Skip to main content

Advertisement

SpringerLink
Log in

Use of In Vivo Animal Models to Assess Pharmacokinetic Drug-Drug Interactions

  • Expert Review
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Animal models are used commonly in various stages of drug discovery and development to aid in the prospective assessment of drug-drug interaction (DDI) potential and the understanding of the underlying mechanism for DDI of a drug candidate. In vivo assessments in an appropriate animal model can be very valuable, when used in combination with in vitro systems, to help verify in vivo relevance of the in vitro animal-based results, and thus substantiate the extrapolation of in vitro human data to clinical outcomes. From a pharmacokinetic standpoint, a key consideration for rational selection of an animal model is based on broad similarities to humans in important physiological and biochemical parameters governing drug absorption, distribution, metabolism or excretion (ADME) processes in question for both the perpetrator and victim drugs. Equally critical are specific in vitro and/or in vivo experiments to demonstrate those similarities, usually both qualitative and quantitative, in the ADME properties/processes under investigation. In this review, theoretical basis and specific examples are presented to illustrate the utility of the animal models in assessing the potential and understanding the mechanisms of DDIs.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ADME:

absorption, distribution, metabolism and excretion

CYP:

Cytochrome P450

DDI:

drug-drug interaction

i.pv.:

intra-hepatic portal vein

MRP:

multidrug resistance proteins

OAT/Oat:

organic anion transporters

OATP/Oatp:

organic anion transport polypeptides

OCT/Oct:

organic cation transporters

Pgp:

P-glycoprotein

REFERENCES

  1. Weaver RJ. Assessment of drug-drug interactions: concepts and approaches. Xenobiotica. 2001;31:499–538.

    Article  CAS  PubMed  Google Scholar 

  2. Worboys PD, Carlile DJ. Implications and consequences of enzyme induction on preclinical and clinical drug development. Xenobiotica. 2001;31:539–56.

    Article  CAS  PubMed  Google Scholar 

  3. Houston JB, Galetin A. Progress towards prediction of human pharmacokinetic parameters from in vitro technologies. Drug Metab Rev. 2003;35:393–415.

    Article  CAS  PubMed  Google Scholar 

  4. Ito K, Brown HS, Houston JB. Database analyses for the prediction of in vivo drug-drug interactions from in vitro data. Br J Clin Pharmacol. 2004;57:473–86.

    Article  CAS  PubMed  Google Scholar 

  5. Kanazu T, Yamaguchi Y, Okamura N, Baba T, Koike M. Model for the drug-drug interaction responsible for CYP3A enzyme inhibition. I: evaluation of cynomolgus monkeys as surrogates for humans. Xenobiotica. 2004;34:391–402.

    Article  CAS  PubMed  Google Scholar 

  6. Prueksaritanont T, Subramanian R, Fang X, Ma B, Qiu Y, Lin JH et al. Glucuronidation of statins in animals and humans: A novel mechanism of statin lactonization. Drug Metab Dispos. 2002;30:505–12.

    Article  CAS  PubMed  Google Scholar 

  7. Lin JH. Applications and limitations of genetically modified mouse models in drug discovery and development. Curr Drug Metab. 2008;9:419–38.

    Article  CAS  PubMed  Google Scholar 

  8. Lin JH. Species similarities and differences in pharmacokinetics. Drug Metab Dispos. 1995;23:1008–21.

    CAS  PubMed  Google Scholar 

  9. Lennernäs H. Animal data: the contributions of the Ussing Chamber and perfusion systems to predicting human oral drug delivery in vivo. Adv Drug Deliv Rev. 2007;59:1103–20.

    Article  PubMed  CAS  Google Scholar 

  10. Lentz KA, Quitko M, Morgan DG, Grace JE, Gleason C, Marathe PH. Development and validation of a preclinical food effect model. J Pharm Sci. 2007;96:459–72.

    Article  CAS  PubMed  Google Scholar 

  11. Paulson SK, Vaughn MB, Jessen SM, Lawal Y, Gresk CJ, Yan B et al. Pharmacokinetics of celecoxib after oral administration in dogs and humans: effect of food and site of absorption. J Pharmacol Exp Ther. 2001;297:638–45.

