Renal excretion of apricitabine in rats: ex vivo and in vivo studies

  • Mariana Babayeva
  • Susan Cox
  • Michael P. White
  • David R. Taft
Original Paper


Apricitabine (ATC) is a novel nucleoside reverse transcriptase inhibitor undergoing phase 2/3 clinical development for the treatment of HIV infection. In this investigation, the renal handling of ATC was evaluated in the isolated perfused rat kidney (IPK) model with follow-up in vivo studies. IPK experiments were performed to characterize the renal excretion of ATC, to probe mechanisms of ATC excretion using known inhibitors of organic cation (cimetidine) and organic anion (probenecid) transport systems, and to screen for potential drug–drug interactions between ATC and clinically relevant medications (dapsone, metformin, pentamidine, stavudine, tenofovir and ritonavir). ATC demonstrated net tubular secretion in the IPK with a baseline excretion ratio (XR) of 2.1 ± 0.56. ATC XR decreased 3.6-fold in the presence of cimetidine and 2-fold in the presence of probenecid. Among the clinically relevant medications, metformin produced the greatest inhibitory effect on ATC excretion. In vivo studies were conducted in rats to evaluate ATC disposition upon co-administration with compounds that showed a significant effect on ATC clearance in the IPK model. Co-administration of cimetidine and trimethoprim significantly reduced ATC renal clearance, but resulted in only a moderate increase in plasma exposure. Metformin had no apparent effect on ATC clearance in rats. These findings indicate that the IPK model is more sensitive to secretory inhibition as compared to in vivo. The medications screened showed minimal effects on ATC renal excretion in the IPK, and should thus be excluded as potential in vivo interactants. Overall, this study generated important information on renal handling of ATC to support its development and commercialization.


Apricitabine Renal excretion Drug:drug interaction 



The authors thank Avexa Limited for supplying apricitabine for this research.


