat with direct oral anticoagulants. Fundam Clin Pharmacol. 2020;34:109–19.

    CAS  PubMed  Google Scholar 

  28. Zhang D, He K, Herbst JJ, Kolb J, Shou W, Wang L, et al. Characterization of efflux transporters involved in distribution and disposition of apixaban. Drug Metab Dispos. 2013;41:827–35.

    CAS  PubMed  Google Scholar 

  29. Wu CY, Benet LZ. Predicting drug disposition via application of BCS: transport / absorbtion / elimination interplay and development of a Biopharmaceutics Drug Disposition Classification System. Pharm Res. 2005;22:11–23.

    CAS  PubMed  Google Scholar 

  30. Zamek-Gliszczynski MJ, Taub ME, Chothe PP, Chu X, Giacomini KM, Kim RB, et al. Transporters in drug development: 2018 ITC recommendations for transporters of emerging clinical importance. Clin Pharmacol Ther. 2018;104:890–9.

    PubMed  Google Scholar 

  31. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. In vitro metabolism- and transporter-mediated drug-drug interaction studies: guidance for industry. Silver Spring, MD; 2017.

  32. Cheong J, Halladay JS, Plise E, Sodhi JK, Salphati L. The effects of drug metabolizing enzymes inhibitors on hepatic efflux and uptake transporters. Drug Metab Lett. 2017;11:111–8.

    CAS  PubMed  Google Scholar 

  33. Brown HS, Ito K, Galetin A, Houston JB. Prediction of in vivo drug-drug interactions from in vitro data: impact of incorporating parallel pathways of drug elimination and inhibitor absorption rate constant. Br J Clin Pharmacol. 2005;60:508–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ito K, Iwatsubo T, Kanamitsu S, Ueda K, Suzuki H, Sugiyama Y. Prediction of pharmacokinetic alterations caused by drug-drug interactions: metabolic interaction in the liver. Pharmacol Rev. 1998;50:387–412.

    CAS  PubMed  Google Scholar 

  35. Smith MT, Eadie MJ, Brophy TO. The pharmacokinetics of midazolam in man. Eur J Clin Pharmacol. 1981;19:271–8.

  36. Heizmann P, Eckert M, Ziegler WH. Pharmacokinetics and bioavailability of midazolam in man. Br J Clin Pharmacol. 1983;16:43S–9S.

    PubMed  PubMed Central  Google Scholar 

  37. Lee JI, Chaves-Gnecco D, Amico JA, Kroboth PD, Wilson JW, Frye RF. Application of semisimultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping. Clin Pharmacol Ther. 2002;72:718–28.

    CAS  PubMed  Google Scholar 

  38. Brazzell RK, Kaplan SA. Factors affecting the accuracy of estimated mean absorption times and mean dissolution times. J Pharm Sci. 1983;72:713–5.

    CAS  PubMed  Google Scholar 

  39. Veering BT, Burm AGL, Vletter AA, van den Hoeven RAM, Spierdijk J. The effect of age on systemic absorption and systemic disposition of bupivacaine after subarachnoid administration. Anesthesiology. 1991;74:250–7.

    CAS  PubMed  Google Scholar 

  40. Fredrick MJ, Pound DC, Hall SD, Brater DC. Furosemide absorption in patients with cirrhosis. Clin Pharmacol Ther. 1991;49:241–7.

    CAS  PubMed  Google Scholar 

  41. Holt S, Heading RC, Clements JA, Tothill P, Prescott LF. Acetaminophen absorption and metabolism in celiac disease and Crohn’s disease. Clin Pharmacol Ther. 1981;30:232–8.

    CAS  PubMed  Google Scholar 

  42. Kitis G, Lucas ML, Bishop H, Sargent A, Schneider RE, Blair JA, et al. Altered jejunal surface pH in coeliac disease: its effect on propranolol and folic acid absorption. Clin Sci. 1982;63:373–80.