    CAS  PubMed  Google Scholar 

  12. Conrad S, Viertelhaus A, Orzechowski A, Hoogstraate J, Gjellan K, Schrenk D et al. Sequencing and tissue distribution of the canine MRP2 gene compared with MRP1 and MDR1. Toxicology. 2001;156:81–91.

    Article  CAS  PubMed  Google Scholar 

  13. Berggren S, Gall C, Wollnitz N, Ekelund M, Karlbom U, Hoogstraate J et al. Gene and protein expression of P-glycoprotein, MRP1, MRP2, and CYP3A4 in the small and large human intestine. Mol Pharm. 2007;4:252–7.

    Article  CAS  PubMed  Google Scholar 

  14. Schnell RC, Miya TS. Altered absorption of drugs from the rat small intestine by carbonic anhydrase inhibition. J Pharmacol Exp Ther. 1970;174:177–84.

    CAS  PubMed  Google Scholar 

  15. Hayton WL, Levy G. Effect of SKF 525-A on drug absorption in rats. Life Sci I. 1971;10:691–7.

    Article  CAS  PubMed  Google Scholar 

  16. McConnell EL, Basit AW, Murdan S. Measurements of rat and mouse gastrointestinal pH fluid and lymphoid tissue, and implications for in-vivo experiments. J Pharm Pharmacol. 2008;60:63–70.

    Article  CAS  PubMed  Google Scholar 

  17. Cao X, Gibbs ST, Fang L, Miller HA, Landowski CP, Shin HC et al. Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model. Pharm Res. 2006;23:1675–86.

    Article  CAS  PubMed  Google Scholar 

  18. Dahan A, Amidon GL. MRP2 mediated drug-drug interaction: Indomethacin increases sulfasalazine absorption in the small intestine, potentially decreasing its colonic targeting. Int J Pharm. 2009 Nov 26. doi:10.1016/j.ijpharm.2009.11.021.

  19. Ikegami K, Tagawa K, Narisawa S, Osawa T. Suitability of the cynomolgus monkey as an animal model for drug absorption studies of oral dosage forms from the viewpoint of gastrointestinal physiology. Biol Pharm Bull. 2003;26:1442–7.

    Article  CAS  PubMed  Google Scholar 

  20. Akabane T, Tabata K, Kadono K, Sakuda S, Terashita S, Teramura T. A Comparison of Pharmacokinetics Between Humans and Monkeys. Drug Metab Dispos. 2010;38:308–16.

    Article  CAS  PubMed  Google Scholar 

  21. Takahashi M, Washio T, Suzuki N, Igeta K, Yamashita S. The species differences of intestinal drug absorption and first-pass metabolism between cynomolgus monkeys and humans. J Pharm Sci. 2009;98:4343–53.

    Article  CAS  PubMed  Google Scholar 

  22. Takahashi M, Washio T, Suzuki N, Igeta K, Fujii Y, Hayashi M et al. Characterization of gastrointestinal drug absorption in cynomolgus monkeys. Mol Pharmaceut. 2008;5:340–8.

    Article  CAS  Google Scholar 

  23. Xia CQ, Xiao G, Liu N, Pimprale S, Fox L, Patten CJ et al. Comparison of species differences of P-glycoproteins in beagle dog, rhesus monkey, and human using Atpase activity assays. Mol Pharm. 2006;3:78–86.

    Article  CAS  PubMed  Google Scholar 

  24. Katoh M, Suzuyama N, Takeuchi T, Yoshitomi S, Asahi S, Yokoi T. Kinetic analyses for species differences in P-glycoprotein-mediated drug transport. J Pharm Sci. 2006;95:2673–83.

    Article  CAS  PubMed  Google Scholar 

  25. Suzuyama N, Katoh M, Takeuchi T, Yoshitomi S, Higuchi T, Asashi S et al. Species differences of inhibitory effects on P-glycoprotein-mediated drug transport. J Pharm Sci. 2007;96:1609–18.

    Article  CAS  PubMed  Google Scholar 

  26. Lai Y. Identification of interspecies difference in hepatobiliary transporters to improve extrapolation of human biliary secretion. Expert Opin Drug Metab Toxicol. 2009;5:1175–87.

