Skip to main content

Advertisement

SpringerLink
Log in

Saturable Absorptive Transport of the Hydrophilic Organic Cation Ranitidine in Caco-2 Cells: Role of pH-Dependent Organic Cation Uptake System and P-Glycoprotein

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Purpose

The purpose of this work was to investigate the involvement of carrier-mediated apical (AP) uptake and efflux mechanisms in the absorptive intestinal transport of the hydrophilic cationic drug ranitidine in Caco-2 cells.

Methods

Absorptive transport and AP uptake of ranitidine were determined in Caco-2 cells as a function of concentration. Permeability of ranitidine in the absorptive and secretory directions was assessed in the absence or presence of the P-glycoprotein (P-gp) inhibitor, GW918. Characterization of the uptake mechanism was performed with respect to inhibitor specificity, pH, energy, membrane potential, and Na+ dependence. Efflux from preloaded monolayers was evaluated over a range of concentrations and in the absence or presence of high extracellular ranitidine concentrations.

Results

Saturable absorptive transport and AP uptake of ranitidine were observed with K m values of 0.27 and 0.45 mM, respectively. The ranitidine absorptive permeability increased and secretory permeability decreased upon inhibition of P-gp. AP ranitidine uptake was inhibited in a concentration-dependent fashion by a diverse set of organic cations including tetraethylammonium, 1-methyl-4-phenylpyridinium, famotidine, and quinidine. AP ranitidine uptake was pH and membrane potential dependent and reduced under conditions that deplete metabolic energy. Efflux of [3H]ranitidine across the basolateral membrane was neither saturable as a function of concentration nor trans stimulated by unlabeled ranitidine.

Conclusions

Saturable absorptive transport of ranitidine in Caco-2 cells is partially mediated via a pH-dependent uptake transporter for organic cations and is subject to attenuation by P-gp. Inhibition and driving force studies suggest the uptake carrier exhibits similar properties to cloned human organic cation transporters. The results also imply ranitidine transport is not solely restricted to the paracellular space.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

AP:

apical

BL:

basolateral

CL eff :

efflux clearance

HBSS:

Hank’s balanced salt solution

MPP+ :

1-methyl-4-phenyl pyridinium

NMDG:

N-methyl-d-glucamine

OCT:

organic cation transporter

OCTN:

novel organic cation transporter

P-gp:

P-glycoprotein

TEA:

tetraethylammonium

TMA:

tetramethylammonium

2,4-DNP:

2,4-dinitrophenol

References

  1. J. H. Lin (1991) ArticleTitlePharmacokinetic and pharmacodynamic properties of histamine H2-receptor antagonists. Relationship between intrinsic potency and effective plasma concentrations Clin. Pharmacokinet. 20 218–236 Occurrence Handle1673880 Occurrence Handle1:CAS:528:DyaK3MXlt1Kjtb4%3D Occurrence Handle10.2165/00003088-199120030-00004

    Article  PubMed  CAS  Google Scholar 

  2. G. Coruzzi M. Adami C. Pozzoli F. Giorgi G. Bertaccini (1996) ArticleTitleCardiac and gastric effects of histamine H2 receptor antagonists: no evidence for a correlation between lipophilicity and receptor affinity Br. J. Pharmacol. 118 1813–1821 Occurrence Handle8842448 Occurrence Handle1:CAS:528:DyaK28XkvVartro%3D

    PubMed  CAS  Google Scholar 

  3. L. S. Gan P. H. Hsyu J. F. Pritchard D. Thakker (1993) ArticleTitleMechanism of intestinal absorption of ranitidine and ondansetron: transport across Caco-2 cell monolayers Pharm. Res. 10 1722–1725 Occurrence Handle8302757 Occurrence Handle1:CAS:528:DyaK2cXmvVyhsg%3D%3D Occurrence Handle10.1023/A:1018965929419

    Article  PubMed  CAS  Google Scholar 

  4. A. Collett N. B. Higgs E. Sims M. Rowland G. Warhurst (1999) ArticleTitleModulation of the permeability of H2 receptor antagonists cimetidine and ranitidine by P-glycoprotein in rat intestine and the human colonic cell line Caco-2 J. Pharmacol. Exp. Ther. 288 171–178 Occurrence Handle9862768 Occurrence Handle1:CAS:528:DyaK1MXisVyrsw%3D%3D