  1. Ajavon A, Bonate P, Taft DR (2010) Renal excretion of clofarabine: assessment of dose-linearity and role of renal transport systems on drug excretion. Eur J Pharm Sci 14:209–216CrossRefGoogle Scholar
  2. Barendt WM, Wright SH (2002) The human organic cation transporter (hOCT2) recognizes the degree of substrate ionization. J Biol Chem 277:2491–2496CrossRefGoogle Scholar
  3. Bekersky I (1983) Use of the isolated perfused kidney as a tool in drug disposition studies. Drug Metab Rev 145:931–960CrossRefGoogle Scholar
  4. Bethell RC, Lie YS, Parkin NT (2005) In vitro activity of SPD754, a new deoxycytidine nucleoside reverse transcriptase inhibitor (NRTI), against 215 HIV-1 isolates resistant to other NRTIs. Antivir Chem Chemother 16:295–302PubMedGoogle Scholar
  5. Brambilla G, Cavanna M, Maura A, Pino A, Robbiano L, Ricci RJ (1982) Absence of DNA damage in liver of rats given high doses of cimetidine. Pharmacol Exp Ther 221:222–227Google Scholar
  6. Cahn P, Wainberg M (2010) Resistance profile of the new nucleoside reverse transcriptase inhibitor apricitabine. J Antimicrob Chemother 65:213–217PubMedCrossRefGoogle Scholar
  7. Cahn P, Cassetti I, Wood R, Phanuphak P, Shiveley L, Bethell RC, Sawyer J (2006) Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naïve, HIV-infected patients. AIDS 20:1261–1268PubMedCrossRefGoogle Scholar
  8. Cahn P, Altclas J, Martins M, Losso M, Cassetti I, Cox S, Cooper D (2008a) 24 Week data from study AVX-201: a prospective, randomised, double-blind, dose-ranging phase 2b study of apricitabine in treatment-experienced patients with M184V and NRTI resistance. Abstracts of the fifteenth conference on retroviruses and opportunistic infections, Boston, MA, USA (abstract 793)Google Scholar
  9. Cahn P, Rolon M, Cassetti I, Shiveley L, Holdich T, Sawyer J (2008b) Multiple-dose pharmacokinetics of apricitabine, a novel nucleoside reverse transcriptase inhibitor, in patients with HIV-1 infection. Clin Drug Invest 28:129–138CrossRefGoogle Scholar
  10. Cahn P, Altclas J, Martins M, Losso M, Cassetti I, Cox S, Cooper D (2008b) 48-Week data from Study AVX-201—a randomised phase 2b study of apricitabine in treatment-experienced patients with M184V and NRTI resistance. Abstracts of the ninth international congress on drug therapy in HIV infection, Glasgow, UK (abstract 0414)Google Scholar
  11. Choi YoungH, Kim SangG, Lee MyungG (2006) Dose-independent pharmacokinetics of metformin in rats: hepatic and gastrointestinal first-pass effects. J Pharm Sci 95:2543–2552PubMedCrossRefGoogle Scholar
  12. Cox S, Southby J (2009a) Apricitabine—a novel nucleoside reverse transcriptase inhibitor for the treatment of HIV infection that is refractory to existing drugs. Expert Opin Invest Drugs 18:199–209CrossRefGoogle Scholar
  13. Cox S, Southby J, Linet O, Tackwell K, Borin M, Perry K (2009b) Comparison of the pharmacokinetics of apricitabine in the presence and absence of ritonavir-boosted tipranavir: a phase I, open label, controlled, single-centre study. Clin Drug Invest 29:721–728CrossRefGoogle Scholar
  14. Devineni D, Gallo GM (1995) Zalcitabine: clinical pharmacokinetics and efficacy. Clin Pharmacokinet 28:351–360PubMedCrossRefGoogle Scholar
  15. Dickinson L, Khoo S, Back D (2010) Pharmacokinetics and drug–drug interactions of antiretrovirals: an update. Antiviral Res 85:176–189PubMedCrossRefGoogle Scholar
  16. Fisher PA, Bogoliuk BA, Ramirez AJ, Sanchez RA, Masnatta LD (2000) A new procedure for evaluation a renal function without urine collection in rat. Kidney Int 58:1336–1341CrossRefGoogle Scholar
  17. Francis RJ, Lanclos L, Shively L, Sawyer J (2003) Pharmacokinetics (PK) of SPD754, a new deoxycytidine analogue, in healthy volunteers. Antivir Ther 8:S325 (abstract 528)Google Scholar
  18. Gaffney MM, Belliveau PP, Spooner LM (2009) Apricitabine: a nucleoside reverse transcriptase inhibitor for HIV infection. Ann Pharmacother 43:1676–1683PubMedCrossRefGoogle Scholar
  19. Greenblatt D (2009) Drug–drug noninteractions. Cardiovasc Ther 27:226–229PubMedCrossRefGoogle Scholar
  20. Gu Z, Allard B, de Muys JM, Lippens J, Rando RF, Nguyen-Ba N, Ren C, McKenna P, Taylor DL, Bethell RC (2006) In vitro antiretroviral activity and in vitro toxicity profile of SPD754, a new deoxycytidine nucleoside reverse transcriptase inhibitor for treatment of human immunodeficiency virus infection. Antimicrob Agents Chemother 50:625–631PubMedCrossRefGoogle Scholar
  21. Hill A, van der Lugt J, Sawyer W, Boffito M (2009) How much ritonavir is needed to boost protease inhibitors? Systematic review of 17 dose-ranging pharmacokinetic trials. AIDS 23:2237–2245PubMedCrossRefGoogle Scholar
  22. Holdich T, Shively L, Sawyer J (2006) Pharmacokinetics of single oral doses of apricitabine, a novel deoxycytidine analogue reverse transcriptase inhibitor, in healthy volunteers. Clin Drug Invest 26:279–286Google Scholar
  23. Holdich T, Shively L, Sawyer J (2007) Effect of lamivudine on the plasma and intracellular pharmacokinetics of apricitabine, a novel nucleoside reverse transcriptase inhibitor, in healthy volunteers. Antimicrob Agents Chemother 51:2943–2947PubMedCrossRefGoogle Scholar
  24. Jackson A, Taylor S, Boffito M (2009) Pharmacokinetics and pharmacodynamics of drug interactions involving HIV1 protease inhibitors. AIDS Rev 6:208–217Google Scholar