    Article  CAS  PubMed  Google Scholar 

  27. Jin H, Di L. Permeability-in vitro assays for assessing drug transporter activity. Curr Drug Metab. 2008;9:911–20.

    Article  CAS  PubMed  Google Scholar 

  28. Löscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx. 2005;2:86–98.

    Article  PubMed  Google Scholar 

  29. Doran A, Obach RS, Smith BJ, Hosea NA, Becker S, Callegari E et al. The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model. Drug Metab Dispos. 2005;33:165–74.

    Article  CAS  PubMed  Google Scholar 

  30. Kemper EM, van Zandbergen AE, Cleypool C, Mos HA, Boogerd W, Beijnen JH et al. Increased penetration of paclitaxel into the brain by inhibition of P-Glycoprotein. Clin Cancer Res. 2003;9:2849–55.

    CAS  PubMed  Google Scholar 

  31. Takeuchi T, Yoshitomi S, Higuchi T, Ikemoto K, Niwa S, Ebihara T et al. Establishment and characterization of the transformants stably-expressing MDR1 derived from various animal species in LLC-PK1. Pharm Res. 2006;23:1460–72.

    Article  CAS  PubMed  Google Scholar 

  32. Kim IW, Booth-Genthe C, Ambudkar SV. Relationship between drugs and functional activity of various mammalian P-glycoproteins (ABCB1). Mini Rev Med Chem. 2008;8:193–200.

    Article  CAS  PubMed  Google Scholar 

  33. Tang C, Kuo Y, Pudvah NT, Ellis JD, Michener MS, Egbertson M et al. Effect of P-glycoprotein-mediated efflux on cerebrospinal fluid concentrations in rhesus monkeys. Biochem Pharmacol. 2009;78:642–7.

    Article  CAS  PubMed  Google Scholar 

  34. Zoghbi SS, Liow JS, Yasuno F, Hong J, Tuan E, Lazarova N et al. 11C-loperamide and its N-desmethyl radiometabolite are avid substrates for brain permeability-glycoprotein efflux. Nucl Med. 2008;49:649–56.

    Article  CAS  Google Scholar 

  35. Eyal S, Chung FS, Muzi M, Link JM, Mankoff DA, Kaddoumi A et al. Simultaneous PET imaging of P-glycoprotein inhibition in multiple tissues in the pregnant nonhuman primate. J Nucl Med. 2009;50:798–806.

    Article  CAS  PubMed  Google Scholar 

  36. Hsiao P, Bui T, Ho R, Unadkat JD. In Vitro to In Vivo Prediction of Pglycoprotein Based Drug Interactions at the Human and Rodent Blood-Brain Barrier. Drug Metab Dispos. 2008;36:481–4.

    Article  CAS  PubMed  Google Scholar 

  37. Eyal S, Hsiao P, Unadkat JD. Drug interactions at the blood-brain barrier: fact or fantasy? Pharmacol Ther. 2009;123:80–104.

    Article  CAS  PubMed  Google Scholar 

  38. Li P, Wang GJ, Robertson TA, Roberts MS. Liver transporters in hepatic drug disposition: an update. Curr Drug Metab. 2009;10:482–98.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  40. Harrison LI, Gibaldi M. Pharmacokinetics of digoxin in the rat. Drug Metab Dispos. 1976;4:88–93.

    CAS  PubMed  Google Scholar 

  41. 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  CAS  PubMed  Google Scholar 

  42. 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  CAS  PubMed  Google Scholar 

  43. Guengerich FP. Role of cytochrome P450 enzymes in drug-drug interactions. Adv Pharmacol. 1997;43:7–35.

    Article  CAS  PubMed  Google Scholar 

  44. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 2000;38:41–57.

    Article  CAS  PubMed  Google Scholar 

  45. Galetin A, Gertz M, Houston JB. Potential role of intestinal first-pass metabolism in the prediction of drug-drug interactions. Expert Opin Drug Metab Toxicol. 2008;4:909–22.

    Article  CAS  PubMed  Google Scholar 

  46. Sharer JE, Shipley LA, Vandenbranden MR, Binkley SN, Wrighton SA. Comparisons of phase I and phase II in vitro hepatic enzyme activities of human, dog, rhesus monkey, and cynomolgus monkey. Drug Metab Dispos. 1995;23:1231–41.

