Skip to main content
Log in

Effects of Drug Transporters on Volume of Distribution

The AAPS Journal Aims and scope Submit manuscript

Abstract

Recently, drug transporters have emerged as significant modifiers of a patient’s pharmacokinetics. In cases where the functioning of drug transporters is altered, such as by drug-drug interactions, by genetic polymorphisms, or as evidenced in knockout animals, the resulting change in volume of distribution can lead to a significant change in drug effect or likelihood of toxicity, as well as a change in half life independent of a change in clearance. Here, we review pharmacokinetic interactions at the transporter level that have been investigated in animals and humans and reported in literature, with a focus on the changes in distribution volume. We pay particular attention to the differing effects of changes in transporter function on the three measures of volume. Further, trends are discussed as they may be used to predict volume changes given the function of a transporter and the primary location of the interaction. Because the liver and kidneys express the greatest level and variety of transporters, we denote these organs as the primary location of transporter-based interactions. We conclude that the liver is a larger contributor to distribution volume than the kidneys, in consideration of both uptake and efflux transporters. Further, while altered distribution due to secondary interactions at tissues other than the liver and kidneys may have a pharmacodynamic effect, these interactions, at least at the blood-brain barrier, do not appear to significantly influence overall distribution volume. The analysis provides a framework for understanding potential pharmacokinetic interactions rooted in drug transporters as they modify drug distribution.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

References

  1. Øie S. Drug distribution and binding. J Clin Pharmacol. 1986;26:583–6.

    PubMed  Google Scholar 

  2. Jette L, Beaulieu E, Leclerc JM, Beliveau R. Cyclosporin A treatment induces overexpression of P-glycoprotein in the kidney and other tissues. Am J Physiol. 1996;270:F756–F65.

    PubMed  CAS  Google Scholar 

  3. Brady JM, Cherrington NJ, Hartley DP, Buist SC, Li N, Klaassen CD. Tissue distribution and chemical induction of multiple drug resistance genes in rats. Drug Metab Dispos. 2002;30:838–44.

    Article  PubMed  CAS  Google Scholar 

  4. Cherrington NJ, Hartley DP, Li N, Johnson DR, Klaassen CD. Organ distribution of multidrug resistance proteins 1, 2, and 3 (Mrp1, 2, and 3) mRNA and hepatic induction of Mrp3 by constitutive androstane receptor activators in rats. J Pharmacol Exp Ther. 2002;300:97–104.

    Article  PubMed  CAS  Google Scholar 

  5. Nakashima E, Benet LZ. General treatment of mean residence time, clearance, and volume parameters in linear mammillary models with elimination from any compartment. J Pharmacokinet Biopharm. 1988;16:475–92.

    Article  PubMed  CAS  Google Scholar 

  6. Yates JW, Arundel PA. Oral and IV dosing: a method to determine the compartment of drug elimination for two-compartment models. J Pharm Sci. 2008;97:2036–40.

    Article  PubMed  CAS  Google Scholar 

  7. Yates JW, Arundel PA. On the volume of distribution at steady state and its relationship with two-compartmental models. J Pharm Sci. 2008;97:111–22.

    Article  PubMed  CAS  Google Scholar 

  8. Kerr DJ, Graham J, Cummings J, Morrison JG, Thompson GG, Brodie MJ, Kaye SB. The effect of verapamil on the pharmacokinetics of adriamycin. Cancer Chemother Pharmacol. 1986;18:239–42.

    Article  PubMed  CAS  Google Scholar 

  9. Tavoloni N, Guarino AM. Biliary and urinary excretion of adriamycin in anesthetized rats. Pharmacology. 1980;20:256–67.

    Article  PubMed  CAS  Google Scholar 

  10. Lau YY, Huang Y, Frassetto L, Benet LZ. Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther. 2007;81:194–204.

    Article  PubMed  CAS  Google Scholar 

  11. Pasanen MK, Fredrikson H, Neuvonen PJ, Niemi M. Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther. 2007;82:726–33.

    Article  PubMed  CAS  Google Scholar 

  12. Brown G, Zemcov SJ, Clarke AM. Effect of probenecid on cefazolin serum concentrations. J Antimicrob Chemother. 1993;31:1009–11.

    Article  PubMed  CAS  Google Scholar 

  13. Shitara Y, Sato H, Sugiyama Y. Evaluation of drug-drug interaction in the hepatobiliary and renal transport of drugs. Annu Rev Pharmacol Toxicol. 2005;45:689–723.