    PubMed  CAS  Google Scholar 

  5. K. Lee D. R. Thakker (1999) ArticleTitleSaturable transport of H2-antagonists ranitidine and famotidine across Caco-2 cell monolayers J. Pharm. Sci. 88 680–687 Occurrence Handle10393565 Occurrence Handle1:CAS:528:DyaK1MXjt1Sjtr0%3D Occurrence Handle10.1021/js980474k

    Article  PubMed  CAS  Google Scholar 

  6. J. H. Moreno (1975) ArticleTitleBlockage of gallbladder tight junction cation-selective channels by 2,4,6-triaminopyrimidinium (TAP) J. Gen. Physiol. 66 97–115 Occurrence Handle1159404 Occurrence Handle1:CAS:528:DyaE2MXkslGqs74%3D Occurrence Handle10.1085/jgp.66.1.97

    Article  PubMed  CAS  Google Scholar 

  7. D. L. Bourdet J. B. Pritchard D. R. Thakker (2005) ArticleTitleDifferential substrate and inhibitory activities of ranitidine and famotidine toward human organic cation transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3) J. Pharmacol. Exp. Ther. 315 1288–1297 Occurrence Handle16141367 Occurrence Handle1:CAS:528:DC%2BD2MXhtlalurnE Occurrence Handle10.1124/jpet.105.091223

    Article  PubMed  CAS  Google Scholar 

  8. W. M. Barendt S. H. Wright (2002) ArticleTitleThe human organic cation transporter (hOCT2) recognizes the degree of substrate ionization J. Biol. Chem. 277 22491–22496 Occurrence Handle11953440 Occurrence Handle1:CAS:528:DC%2BD38XltVGkt7s%3D Occurrence Handle10.1074/jbc.M203114200

    Article  PubMed  CAS  Google Scholar 

  9. H. Motohashi Y. Uwai K. Hiramoto M. Okuda K. Inui (2004) ArticleTitleDifferent transport properties between famotidine and cimetidine by human renal organic ion transporters (SLC22A) Eur. J. Pharmacol. 503 25–30 Occurrence Handle15496291 Occurrence Handle1:CAS:528:DC%2BD2cXovFagur0%3D Occurrence Handle10.1016/j.ejphar.2004.09.032

    Article  PubMed  CAS  Google Scholar 

  10. S. H. Cha T. Sekine J. I. Fukushima Y. Kanai Y. Kobayashi T. Goya H. Endou (2001) ArticleTitleIdentification and characterization of human organic anion transporter 3 expressing predominantly in the kidney Mol. Pharmacol. 59 1277–1286 Occurrence Handle11306713 Occurrence Handle1:CAS:528:DC%2BD3MXjt1aqtbo%3D

    PubMed  CAS  Google Scholar 

  11. Y. Nagata H. Kusuhara S. Hirono H. Endou Y. Sugiyama (2004) ArticleTitleCarrier-mediated uptake of H2-receptor antagonists by the rat choroid plexus: involvement of rat organic anion transporter 3 Drug Metab. Dispos. 32 1040–1047 Occurrence Handle15319347 Occurrence Handle1:CAS:528:DC%2BD2cXnsVegtbk%3D

    PubMed  CAS  Google Scholar 

  12. H. Nakamura H. Sano M. Yamazaki Y. Sugiyama (1994) ArticleTitleCarrier-mediated active transport of histamine H2 receptor antagonists, cimetidine and nizatidine, into isolated rat hepatocytes: contribution of type I system J. Pharmacol. Exp. Ther. 269 1220–1227 Occurrence Handle7912279 Occurrence Handle1:CAS:528:DyaK2cXkslenurY%3D

    PubMed  CAS  Google Scholar 

  13. S. P. Boom F. G. Russel (1993) ArticleTitleCimetidine uptake and interactions with cationic drugs in freshly isolated proximal tubular cells of the rat J. Pharmacol. Exp. Ther. 267 1039–1044 Occurrence Handle8263763 Occurrence Handle1:CAS:528:DyaK2cXmvVygsg%3D%3D

    PubMed  CAS  Google Scholar 

  14. K. J. Ullrich G. Rumrich C. David G. Fritzsch (1993) ArticleTitleBisubstrates: substances that interact with renal contraluminal organic anion and organic cation transport systems. I. Amines, piperidines, piperazines, azepines, pyridines, quinolines, imidazoles, thiazoles, guanidines and hydrazines Pflugers Arch. 425 280–299 Occurrence Handle8309790 Occurrence Handle1:CAS:528:DyaK2cXpsVOltg%3D%3D Occurrence Handle10.1007/BF00374179