    CAS  PubMed  Google Scholar 

  47. Prueksaritanont T, Gorham LM, Hochman JH, Tran L, Vyas KP. Comparative studies of drug-metabolizing enzymes in dog, monkey, and human small intestines, and in Caco-2 cells. Drug Metab Dispos. 1996;24:634–42.

    CAS  PubMed  Google Scholar 

  48. Martignoni M, Groothuis GMM, de Kanter R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Op Drug Metab Toxico. 2006;2:875–94.

    Article  CAS  Google Scholar 

  49. Carr B, Norcross R, Fang YL, Lu P, Rodrigues AD, Shou MG et al. Characterization of the rhesus monkey CYP3A64 enzyme: Species comparisons of CYP3A substrate specificity and kinetics using baculovirus-expressed recombinant enzymes. Drug Metab Dispos. 2007;34:1703–12.

    Article  CAS  Google Scholar 

  50. Tang C, Fang Y, Booth-Genthe C, Kuo Y, Kuduk SD, Rushmore TH et al. Diclofenac hydroxylation in monkeys: efficiency, regioselectivity, and response to inhibitors. Biochem Pharmacol. 2007;73:880–90.

    Article  CAS  PubMed  Google Scholar 

  51. Eagling VA, Tjia JF, Back DJ. Differential selectivity of cytochrome P450 inhibitors against probe substrates in human and rat liver microsomes. Br J Clin Pharmacol. 1998;45:107–14.

    Article  CAS  PubMed  Google Scholar 

  52. Swinney DC. Progesterone metabolism in hepatic microsomes. Effect of the cytochrome P-450 inhibitor, ketoconazole, and the NADPH 5 alpha-reductase inhibitor, 4-MA, upon the metabolic profile in human, monkey, dog, and rat. Drug Metab Dispos. 1990;18:859–65.

    CAS  PubMed  Google Scholar 

  53. Ogasawara A, Negishi I, Kozakai K, Kume T. In vivo evaluation of drug-drug interaction via mechanism-based inhibition by macrolide antibiotics in cynomolgus monkeys. Drug Metab Dispos. 2009;37:2127–36.

    Article  CAS  PubMed  Google Scholar 

  54. Tang W, Stearns RA, Wang RW, Miller RR, Chen Q, Ngui J et al. Assessing and minimizing time-dependent inhibition of cytochrome P450 3A in drug discovery: a case study with melanocortin-4 receptor agonists. Xenobiotica. 2008;38:1437–51.

    Article  CAS  PubMed  Google Scholar 

  55. Prueksaritanont T, Kuo Y, Tang C, Li C, Qiu Y, Lu B et al. In vitro and in vivo CYP3A64 induction and inhibition studies in rhesus monkeys: A preclinical approach for CYP3A-mediated drug interaction studies. Drug Metab Dispos. 2006;34:1546–55.

    Article  CAS  PubMed  Google Scholar 

  56. Kim S, Dinchuk JE, Anthony MN, Orcutt T, Zoeckler ME, Sauer MB et al. Evaluation of cynomolgus monkey pregnane X receptor, primary hepatocyte, and in vivo pharmacokinetic changes in predicting human CYP3A4 induction. Drug Metab Dispos. 2010;38:16–24.

    Article  CAS  PubMed  Google Scholar 

  57. Nishibe Y, Wakabayashi M, Harauchi T, Ohno K. Characterization of cytochrome P450 (CYP3A12) induction by rifampicin in dog liver. Xenobiotica. 1998;28:549–57.

    Article  CAS  PubMed  Google Scholar 

  58. Graham RA, Downey A, Mudra D, Krueger L, Carroll K, Chengelis C et al. In vivo and in vitro induction of cytochrome P450 enzymes in beagle dogs. Drug Metab Dispos. 2002;30:1206–13.

    Article  CAS  PubMed  Google Scholar 

  59. Graham RA, Tyler LO, Krol WL, Silver IS, Webster LO, Clark P et al. Temporal kinetics and concentration-response relationships for induction of CYP1A, CYP2B, and CYP3A in primary cultures of beagle dog hepatocytes. J Biochem Mol Toxicol. 2006;20(2):69–78.