    Article  PubMed  CAS  Google Scholar 

  14. Sakurai Y, Motohashi H, Ogasawara K, Terada T, Masuda S, Katsura T, Mori N, Matsuura M, Doi T, Fukatsu A, Inui K. Pharmacokinetic significance of renal OAT3 (SLC22A8) for anionic drug elimination in patients with mesangial proliferative glomerulonephritis. Pharm Res. 2005;22:2016–22.

    Article  PubMed  CAS  Google Scholar 

  15. Khamdang S, Takeda M, Babu E, Noshiro R, Onozato ML, Tojo A, Enomoto A, Huang XL, Narikawa S, Anzai N, Piyachaturawat P, Endou H. Interaction of human and rat organic anion transporter 2 with various cephalosporin antibiotics. Eur J Pharmacol. 2003;465:1–7.

    Article  PubMed  CAS  Google Scholar 

  16. Muck W, Mai I, Fritsche L, Ochmann K, Rohde G, Unger S, Johne A, Bauer S, Budde K, Roots I, Neumayer HH, Kuhlmann J. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin Pharmacol Ther. 1999;65:251–61.

    Article  PubMed  CAS  Google Scholar 

  17. Shitara Y, Horie T, Sugiyama Y. Transporters as a determinant of drug clearance and tissue distribution. Eur J Pharm Sci. 2006;27:425–46.

    Article  PubMed  CAS  Google Scholar 

  18. Tsuruoka S, Ioka T, Wakaumi M, Sakamoto K, Ookami H, Fujimura A. Severe arrhythmia as a result of the interaction of cetirizine and pilsicainide in a patient with renal insufficiency: first case presentation showing competition for excretion via renal multidrug resistance protein 1 and organic cation transporter 2. Clin Pharmacol Ther. 2006;79:389–96.

    Article  PubMed  CAS  Google Scholar 

  19. Jaehde U, Sorgel F, Reiter A, Sigl G, Naber KG, Schunack W. Effect of probenecid on the distribution and elimination of ciprofloxacin in humans. Clin Pharmacol Ther. 1995;58:532–41.

    Article  PubMed  CAS  Google Scholar 

  20. Desrayaud S, Guntz P, Scherrmann JM, Lemaire M. Effect of the P-glycoprotein inhibitor, SDZ PSC 833, on the blood and brain pharmacokinetics of colchicine. Life Sci. 1997;61:153–63.

    Article  PubMed  CAS  Google Scholar 

  21. Speeg KV, Maldonado AL, Liaci J, Muirhead D. Effect of cyclosporine on colchicine secretion by a liver canalicular transporter studied in vivo. Hepatology 1992;15:899–903.

    Article  PubMed  CAS  Google Scholar 

  22. Nooter K, Oostrum R, Deurloo J. Effects of verapamil on the pharmacokinetics of daunomycin in the rat. Cancer Chemother Pharmacol. 1987;20:176–8.

    Article  PubMed  CAS  Google Scholar 

  23. Yesair DW, Schwartzbach E, Shuck D, Denine EP, Asbell MA. Comparative pharmacokinetics of daunomycin and adriamycin in several animal species. Cancer Res. 1972;32:1177–83.

    PubMed  CAS  Google Scholar 

  24. Lam JL, Shugarts SB, Okochi H, Benet LZ. Elucidating the effect of final-day dosing of rifampin in induction studies on hepatic drug disposition and metabolism. J Pharmacol Exp Ther. 2006;319:864–70.

    Article  PubMed  CAS  Google Scholar 

  25. Ding R, Tayrouz Y, Riedel KD, Burhenne J, Weiss J, Mikus G, Haefeli WE. Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers. Clin Pharmacol Ther. 2004;76:73–84.

    Article  PubMed  CAS  Google Scholar 

  26. Inotsume N, Nishimura M, Nakano M, Fujiyama S, Sato T. The inhibitory effect of probenecid on renal excretion of famotidine in young, healthy volunteers. J Clin Pharmacol. 1990;30:50–6.

    PubMed  CAS  Google Scholar 

  27. Tahara H, Kusuhara H, Chida M, Fuse E, Sugiyama Y. Is the monkey an appropriate animal model to examine drug-drug interactions involving renal clearance? Effect of probenecid on the renal elimination of H2 receptor antagonists. J Pharmacol Exp Ther. 2006;316:1187–94.