    Article  PubMed  CAS  Google Scholar 

  15. N. Piyapolrungroj C. Li R. L. Pisoni D. Fleisher (1999) ArticleTitleCimetidine transport in brush-border membrane vesicles from rat small intestine J. Pharmacol. Exp. Ther. 289 346–353 Occurrence Handle10087023 Occurrence Handle1:CAS:528:DyaK1MXit1Kht7o%3D

    PubMed  CAS  Google Scholar 

  16. K. Lee C. Ng K. L. R. Brouwer D. R. Thakker (2002) ArticleTitleSecretory transport of ranitidine and famotidine across Caco-2 cell monolayers J. Pharmacol. Exp. Ther. 303 574–580 Occurrence Handle12388638 Occurrence Handle1:CAS:528:DC%2BD38XotlCgu70%3D Occurrence Handle10.1124/jpet.102.038521

    Article  PubMed  CAS  Google Scholar 

  17. M. D. Troutman D. R. Thakker (2003) ArticleTitleRhodamine 123 requires carrier-mediated influx for its activity as a P-glycoprotein substrate in Caco-2 cells Pharm. Res. 20 1192–1199 Occurrence Handle12948017 Occurrence Handle1:CAS:528:DC%2BD3sXmtVGrtLk%3D Occurrence Handle10.1023/A:1025096930604

    Article  PubMed  CAS  Google Scholar 

  18. M. D. Troutman D. R. Thakker (2003) ArticleTitleEfflux ratio cannot assess P-glycoprotein-mediated attenuation of absorptive transport: asymmetric effect of P-glycoprotein on absorptive and secretory transport across Caco-2 cell monolayers Pharm. Res. 20 1200–1209 Occurrence Handle12948018 Occurrence Handle1:CAS:528:DC%2BD3sXmtVGrtLY%3D Occurrence Handle10.1023/A:1025049014674

    Article  PubMed  CAS  Google Scholar 

  19. P. Schmiedlin-Ren K. E. Thummel J. M. Fisher M. F. Paine K. S. Lown P. B. Watkins (1997) ArticleTitleExpression of enzymatically active CYP3A4 by Caco-2 cells grown on extracellular matrix-coated permeable supports in the presence of 1alpha,25-dihydroxyvitamin D3 Mol. Pharmacol. 51 741–754 Occurrence Handle9145912 Occurrence Handle1:CAS:528:DyaK2sXjt1ehtr0%3D

    PubMed  CAS  Google Scholar 

  20. F. Hyafil C. Vergely P. Vignaud ParticleDu T. Grand-Perret (1993) ArticleTitleIn vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative Cancer Res. 53 4595–4602 Occurrence Handle8402633 Occurrence Handle1:CAS:528:DyaK2cXitlWnsA%3D%3D

    PubMed  CAS  Google Scholar 

  21. A. Blais P. Bissonnette A. Berteloot (1987) ArticleTitleCommon characteristics for Na+-dependent sugar transport in Caco-2 cells and human fetal colon J. Membr. Biol. 99 113–125 Occurrence Handle3123697 Occurrence Handle1:CAS:528:DyaL1cXhvFKmsA%3D%3D Occurrence Handle10.1007/BF01871231

    Article  PubMed  CAS  Google Scholar 

  22. A. H. Dantzig L. Bergin (1990) ArticleTitleUptake of the cephalosporin, cephalexin, by a dipeptide transport carrier in the human intestinal cell line, Caco-2 Biochim. Biophys. Acta 1027 211–217 Occurrence Handle2397233 Occurrence Handle1:CAS:528:DyaK3cXls1Cqs78%3D Occurrence Handle10.1016/0005-2736(90)90309-C

    Article  PubMed  CAS  Google Scholar 

  23. W. S. Putnam S. Ramanathan L. Pan L. H. Takahashi L. Z. Benet (2002) ArticleTitleFunctional characterization of monocarboxylic acid, large neutral amino acid, bile acid and peptide transporters, and P-glycoprotein in MDCK and Caco-2 cells J. Pharm. Sci. 91 2622–2635 Occurrence Handle12434407 Occurrence Handle1:CAS:528:DC%2BD38XptVeksbc%3D Occurrence Handle10.1002/jps.10264