    Article  CAS  PubMed  Google Scholar 

  60. Kyokawa Y, Nishibe Y, Wakabayashi M, Harauchi T, Maruyama T, Baba T et al. Induction of intestinal cytochrome P450 (CYP3A) by rifampicin in beagle dogs. Chem Biol Interact. 2001;134:291–305.

    Article  CAS  PubMed  Google Scholar 

  61. Gibson GG, Plant NJ, Swales KE, Ayrton A, El-Sankary W. Receptor-dependent transcriptional activation of cytochrome P450 3A genes: induction, mechanisms, species differences and interindividual variations in man. Xenobiotica. 2002;32:165–206.

    Article  CAS  PubMed  Google Scholar 

  62. Komura H, Iwaki M. Species differences in in vitro and in vivo small intestinal metabolism of CYP3A substrates. J Pharm Sci. 2008;97:1775–800.

    Article  CAS  PubMed  Google Scholar 

  63. Iwasaki K, Uno Y. Cynomolgus monkey CYPs: a comparison with human CYPs. Xenobiotica. 2009;39:578–81.

    Article  CAS  PubMed  Google Scholar 

  64. Uno Y, Hiroko S, Shotaro U, Takayuki K, Kiyomi M, Chika N et al. A null allele impairs function of CYP2C76 gene in cynomolgus monkeys: a possible genetic tool for generation of a better animal model in drug metabolism. Mol Pharmacol. 2006;70:477–86.

    Article  CAS  PubMed  Google Scholar 

  65. Tang C, Carr BA, Poignant F, Ma B, Polsky-Fisher S, Kuo Y et al. CYP2C75-Involved Autoinduction of Metabolism in Rhesus Monkeys of MK-0686, a Bradykinin B1 Receptor Antagonist. J Pharmacol Exp Ther. 2008;325:935–46.

    Article  CAS  PubMed  Google Scholar 

  66. Grossman WH, SJ BSA, Diamond S, Wright MR, Grace JE, Qian MX et al. The chimpanzee (Pan troglodytes) as a pharmacokinetic model for selection of drug candidates: Model characterization and application. Drug Metab Dispos. 2004;32:1359–69.

    Article  PubMed  CAS  Google Scholar 

  67. Wong H, Grace JE, Wright MR, Browning MR, Grossman SJ, Bai SA et al. Glucuronidation in the chimpanzee (Pan troglodytes): Studies with acetaminophen, oestradiol and morphine. Xenobiotica. 2006;36:1178–90.

    Article  CAS  PubMed  Google Scholar 

  68. Williams ET, Schouest KR, Leyk M, Strobel HW. The chimpanzee cytochrome P450 3A subfamily: Is our closest related species really that similar? Comp Biochem Physiol D-Genom & Proteom. 2007;2:91–100.

    Google Scholar 

  69. Obach RS. Predicting drug-drug interactions from in vitro drug metabolism data: challenges and recent advances. Curr Opin Drug Discov Devel. 2009;12:81–9.

    CAS  PubMed  Google Scholar 

  70. Almond LM, Yang J, Jamei M, Tucker GT, Rostami-Hodjegan A. Towards a quantitative framework for the prediction of DDIs arising from cytochrome P450 induction. Curr Drug Metab. 2009 May;10(4):420–32.

    Article  CAS  PubMed  Google Scholar 

  71. Ohno Y, Hisaka A, Ueno M, Suzuki H. General framework for the prediction of oral drug interactions caused by CYP3A4 induction from in vivo information. Clin Pharmacokinet. 2008;47(10):669–80.

    Article  CAS  PubMed  Google Scholar 

  72. Kato M, Chiba K, Horikawa M, Sugiyama Y. The quantitative prediction of in vivo enzyme-induction caused by drug exposure from in vitro information on human hepatocytes. Drug Metab Pharmacokinet. 2005;20:236–43.

    Article  CAS  PubMed  Google Scholar 

  73. Xing L, Hu Y, Lai Y. Advancement of structure-activity relationship of multidrug resistance-associated protein 2 interactions. AAPS J. 2009;11:406–13.

    Article  CAS  PubMed  Google Scholar 

  74. Chandra P, Brouwer KL. The complexities of hepatic drug transport: current knowledge and emerging concepts. Pharm Res. 2004;21:719–35.