  25. Johnson MA, Moore KHP, Yuen GJ, Bye A, Pakes GE (1999) Clinical pharmacokinetics of lamivudine. Clin Pharmacokinet 36:41–66PubMedCrossRefGoogle Scholar
  26. Kaewmokul S, Chatsudthipong V, Evans KK, Dantzler WH, Wright SH (2003) Functional mapping of rbOCT1 and rbOCT2 activity in the S2 segment of rabbit proximal tubule. Am J Physiol Renal Physiol 285:F1149–F1159PubMedGoogle Scholar
  27. Klinker H, Langmann P, Zilly M, Richter E (1998) Drug monitoring during the treatment of AIDS-associated Pneumocystis carinii pneumonia with trimethoprim–sulfamethoxazole. J Clin Pharm Ther 23:149–154PubMedCrossRefGoogle Scholar
  28. Koepsell H, Lips K, Volk C (2007) Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm. Research 24:1227–1251CrossRefGoogle Scholar
  29. Lai Y, Sampson KE, Balogh LM, Brayman TG, Cox SR, Adams WJ, Kumar V, Stevens JC (2010) Preclinical and clinical evidence for the collaborative transport and renal secretion of an oxazolidinone antibiotic by organic anion transporter 3 (OAT3/SLC22A8) and multidrug and toxin extrusion protein 1 (MATE1/SLC47A1). J Pharmacol Exp Ther 334:936–944PubMedCrossRefGoogle Scholar
  30. Launay-Vacher V, Izzedine H, Karie S, Hulot JS, Baumelou A, Deray G (2006) Renal tubular drug transporters. Nephron Physiol 103:97–106CrossRefGoogle Scholar
  31. Maiza A, Dayley Yates PT (1991) Prediction of the renal clearance of cimetidine using endogenous N-1-methylnicotinamide. J Pharmacokinet Biopharm 19:175–187PubMedCrossRefGoogle Scholar
  32. Matsushima S, Maeda K, Inoue K, Ohta K, Yuasa H, Kondo T, Nakayama H, Horita S, Kusuhara H, Sugiyama Y (2009) The inhibition of human multidrug and toxin extrusion 1 is involved in the drug–drug interaction caused by cimetidine. Drug Metab Dispos 37:555–559PubMedCrossRefGoogle Scholar
  33. Modrzejewski KA, Herman RA (2004) Emtricitabine: a once-daily nucleoside reverse transcriptase inhibitor. Ann Pharmacother 38:1006–1014PubMedCrossRefGoogle Scholar
  34. Moore KHP, Yuen GJ, Raasch RH, Eron JJ, Martin D, Mydlow PK, Hussey EK (1996) Pharmacokinetics of lamivudine administered alone and with trimethoprim–sulfamethoxazole. Clin Pharmacol Ther 59:550–558PubMedCrossRefGoogle Scholar
  35. Nakatani-Freshwater T, Taft DR (2008) Renal excretion of emtricitabine II. Effect of trimethoprim on emtricitabine excretion: in vitro and in vivo studies. J Pharm Sci 97:5411–5420PubMedCrossRefGoogle Scholar
  36. Nakatani-Freshwater T, Babayeva M, Dontabhaktuni A, Taft DR (2006) Effects of trimethoprim on the clearance of apricitabine, a deoxycytidine analog reverse transcriptase inhibitor, and lamivudine in the isolated perfused rat kidney. J Pharmacol Exp Ther 319:941–947PubMedCrossRefGoogle Scholar
  37. Poola NR, Bhuiyan D, Kalis M, Ortiz SR, Savant IA, Kirschenbaum H, Sidhom M, Taft DR (2002) A novel HPLC assay for pentamidine: comparative effects of creatinine and Inulin on GFR estimation and pentamidine renal excretion in the isolated perfused rat kidney. J Pharm Pharm Sci 5:130–140Google Scholar
  38. Sattler FR, Cowan R, Nielsen DM, Ruskin J (1988) Trimethoprim–sulfamethoxazole compared with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a prospective, noncrossover study. Ann Intern Med 109:280–287PubMedGoogle Scholar
  39. Shiveley L, Struthers-Semple C, Cox S, Sawyer J (2008) Pharmacokinetics of apricitabine, a novel nucleoside reverse transcriptase inhibitor, in healthy volunteers treated with trimethoprim–sulphamethoxazole. Clin Pharm Ther 33:45–54Google Scholar
  40. Stevens RC, Laizure SC, Williams CL, Stein DS (1991) Pharmacokinetics and adverse effects of 20-mg/kg/day trimethoprim and 100-mg/kg/day sulfamethoxazole in healthy adult subjects. Antimicrob Agents Chemother 35:1884–1890PubMedGoogle Scholar
  41. Taft DR (2004) The isolated perfused rat kidney model: a useful tool for drug discovery and development. Curr Drug Discov Technol 1:97–111PubMedCrossRefGoogle Scholar
  42. Taft D (2009) Drug excretion. In: Hacker M, Bachman K, Messer W (eds) Pharmacology: principles and practice. Academic Press, Burlington, pp 175–200Google Scholar
  43. Takeda M, Khamdang S, Narikawa S, Kimura H, Kobayashi Y, Yamamoto T, Cha SH, Sekine T, Endou H (2002) Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J Pharmacol Exp Ther 300:918–924PubMedCrossRefGoogle Scholar
  44. Taylor Dl, Ahmed PS, Tyms AS, Wood LJ, Kelly LA, Chambers P, Clarke J, Bedard J, Bowlin TL, Rando RF (2000) Drug resistance and drug combination features of the human immunodeficiency virus inhibitor, BCH-10652 [(±)-2′-deoxy-3′-oxa-4′-thiocytidine, dOTC]. Antivir Chem Chemother 11:291–301PubMedGoogle Scholar
  45. Urakami Y, Kimura N, Okuda M, Inui K (2004) Creatinine transport by basolateral organic cation transporter hOCT2 in the human kidney. Pharm Res 21:976–981PubMedCrossRefGoogle Scholar
  46. Van Aubel R, Masereeuw R, Russel F (2000) Molecular pharmacology of renal organic anion transporters. Am J Physiol 279:F216–F232Google Scholar

Copyright information

© Springer-Verlag France 2011

Authors and Affiliations

  • Mariana Babayeva
    • 1
    • 3
  • Susan Cox
    • 2
  • Michael P. White
    • 1
  • David R. Taft
    • 1
  1. 1.College of Pharmacy, Long Island UniversityBrooklynUSA
  2. 2.Avexa LtdRichmondAustralia
  3. 3.Touro College of PharmacyNew YorkUSA

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