    Article  PubMed  CAS  Google Scholar 

  24. H. Mizuuchi T. Katsura K. Ashida Y. Hashimoto K. Inui (2000) ArticleTitleDiphenhydramine transport by pH-dependent tertiary amine transport system in Caco-2 cells Am. J. Physiol. Gastrointest. Liver Physiol. 278 G563–G569 Occurrence Handle10762610 Occurrence Handle1:CAS:528:DC%2BD3cXis12iu7c%3D

    PubMed  CAS  Google Scholar 

  25. Y. H. Han D. H. Sweet D. N. Hu J. B. Pritchard (2001) ArticleTitleCharacterization of a novel cationic drug transporter in human retinal pigment epithelial cells J. Pharmacol. Exp. Ther. 296 450–457 Occurrence Handle11160630 Occurrence Handle1:CAS:528:DC%2BD3MXoslaqtA%3D%3D

    PubMed  CAS  Google Scholar 

  26. O. H. Brokl C. L. Martinez A. Shuprisha D. E. Abbott W. H. Dantzler (1998) ArticleTitleRegulation of intracellular pH in proximal tubules of avian long-looped mammalian-type nephrons Am. J. Physiol. 274 R1526–R1535 Occurrence Handle9608005 Occurrence Handle1:CAS:528:DyaK1cXkt1ajsr8%3D

    PubMed  CAS  Google Scholar 

  27. F. Martel D. Grundemann C. Calhau E. Schomig (2001) ArticleTitleApical uptake of organic cations by human intestinal Caco-2 cells: putative involvement of ASF transporters Naunyn Schmiedebergs Arch. Pharmacol. 363 40–49 Occurrence Handle11191835 Occurrence Handle1:CAS:528:DC%2BD3MXitVyisQ%3D%3D Occurrence Handle10.1007/s002100000335

    Article  PubMed  CAS  Google Scholar 

  28. H. Mizuuchi T. Katsura Y. Hashimoto K. Inui (2000) ArticleTitleTransepithelial transport of diphenhydramine across monolayers of the human intestinal epithelial cell line Caco-2 Pharm. Res. 17 539–545 Occurrence Handle10888305 Occurrence Handle1:CAS:528:DC%2BD3cXksVGqurw%3D Occurrence Handle10.1023/A:1007560731098

    Article  PubMed  CAS  Google Scholar 

  29. L. Zhang W. Gorset M. J. Dresser K. M. Giacomini (1999) ArticleTitleThe interaction of n-tetraalkylammonium compounds with a human organic cation transporter, hOCT1 J. Pharmacol. Exp. Ther. 288 1192–1198 Occurrence Handle10027858 Occurrence Handle1:CAS:528:DyaK1MXhs1Kisrg%3D

    PubMed  CAS  Google Scholar 

  30. S. Hong. A Novel Paracellular Transport Mechanism of Hydrophilic Cations Across Intestinal Epithelium. Division of Drug Delivery and Disposition, University of North Carolina at Chapel Hill, Chapel Hill, 2004, p. 171.

  31. A. Collett E. Sims D. Walker Y. L. He J. Ayrton M. Rowland G. Warhurst (1996) ArticleTitleComparison of HT29-18-C1 and Caco-2 cell lines as models for studying intestinal paracellular drug absorption Pharm. Res. 13 216–221 Occurrence Handle8932439 Occurrence Handle1:CAS:528:DyaK28Xht1Okur0%3D Occurrence Handle10.1023/A:1016082829111

    Article  PubMed  CAS  Google Scholar 

  32. M. Maliepaard M. A. Gastelen Particlevan A. Tohgo F. H. Hausheer R. C. Waardenburg Particlevan L. A. Jong Particlede D. Pluim J. H. Beijnen J. H. Schellens (2001) ArticleTitleCircumvention of breast cancer resistance protein (BCRP)-mediated resistance to camptothecins in vitro using non-substrate drugs or the BCRP inhibitor GF120918 Clin. Cancer Res. 7 935–941 Occurrence Handle11309344 Occurrence Handle1:CAS:528:DC%2BD3MXjs1elsbo%3D

    PubMed  CAS  Google Scholar 

  33. P. Pavek G. Merino E. Wagenaar E. Bolscher M. Novotna J. W. Jonker A. H. Schinkel (2005) ArticleTitleHuman breast cancer resistance protein: interactions with steroid drugs, hormones, the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and transport of cimetidine J. Pharmacol. Exp. Ther. 312 144–152 Occurrence Handle15365089 Occurrence Handle1:CAS:528:DC%2BD2MXhtVWmt7c%3D Occurrence Handle10.1124/jpet.104.073916