    Article  PubMed  CAS  Google Scholar 

  28. 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  PubMed  CAS  Google Scholar 

  29. Shu Y, Brown C, Castro RA, Shi RJ, Lin ET, Owen RP, Sheardown SA, Yue L, Burchard EG, Brett CM, Giacomini KM. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther. 2008;83:273–80.

    Article  PubMed  CAS  Google Scholar 

  30. Breedveld P, Zelcer N, Pluim D, Sonmezer O, Tibben MM, Beijnen JH, Schinkel AH, van Tellingen O, Borst P, Schellens JH. Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions. Cancer Res. 2004;64:5804–11.

    Article  PubMed  CAS  Google Scholar 

  31. VanWert AL, Bailey RM, Sweet DH. Organic anion transporter 3 (Oat3/Slc22a8) knockout mice exhibit altered clearance and distribution of penicillin G. Am J Physiol Renal Physiol. 2007;293:F1332–F41.

    Article  PubMed  CAS  Google Scholar 

  32. Shiga T, Hashiguchi M, Urae A, Kasanuki H, Rikihisa T. Effect of cimetidine and probenecid on pilsicainide renal clearance in humans. Clin Pharmacol Ther. 2000;67:222–8.

    Article  PubMed  CAS  Google Scholar 

  33. Chung JY, Cho JY, Yu KS, Kim JR, Oh DS, Jung HR, Lim KS, Moon KH, Shin SG, Jang IJ. Effect of OATP1B1 (SLCO1B1) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers. Clin Pharmacol Ther. 2005;78:342–50.

    Article  PubMed  CAS  Google Scholar 

  34. Hirano M, Maeda K, Matsushima S, Nozaki Y, Kusuhara H, Sugiyama Y. Involvement of BCRP (ABCG2) in the biliary excretion of pitavastatin. Mol Pharmacol. 2005;68:800–7.

    PubMed  CAS  Google Scholar 

  35. Bauer LA, Black DJ, Lill JS, Garrison J, Raisys VA, Hooton TM. Levofloxacin and ciprofloxacin decrease procainamide and N-acetylprocainamide renal clearances. Antimicrob Agents Chemother. 2005;49:1649–51.

    Article  PubMed  CAS  Google Scholar 

  36. Somogyi A, McLean A, Heinzow B. Cimetidine-procainamide pharmacokinetic interaction in man: evidence of competition for tubular secretion of basic drugs. Eur J Clin Pharmacol. 1983;25:339–45.

    Article  PubMed  CAS  Google Scholar 

  37. Kajosaari LI, Niemi M, Neuvonen M, Laitila J, Neuvonen PJ, Backman JT. Cyclosporine markedly raises the plasma concentrations of repaglinide. Clin Pharmacol Ther. 2005;78:388–99.

    Article  PubMed  CAS  Google Scholar 

  38. Simonson SG, Raza A, Martin PD, Mitchell PD, Jarcho JA, Brown CD, Windass AS, Schneck DW. Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine. Clin Pharmacol Ther. 2004;76:167–77.

    Article  PubMed  CAS  Google Scholar 

  39. Schneck DW, Birmingham BK, Zalikowski JA, Mitchell PD, Wang Y, Martin PD, Lasseter KC, Brown CD, Windass AS, Raza A. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther. 2004;75:455–63.

    Article  PubMed  CAS  Google Scholar 

  40. Carr RA, Pasutto FM, Foster RT. Influence of cimetidine coadministration on the pharmacokinetics of sotalol enantiomers in an anaesthetized rat model: evidence supporting active renal excretion of sotalol. Biopharm Drug Dispos. 1996;17:55–69.

    Article  PubMed  CAS  Google Scholar 

  41. Ullrich KJ. Affinity of drugs to the different renal transporters for organic anions and organic cations. In: Amidon GL, Sadee W, editors. Membrane Transporters as Drug Targets. New York: Kluwer Academic/Plenum Publishers; 1999. pp. 159–79.

    Google Scholar 

  42. Yokogawa K, Takahashi M, Tamai I, Konishi H, Nomura M, Moritani S, Miyamoto K, Tsuji A. P-glycoprotein-dependent disposition kinetics of tacrolimus: studies in mdr1a knockout mice. Pharm Res. 1999;16:1213–8.

