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In Silico Absorption Analysis of Valacyclovir in Wildtype and Pept1 Knockout Mice Following Oral Dose Escalation

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Abstract

Purpose

We developed simulation and modeling methods to predict the in vivo pharmacokinetic profiles of acyclovir, following escalating oral doses of valacyclovir, in wildtype and Pept1 knockout mice. We also quantitated the contribution of specific intestinal segments in the absorption of valacyclovir in these mice.

Methods

Simulations were conducted using a mechanistic advanced compartmental absorption and transit (ACAT) model implemented in GastroPlus™. Simulations were performed for 3 h post-dose in wildtype and Pept1 knockout mice following single oral doses of 10, 25, 50 and 100 nmol/g valacyclovir, and compared to experimentally observed plasma concentration-time profiles of acyclovir.

Results

Good fits were obtained in wildtype and Pept1 knockout mice. Valacyclovir was primarily absorbed from duodenum (42%) and jejunum (24%) of wildtype mice, with reduced uptake from ileum (3%) and caecum/colon (1%), for a total of 70% absorption. In contrast, the absorption of valacyclovir in Pept1 knockout mice was slow and sustained throughout the entire intestinal tract in which duodenum (4%), jejunum (14%), ileum (10%) and caecum/colon (12%) accounted for a total of 40% absorption.

Conclusion

The ACAT model bridged the gap between in situ and in vivo experimental findings, and facilitated our understanding of the complicated intestinal absorption processes of valacyclovir.

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Abbreviations

ACAT:

Advanced compartmental absorption and transit

AUC0–180 :

Area under the plasma concentration-time curve from time 0 to 180 min

Cmax :

Peak plasma concentration

GI:

Gastrointestinal

Peff :

Intestinal permeability

PEPT1:

Peptide Transporter 1

PSA:

Parameter sensitivity analysis

References

  1. Brandsch M, Knütter I, Bosse-Doenecke E. Pharmaceutical and pharmacological importance of peptide transporters. J Pharm Pharmacol. 2008;60:543–85.

    Article  CAS  PubMed  Google Scholar 

  2. Rubio-Aliaga I, Daniel H. Peptide transporters and their roles in physiological processes and drug disposition. Xenobiotica. 2008;38:1022–42.

    Article  CAS  PubMed  Google Scholar 

  3. Brandsch M. Transport of drugs by proton-coupled peptide transporters: pearls and pitfalls. Expert Opin Drug Metab Toxicol. 2009;5:887–905.

    Article  CAS  PubMed  Google Scholar 

  4. Brandsch M. Drug transport via the intestinal peptide transporter PepT1. Curr Opin Pharmacol. 2013;13:881–7.

    Article  CAS  PubMed  Google Scholar 

  5. Smith DE, Clémençon B, Hediger MA. Proton-coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications. Mol Asp Med. 2013;34:323–36.

    Article  CAS  Google Scholar 

  6. Varma MV, Ambler CM, Ullah M, Rotter CJ, Sun H, Litchfield J, et al. Targeting intestinal transporters for optimizing oral drug absorption. Curr Drug Metab. 2010;11:730–42.

    Article  CAS  PubMed  Google Scholar 

  7. Dahan A, Khamis M, Agbaria R, Karaman R. Targeted prodrugs in oral drug delivery: the modern molecular biopharmaceutical approach. Expert Opin Drug Deliv. 2012;9:1001–13.

    Article  CAS  PubMed  Google Scholar 

  8. Zhang L, Zhang L, Luo T, Zhou J, Sun L, Xu Y. Synthesis and evaluation of a dipeptide-drug conjugate library as substrates for PEPT1. ACS Comb Sci. 2012;14:108–14.

    Article  CAS  PubMed  Google Scholar 

  9. Gupta D, Varghese Gupta S, Dahan A, Tsume Y, Hilfinger J, Lee KD, et al. Increasing oral absorption of polar neuraminidase inhibitors: a prodrug transporter approach applied to oseltamivir analogue. Mol Pharm. 2013;10:512–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yang B, Smith DE. Significance of peptide transporter 1 in the intestinal permeability of valacyclovir in wild-type and PepT1 knockout mice. Drug Metab Dispos. 2013;41:608–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yang B, Hu Y, Smith DE. Impact of peptide transporter 1 on the intestinal absorption and pharmacokinetics of valacyclovir after oral dose escalation in wild-type and PepT1 knockout mice. Drug Metab Dispos. 2013;41:1867–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Grass GM. Simulation models to predict oral drug absorption from in vitro data. Adv Drug Deliv Rev. 1997;23:199–219.

    Article  CAS  Google Scholar 

  13. Huang W, Lee SL, Yu LX. Mechanistic approaches to predicting oral drug absorption. AAPS J. 2009;11:217–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yu LX, Amidon GL. Saturable small intestinal drug absorption in humans: modeling and interpretation of cefatrizine data. Eur J Pharm Biopharm. 1998;45:199–203.

    Article  CAS  PubMed  Google Scholar 

  15. Yokoe J, Iwasaki N, Haruta S, Kadono K, Ogawara K, Higaki K, et al. Analysis and prediction of absorption behavior of colon-targeted prodrug in rats by GI-transit-absorption model. J Control Release. 2003;86:305–13.

    Article  CAS  PubMed  Google Scholar 

  16. Haddish-Berhane N, Farhadi A, Nyquist C, Haghighi K, Keshavarzian A. SIMDOT-AbMe: microphysiologically based simulation tool for quantitative prediction of systemic and local bioavailability of targeted oral delivery formulations. Drug Metab Dispos. 2009;37:608–18.