    Article  PubMed  CAS  Google Scholar 

  34. J. Taipalensuu H. Tornblom G. Lindberg C. Einarsson F. Sjoqvist H. Melhus P. Garberg B. Sjostrom B. Lundgren P. Artursson (2001) ArticleTitleCorrelation of gene expression of ten drug efflux proteins of the ATP-binding cassette transporter family in normal human jejunum and in human intestinal epithelial Caco-2 cell monolayers J. Pharmacol. Exp. Ther. 299 164–170 Occurrence Handle11561076 Occurrence Handle1:CAS:528:DC%2BD3MXntFWlt7Y%3D

    PubMed  CAS  Google Scholar 

  35. K. Bleasby S. Chauhan C. D. Brown (2000) ArticleTitleCharacterization of MPP+ secretion across human intestinal Caco-2 cell monolayers: role of P-glycoprotein and a novel Na(+)-dependent organic cation transport mechanism Br. J. Pharmacol. 129 619–625 Occurrence Handle10711363 Occurrence Handle1:CAS:528:DC%2BD3cXht1ynt70%3D Occurrence Handle10.1038/sj.bjp.0703078

    Article  PubMed  CAS  Google Scholar 

  36. M. Hayer-Zillgen M. Bruss H. Bonisch (2002) ArticleTitleExpression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3 Br. J. Pharmacol. 136 829–836 Occurrence Handle12110607 Occurrence Handle1:CAS:528:DC%2BD38XlvV2rurk%3D Occurrence Handle10.1038/sj.bjp.0704785

    Article  PubMed  CAS  Google Scholar 

  37. I. Elimrani K. Lahjouji E. Seidman M. J. Roy G. A. Mitchell I. Qureshi (2003) ArticleTitleExpression and localization of organic cation/carnitine transporter OCTN2 in Caco-2 cells Am. J. Physiol. Gastrointest. Liver Physiol. 284 G863–G871 Occurrence Handle12684216 Occurrence Handle1:CAS:528:DC%2BD3sXjvFGqu7c%3D

    PubMed  CAS  Google Scholar 

  38. Y. Urakami M. Okuda S. Masuda H. Saito K. I. Inui (1998) ArticleTitleFunctional characteristics and membrane localization of rat multispecific organic cation transporters, OCT1 and OCT2, mediating tubular secretion of cationic drugs J. Pharmacol. Exp. Ther. 287 800–805 Occurrence Handle9808712 Occurrence Handle1:CAS:528:DyaK1cXnsVerurk%3D

    PubMed  CAS  Google Scholar 

  39. R. Kekuda P. D. Prasad X. Wu H. Wang Y. J. Fei F. H. Leibach V. Ganapathy (1998) ArticleTitleCloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta J. Biol. Chem. 273 15971–15979 Occurrence Handle9632645 Occurrence Handle1:CAS:528:DyaK1cXkt1Gitbg%3D Occurrence Handle10.1074/jbc.273.26.15971

    Article  PubMed  CAS  Google Scholar 

  40. A. B. Suttle K. L. Brouwer (1995) ArticleTitleRegional gastrointestinal absorption of ranitidine in the rat Pharm. Res. 12 1311–1315 Occurrence Handle8570527 Occurrence Handle1:CAS:528:DyaK2MXpslOitLo%3D Occurrence Handle10.1023/A:1016269522828

    Article  PubMed  CAS  Google Scholar 

  41. C. M. Brandquist C. Ng D. R. Thakker K. L. Brouwer (2003) ArticleTitleNovel interactions in the oral absorption of hydrophilic cations: a clinical study with ranitidine and famotidine Clin. Pharmacol. Ther. 73 19 Occurrence Handle10.1016/S0009-9236(03)90425-5

    Article  Google Scholar 

  42. H. Koepsell B. M. Schmitt V. Gorboulev (2003) ArticleTitleOrganic cation transporters Rev. Physiol. Biochem. Pharmacol. 150 36–90 Occurrence Handle12827517 Occurrence Handle1:CAS:528:DC%2BD2cXjs1Wmsbw%3D