    Article  PubMed  CAS  Google Scholar 

  43. Bajcetic M, Benndorf RA, Appel D, Schwedhelm E, Schulze F, Riekhof D, Maas R, Boger RH. Pharmacokinetics of oral doses of telmisartan and nisoldipine, given alone and in combination, in patients with essential hypertension. J Clin Pharmacol. 2007;47:295–304.

    Article  PubMed  CAS  Google Scholar 

  44. Oh YH, Han HK. Pharmacokinetic interaction of tetracycline with non-steroidal anti-inflammatory drugs via organic anion transporters in rats. Pharmacol Res. 2006;53:75–9.

    Article  PubMed  CAS  Google Scholar 

  45. Dresser MJ, Leabman MK, Giacomini KM. Transporters involved in the elimination of drugs in the kidney: organic anion transporters and organic cation transporters. J Pharm Sci. 2001;90:397–421.

    Article  PubMed  CAS  Google Scholar 

  46. van Giersbergen PL, Bodin F, Dingemanse J. Cyclosporin increases the exposure to tezosentan, an intravenous dual endothelin receptor antagonist. Eur J Clin Pharmacol. 2002;58:243–5.

    Article  PubMed  Google Scholar 

  47. Zamboni WC, Houghton PJ, Johnson RK, Hulstein JL, Crom WR, Cheshire PJ, Hanna SK, Richmond LB, Luo X, Stewart CF. Probenecid alters topotecan systemic and renal disposition by inhibiting renal tubular secretion. J Pharmacol Exp Ther. 1998;284:89–94.

    PubMed  CAS  Google Scholar 

  48. Su Y, Hu P, Lee SH, Sinko PJ. Using novobiocin as a specific inhibitor of breast cancer resistant protein to assess the role of transporter in the absorption and disposition of topotecan. J Pharm Pharmaceut Sci. 2007;10:519–36.

    Google Scholar 

  49. Yagi Y, Shibutani S, Hodoshima N, Ishiwata K, Okudaira N, Li Q, Sai Y, Kato Y, Tsuji A. Involvement of multiple transport systems in the disposition of an active metabolite of a prodrug-type new quinolone antibiotic, prulifloxacin. Drug Metab Pharmacokinet. 2003;18:381–9.

    Article  PubMed  CAS  Google Scholar 

  50. Yagi Y, Aoki M, Iguchi M, Shibasaki S, Kurosawa T, Kato Y, Tsuji A. Transporter-mediated hepatic uptake of ulifloxacin, an active metabolite of a prodrug-type new quinolone antibiotic prulifloxacin, in rats. Drug Metab Pharmacokinet. 2007;22:350–7.

    Article  PubMed  Google Scholar 

  51. Nakashima M, Uematsu T, Kosuge K, Okuyama Y, Morino A, Ozaki M, Takebe Y. Pharmacokinetics and safety of NM441, a new quinolone, in healthy male volunteers. J Clin Pharmacol. 1994;34:930–7.

    PubMed  CAS  Google Scholar 

  52. Yamashiro W, Maeda K, Hirouchi M, Adachi Y, Hu Z, Sugiyama Y. Involvement of transporters in the hepatic uptake and biliary excretion of valsartan, a selective antagonist of the angiotensin II AT1-receptor, in humans. Drug Metab Dispos. 2006;34:1247–54.

    Article  PubMed  CAS  Google Scholar 

  53. 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.

    Article  PubMed  CAS  Google Scholar 

  54. Hagenbuch B, Meier PJ. Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch. 2004;447:653–65.

    Article  PubMed  CAS  Google Scholar 

  55. Guyton AC, Hall JE. Textbook of Medical Physiology. Philadelphia: Elsevier Saunders; 2006.

    Google Scholar 

  56. Sweet DH, Miller DS, Pritchard JB, Fujiwara Y, Beier DR, Nigam SK. Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice. J Biol Chem. 2002;277:26934–43.

    Article  PubMed  CAS  Google Scholar 

  57. van der Valk P, van Kalken CK, Ketelaars H, Broxterman HJ, Scheffer G, Kuiper CM, Tsuruo T, Lankelma J, Meijer CJ, Pinedo HM. Distribution of multi-drug resistance-associated P-glycoprotein in normal and neoplastic human tissues. Analysis with 3 monoclonal antibodies recognizing different epitopes of the P-glycoprotein molecule. Ann Oncol 1990;1:56–64.