    CAS  PubMed  Google Scholar 

  43. Pfeffer M, Gaver RC, Ximenez J. Human intravenous pharmacokinetics and absolute oral bioavailability of cefatrizine. Antimicrob Agents Chemother. 1983;24:915–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Reigner BG, Couet W, Guedes JP, Fourtillan JB, Tozer TN. Saturable rate of cefatrizine absorption after oral administration to humans. J Pharmacokinet Biopharm. 1990;18:17–24.

    CAS  PubMed  Google Scholar 

  45. Estudante M, Morais JG, Soveral G, Benet LZ. Intestinal drug transporters: an overview. Adv Drug Deliv Rev. 2013;65:1340–56.

    CAS  PubMed  Google Scholar 

  46. Morse BL, Alberts JJ, Posada MM, Rehmel J, Kolur A, Tham LS, et al. Physiologically-based pharmacokinetic modeling of atorvastatin incorporating delayed gastric emptying and acid-to-lactone conversion. CPT Pharmacometrics Syst Pharmacol. 2019;8:664–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Custodio JM, Wu CY, Benet LZ. Predicting drug disposition, absorption / elimination / transporter interplay and the role of food on drug absorption. Adv Drug Deliv Rev. 2008;60:717–33.

    CAS  PubMed  Google Scholar 

  48. Levy G, Jusko WJ. Effect of viscosity on drug absorption. J Pharm Sci. 1965;54:219–25.

    CAS  PubMed  Google Scholar 

  49. Tanaka Y, Goto T, Kataoka M, Sakuma S, Yamashita S. Impact of luminal fluid volume on the drug absorption after oral administration: analysis based on in vivo drug concentration-time profile in the gastrointestinal tract. J Pharm Sci. 2015;104:3120–7.

    CAS  PubMed  Google Scholar 

  50. Martinez MN, Amidon GL. A mechanistic approach to understanding factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol. 2002;42:620–43.

    CAS  PubMed  Google Scholar 

  51. Rodrigues AD, Lai Y, Shen H, Varma MVS, Rowland A, Oswald S. Induction of human intestinal and hepatic organic anion transporting polypeptides: where is the evidence for its relevance in drug-drug interactions? Drug Metab Dispos. 2020;48:205–16.

    PubMed  Google Scholar 

  52. Yu J, Zhou Z, Tay-Sontheimer J, Levy RH, Ragueneau-Majlessi I. Intestinal drug interactions mediated by OATPs: a systemic review of preclinical and clinical findings. J Pharm Sci. 2017;106:2312–25.

    CAS  PubMed  Google Scholar 

  53. McFeely SJ, Wu L, Ritchie TK, Unadkat J. Organic anion transporting polypeptide 2B1 – more than a glass-full of drug interactions. Pharmacol Ther. 1996;2019:204–15.

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank members of our laboratory for their thoughtful discussions in the development of this manuscript, including Dr. Annette Chu, Caroline Huang, Wen Kou, Dr. Ivan Kozachenko, Shuaibing Liu, and Dr. Yue Xiang.

This work was supported in part by a Mary Ann Koda-Kimble Seed Award for Innovation. Ms. Sodhi was supported in part by an American Foundation for Pharmaceutical Education Predoctoral Fellowship, NIGMS grant R25 GM56847 and a Louis Zeh Fellowship. Dr. Benet is a member of the UCSF Liver Center supported by NIH grant P30 DK026743

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  1. Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, 513 Parnassus Ave Rm HSE 1164, UCSF Box 0912, San Francisco, CA, 94143, USA

    Jasleen K. Sodhi & Leslie Z. Benet

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  1. Jasleen K. Sodhi
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  2. Leslie Z. Benet
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Correspondence to Leslie Z. Benet.

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Sodhi, J.K., Benet, L.Z. The Necessity of Using Changes in Absorption Time to Implicate Intestinal Transporter Involvement in Oral Drug-Drug Interactions. AAPS J 22, 111 (2020). https://doi.org/10.1208/s12248-020-00469-6

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