    Article  CAS  PubMed  Google Scholar 

  17. Hironaka T, Itokawa S, Ogawara KI, Higaki K, Kimura T. Quantitative evaluation of PEPT1 contribution to oral absorption of cephalexin in rats. Pharm Res. 2009;26:40–50.

    Article  CAS  PubMed  Google Scholar 

  18. Yu LX, Lipka E, Crison JR, Amidon G.L. Transport approaches to the biopharmaceutical design of oral drug delivery systems: prediction of intestinal absorption. Adv Drug Deliv Rev 1996;19:359–376.

  19. Yu LX, Amidon GL. A compartmental absorption and transit model for estimating oral drug absorption. Int J Pharm. 1999;186:119–25.

    Article  CAS  PubMed  Google Scholar 

  20. Agoram B, Woltosz WS, Bolger MB. Predicting the impact of physiological and biochemical processes on oral drug bioavailability. Adv Drug Deliv Rev. 2001;50(Suppl 1):S41–67.

    Article  CAS  PubMed  Google Scholar 

  21. Tubic M, Wagner D, Spahn-Langguth H, Bolger MB, Langguth P. In silico modeling of non-linear drug absorption for the P-gp substrate talinolol and of consequences for the resulting pharmacodynamic effect. Pharm Res. 2006;23:1712–20.

    Article  CAS  PubMed  Google Scholar 

  22. Bolger MB, Lukacova V, Woltosz WS. Simulations of the nonlinear dose dependence for substrates of influx and efflux transporters in the human intestine. AAPS J. 2009;11:353–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Abuasal BS, Bolger MB, Walker DK, Kaddoumi A. In silico modeling for the nonlinear absorption kinetics of UK-343,664: a P-gp and CYP3A4 substrate. Mol Pharm. 2012;9:492–504.

    Article  CAS  PubMed  Google Scholar 

  24. Balimane P, Sinko P. Effect of ionization on the variable uptake of valacyclovir via the human intestinal peptide transporter (hPepT1) in CHO cells. Biopharm Drug Dispos. 2000;21:165–74.

    Article  CAS  PubMed  Google Scholar 

  25. Jappar D, Wu SP, Hu Y, Smith DE. Significance and regional dependency of peptide transporter (PEPT) 1 in the intestinal permeability of glycylsarcosine: in situ single-pass perfusion studies in wild-type and Pept1 knockout mice. Drug Metab Dispos. 2010;38:1740–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yang B. Role of peptide transporter PEPT1 in the intestinal absorption and pharmacokinetics of the amino acid ester prodrug valacyclovir (doctoral dissertation). Ann Arbor: The University of Michigan; 2012.

    Google Scholar 

  27. de Miranda P, Krasny HC, Page DA, Elion GB. The disposition of acyclovir in different species. J Pharmacol Exp Ther. 1981;219:309–15.

    PubMed  Google Scholar 

  28. Granero GE, Amidon GL. Stability of valacyclovir: implications for its oral bioavailability. Int J Pharm. 2006;317:14–8.

    Article  CAS  PubMed  Google Scholar 

  29. Takeda M, Khamdang S, Narikawa S, Kimura H, Kobayashi Y, Yamamoto T, et al. Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J Pharmacol Exp Ther. 2002;300:918–24.

    Article  CAS  PubMed  Google Scholar 

  30. Jappar D, Hu Y, Smith DE. Effect of dose escalation on the in vivo oral absorption and disposition of glycylsarcosine in wild-type and Pept1 knockout mice. Drug Metab Dispos. 2011;39:2250–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Weller S, Blum MR, Doucette M, Burnette T, Cederberg DM, de Miranda P, et al. Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating single- and multiple-dose administration to normal volunteers. Clin Pharmacol Ther. 1993;54:595–605.

    Article  CAS  PubMed  Google Scholar 

  32. Ormrod D. Goa K (2000) Valaciclovir: a review of its use in the management of herpes zoster. Drugs. 2000;59:1317–40.

    Article  CAS  PubMed  Google Scholar 

  33. Anand BS, Katragadda S, Mitra AK. Pharmacokinetics of novel dipeptide ester prodrugs of acyclovir after oral administration: intestinal absorption and liver metabolism. J Pharmacol Exp Ther. 2004;311:659–67.

    Article  CAS  PubMed  Google Scholar 

  34. Hu Y, Smith DE. Species differences in the pharmacokinetics of cefadroxil as determined in wildtype and humanized PepT1 mice. Biochem Pharmacol. 2016;107:81–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hu Y, Xie Y, Wang Y, Chen X, Smith DE. Development and characterization of a novel mouse line humanized for the intestinal peptide transporter. Mol Pharm. 2014;11(10):3737–46.

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Acknowledgments and Disclosures

This work was supported by Public Health Service grant R01GM115481 from the National Institute of General Medical Sciences (to D.E.S.). We would like to thank Dr. Michael B. Bolger (Simulations Plus, Inc., Lancaster, CA) for his suggestions with modeling and insightful comments on our findings.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan, 48109-1065, USA

    Bei Yang & David E. Smith

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  1. Bei Yang
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  2. David E. Smith
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Correspondence to David E. Smith.

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Yang, B., Smith, D.E. In Silico Absorption Analysis of Valacyclovir in Wildtype and Pept1 Knockout Mice Following Oral Dose Escalation. Pharm Res 34, 2349–2361 (2017). https://doi.org/10.1007/s11095-017-2242-z

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  • DOI: https://doi.org/10.1007/s11095-017-2242-z

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