    PubMed  Google Scholar 

  58. Croop JM, Raymond M, Haber D, Devault A, Arceci RJ, Gros P, Housman DE. The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues. Mol Cell Biol. 1989;9:1346–50.

    PubMed  CAS  Google Scholar 

  59. Tanaka Y, Slitt AL, Leazer TM, Maher JM, Klaassen CD. Tissue distribution and hormonal regulation of the breast cancer resistance protein (Bcrp/Abcg2) in rats and mice. Biochem Biophys Res Commun. 2005;326:181–7.

    Article  PubMed  CAS  Google Scholar 

  60. Pavlova A, Sakurai H, Leclercq B, Beier DR, Yu AS, Nigam SK. Developmentally regulated expression of organic ion transporters NKT (OAT1), OCT1, NLT (OAT2), and Roct. Am J Physiol Renal Physiol. 2000;278:F635–F43.

    PubMed  CAS  Google Scholar 

  61. Sekine T, Cha SH, Endou H. The multispecific organic anion transporter (OAT) family. Eur J Physiol. 2000;440:337–50.

    Article  CAS  Google Scholar 

  62. Cha SH, Sekine T, Kusuhara H, Yu E, Kim JY, Kim DK, Sugiyama Y, Kanai Y, Endou H. Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta. J Biol Chem. 2000;275:4507–12.

    Article  PubMed  CAS  Google Scholar 

  63. Kobayashi Y, Ohshiro N, Shibusawa A, Sasaki T, Tokuyama S, Sekine T, Endou H, Yamamoto T. Isolation, characterization and differential gene expression of multispecific organic anion transporter 2 in mice. Mol Pharmacol. 2002;62:7–14.

    Article  PubMed  CAS  Google Scholar 

  64. Wang Q, Yang H, Miller DW, Elmquist WF. Effect of the P-glycoprotein inhibitor, cyclosporin A, on the distribution of rhodamine-123 to the brain: an in vivo microdialysis study in freely moving rats. Biochem Biophys Res Commun. 1995;211:719–26.

    Article  PubMed  CAS  Google Scholar 

  65. Kunihara M, Nagai J, Murakami T, Takano M. Renal excretion of rhodamine 123, a P-glycoprotein substrate, in rats with glycerol-induced acute renal failure. J Pharm Pharmacol. 1998;50:1161–5.

    PubMed  CAS  Google Scholar 

  66. Tachibana-Iimori R, Tabara Y, Kusuhara H, Kohara K, Kawamoto R, Nakura J, Tokunaga K, Kondo I, Sugiyama Y, Miki T. Effect of genetic polymorphism of OATP-C (SLCO1B1) on lipid-lowering response to HMG-CoA reductase inhibitors. Drug Metab Pharmacokinet. 2004;19:375–80.

    Article  PubMed  CAS  Google Scholar 

  67. Lin JH, Los LE, Ulm EH, Duggan DE. Kinetic studies on the competition between famotidine and cimetidine in rats. Evidence of multiple renal secretory systems for organic cations. Drug Metab Dispos 1988;16:52–6.

    PubMed  CAS  Google Scholar 

  68. Lau YY. Examining the regulation of hepatic drug disposition and metabolism by organic anion transporting peptide, p-glycoprotein, and multidrug resistance-associated protein 2 [dissertation]. San Francisco: University of California; 2006.

    Google Scholar 

  69. Kugler AR, Olson SC, Smith DE. Tubular transport mechanisms of quinapril and quinaprilat in the isolated perfused rat kidney: effect of organic anions and cations. J Pharmacokinet Biopharm. 1996;24:349–68.

    Article  PubMed  CAS  Google Scholar 

  70. Wu CY. The interactive roles of p-glycoprotein and cytochrome P-450 3A in intestinal and hepatic drug disposition [dissertation]. San Francisco: University of California; 2003.

    Google Scholar 

  71. Booth CL, Brouwer KR, Brouwer KL. Effect of multidrug resistance modulators on the hepatobiliary disposition of doxorubicin in the isolated perfused rat liver. Cancer Res. 1998;58:3641–8.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by NIH grants GM61390 and GM75900, as well as by an unrestricted grant from Amgen, Inc.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Leslie Z. Benet.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grover, A., Benet, L.Z. Effects of Drug Transporters on Volume of Distribution. AAPS J 11, 250–261 (2009). https://doi.org/10.1208/s12248-009-9102-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12248-009-9102-7

Key words

Navigation