    Article  CAS  PubMed  Google Scholar 

  75. Li N, Zhang Y, Hua F, Lai Y. Absolute difference of hepatobiliary transporter multidrug resistance-associated protein (MRP2/Mrp2) in liver tissues and isolated hepatocytes from rat, dog, monkey, and human. Drug Metab Dispos. 2009;37:66–73.

    Article  CAS  PubMed  Google Scholar 

  76. Ninomiya M, Ito K, Horie T. Functional analysis of dog multidrug resistance-associated protein 2 (Mrp2) in comparison with rat Mrp2. Drug Metab Dispos. 2005;33:225–32.

    Article  CAS  PubMed  Google Scholar 

  77. Tahara H, Shono M, Kusuhara H, Kinoshita H, Fuse E, Takadate A et al. Molecular cloning and functional analyses of OAT1 and OAT3 from cynomolgus monkey kidney. Pharm Res. 2005;22:647–60.

    Article  CAS  PubMed  Google Scholar 

  78. Timchalk C. Comparative inter-species pharmacokinetics of phenoxyacetic acid herbicides and related organic acids. Evidence that the dog is not a relevant species for evaluation of human health risk. Toxicology. 2004;200:1–19.

    Article  CAS  PubMed  Google Scholar 

  79. Hasegawa M, Kusuhara H, Endou H, Sugiyama Y. Contribution of organic anion transporters to the renal uptake of anionic compounds and nucleoside derivatives in rat. J Pharmacol Exp Ther. 2003;305:1087–97.

    Article  CAS  PubMed  Google Scholar 

  80. Khamdang S, Takeda M, Shimoda M, Noshiro R, Narikawa S, Huang XL et al. Interactions of human- and rat-organic anion transporters with pravastatin and cimetidine. J Pharmacol Sci. 2004;94:197–202.

    Article  CAS  PubMed  Google Scholar 

  81. Zhang L, Zhang Y, Huang SM. Scientific and regulatory perspectives on metabolizing enzyme-transporter interplay and its role in drug interactions: challenges in predicting drug interactions. Mol Pharm. 2009;6:1766–74.

    Article  CAS  PubMed  Google Scholar 

  82. Endres CJ, Endres MG, Unadkat JD. Interplay of drug metabolism and transport: a real phenomenon or an artifact of the site of measurement? Mol Pharm. 2009;6:1756–65.

    Article  CAS  PubMed  Google Scholar 

  83. Benet LZ. The drug transporter-metabolism alliance: uncovering and defining the interplay. Mol Pharm. 2009;6:1631–43.

    Article  CAS  PubMed  Google Scholar 

  84. Shitara Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther. 2006;112:71–105.

    Article  CAS  PubMed  Google Scholar 

  85. Pal D, Mitra AK. MDR-and CYP3A4-mediated drug-drug interactions. J Neuroimmune Pharmacol. 2006;1:323–39.

    Article  PubMed  Google Scholar 

  86. Lam JL, Okochi H, Huang Y, Benet LZ. In vitro and in vivo correlation of hepatic transporter effects on erythromycin metabolism: characterizing the importance of transporter-enzyme interplay. Drug Metab Dispos. 2006;34:1336–44.

    Article  CAS  PubMed  Google Scholar 

  87. Schuetz EG, Yasuda K, Arimori K, Schuetz JD. Human MDR1 and mouse mdr1 P-glycoprotein alter the cellular retention and disposition of erythromycin, but not of retinoic acid or benzo(a)pyrene. Arch Biochem Biophys. 1998;350:340–7.

    Article  CAS  PubMed  Google Scholar 

  88. Sun H, Huang Y, Frassetto L, Benet LZ. Effects of uremic toxins on hepatic uptake and metabolism of erythromycin. Drug Metab Dispos. 2004;32:1239–46.

    Article  CAS  PubMed  Google Scholar 

  89. Ernest CS, Hall SD, Jones DR. Mechanism-based inactivation of CYP3A by HIV protease inhibitors. J Pharmacol Exp Ther. 2005;312:583–91.

    Article  CAS  PubMed  Google Scholar 

  90. Ogasawara A, Utoh M, Nii K, Ueda A, Yoshikawa T, Kume T et al. Effect of oral ketoconazole on oral and intravenous pharmacokinetics of simvastatin and its acid in cynomolgus monkeys. Drug Metab Dispos. 2009;37:122–8.

    Article  CAS  PubMed  Google Scholar 

  91. Kumar S, Samuel K, Subramanian R, Braun MP, Stearns RA, Chiu SL et al. Extrapolation of diclofenac clearance from in vitro microsomal metabolism data: role of acyl glucuronidation and sequential oxidative metabolism of the acyl glucuronide. J Pharmacol Exp Ther. 2002;303:969–78.

    Article  CAS  PubMed  Google Scholar 

  92. Prueksaritanont T, Li C, Kuo Y, Tang C, Strong-Basalyga K, Carr B. Rifampin induces the in vitro oxidative metabolism, but not the in vivo clearance of Diclofenac in rhesus monkeys. Drug Metab Dispos. 2006;34:1806–10.

    Article  CAS  PubMed  Google Scholar 

  93. Mandlekar SV, Rose AV, Cornelius G, Sleczka B, Caporuscio C, Wang J et al. Development of an in vivo rat screen model to predict pharmacokinetic interactions of CYP3A4 substrates. Xenobiotica. 2007;37:923–42.

    Article  CAS  PubMed  Google Scholar 

  94. Lin JH. Pharmacokinetic and pharmacodynamic properties of histamine H2-receptor antagonists: relationship between intrinsic potency and effective plasmaconcentrations. Clin Pharmacokinet. 1991;20:218–36.

    Article  CAS  PubMed  Google Scholar 

  95. 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.

    CAS  PubMed  Google Scholar 

  96. 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.

    CAS  PubMed  Google Scholar 

  97. Tahara H, Kusuhara H, Endou H, Koepsell H, Imaoka T, Fuse E et al. A species difference in the transport activities of H2 receptor antagonists by rat and human renal organic anion and cation transporters. J Pharmacol Exp Ther. 2005;315:337–45.

    Article  CAS  PubMed  Google Scholar 

  98. 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  CAS  PubMed  Google Scholar 

  99. Gisclon LG, Boyd RA, Williams RL, Giacomini KM. The effect of probenecid on the renal elimination of cimetidine. Clin Pharmacol Ther. 1989;45:444–52.

    CAS  PubMed  Google Scholar 

  100. Prueksaritanont T, Hochman JH, Meng Y, Pudvah NT, Barrish A, Ma B et al. Renal elimination of a novel and potent αvβ3 antagonist in animals. Xenobiotica. 2004;34:1059–74.

    Article  CAS  PubMed  Google Scholar 

  101. Matsubara T, Kim HJ, Miyata M, Shimada M, Nagata K, Yamazoe Y. Isolation and characterization of a new major intestinal CYP3A form, CYP3A62, in the rat. J Pharmacol Exp Ther. 2004;309:1282–90.

    Article  CAS  PubMed  Google Scholar 

  102. Shou M, Norcross R, Sandig G, Lu P, Li Y, Lin Y et al. Substrate specificity and kinetic properties of seven heterologously expressed dog cytochromes p450. Drug Metab Dispos. 2003;31:1161–9.

    Article  CAS  PubMed  Google Scholar 

  103. Wang H, Cheng JD, Montgomery D, Cheng KC. Evaluation of the binding orientations of testosterone in the active site of homology models for CYP2C11 and CYP2C13. Biochem Pharmacol. 2009;78:406–13.

    Article  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGEMENTS

The authors would like to thank Dr. Brian Carr for providing amino acid sequence homology information for primate CYPs and Dr. Kerry Fillgrove for proofreading the manuscript.

Author information

Authors and Affiliations

  1. Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Merck & Co., Inc., WP75A-203, West Point, Pennsylvania, 19486, USA

    Cuyue Tang & Thomayant Prueksaritanont

Authors
  1. Cuyue Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomayant Prueksaritanont
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomayant Prueksaritanont.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tang, C., Prueksaritanont, T. Use of In Vivo Animal Models to Assess Pharmacokinetic Drug-Drug Interactions. Pharm Res 27, 1772–1787 (2010). https://doi.org/10.1007/s11095-010-0157-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-010-0157-z

KEY WORDS

Search

Navigation