    PubMed  CAS  Google Scholar 

  43. L. Zhang M. J. Dresser A. T. Gray S. C. Yost S. Terashita K. M. Giacomini (1997) ArticleTitleCloning and functional expression of a human liver organic cation transporter Mol. Pharmacol. 51 913–921 Occurrence Handle9187257 Occurrence Handle1:CAS:528:DyaK2sXjvFWnsbo%3D

    PubMed  CAS  Google Scholar 

  44. S. Y. Zhou N. Piyapolrungroj L. Pao C. Li G. Liu E. Zimmermann D. Fleisher (1999) ArticleTitleRegulation of paracellular absorption of cimetidine and 5-aminosalicylate in rat intestine Pharm. Res. 16 1781–1785 Occurrence Handle10571287 Occurrence Handle1:CAS:528:DyaK1MXnt1GgsLc%3D Occurrence Handle10.1023/A:1018974519984

    Article  PubMed  CAS  Google Scholar 

  45. C. Grimellec ParticleLe G. Friedlander M. C. Giocondi (1988) ArticleTitleAsymmetry of plasma membrane lipid order in Madin–Darby canine kidney cells Am. J. Physiol. 255 F22–F32 Occurrence Handle3134820

    PubMed  Google Scholar 

  46. S. Ito C. Woodland B. Sarkadi G. Hockmann S. E. Walker G. Koren (1999) ArticleTitleModeling of P-glycoprotein-involved epithelial drug transport in MDCK cells Am. J. Physiol. 277 F84–F96 Occurrence Handle10409301 Occurrence Handle1:CAS:528:DyaK1MXkslKmtLg%3D

    PubMed  CAS  Google Scholar 

  47. K. A. Lentz J. W. Polli S. A. Wring J. E. Humphreys J. E. Polli (2000) ArticleTitleInfluence of passive permeability on apparent P-glycoprotein kinetics Pharm. Res. 17 1456–1460 Occurrence Handle11303953 Occurrence Handle1:CAS:528:DC%2BD3MXit1egsL8%3D Occurrence Handle10.1023/A:1007692622216

    Article  PubMed  CAS  Google Scholar 

  48. P. Artursson A. L. Ungell J. E. Lofroth (1993) ArticleTitleSelective paracellular permeability in two models of intestinal absorption: cultured monolayers of human intestinal epithelial cells and rat intestinal segments Pharm. Res. 10 1123–1129 Occurrence Handle8415396 Occurrence Handle1:CAS:528:DyaK3sXmtFKks74%3D Occurrence Handle10.1023/A:1018903931777

    Article  PubMed  CAS  Google Scholar 

  49. D. Sun H. Lennernas L. S. Welage J. L. Barnett C. P. Landowski D. Foster D. Fleisher K. D. Lee G. L. Amidon (2002) ArticleTitleComparison of human duodenum and Caco-2 gene expression profiles for 12,000 gene sequences tags and correlation with permeability of 26 drugs Pharm. Res. 19 1400–1416 Occurrence Handle12425456 Occurrence Handle1:CAS:528:DC%2BD38XnsFSgsLg%3D Occurrence Handle10.1023/A:1020483911355

    Article  PubMed  CAS  Google Scholar 

  50. D. L. Bourdet, G. M. Pollack, and D. R. Thakker. Intestinal absorptive transport of the hydrophilic cation ranitidine: a kinetic modeling approach to elucidate the role of uptake and efflux transporters and paracellular vs. transcellular transport in caco-2 cells. Pharm. Res. 23(6): (2006).

  51. C. Ng, D. R. Thakker, and K.L. Brouwer. Localization and expression of hOCT1 in Caco-2 cell monolayers. AAPS Pharm. Sci. 4:Abstract T2207 (2002).

Download references

Acknowledgments

David L. Bourdet was supported by a Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation predoctoral fellowship in Pharmaceutics. The Caco-2 cell line was kindly provided by Drs. Mary F. Paine and Paul Watkins of the University of North Carolina at Chapel Hill. GW918 and [3H]ranitidine were kindly provided by GlaxoSmithKline.

Author information

Authors and Affiliations

  1. Division of Molecular Pharmaceutics, School of Pharmacy, Kerr Hall, CB #7360, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-7360, USA

    David L. Bourdet & Dhiren R. Thakker

Authors
  1. David L. Bourdet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dhiren R. Thakker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dhiren R. Thakker.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bourdet, D.L., Thakker, D.R. Saturable Absorptive Transport of the Hydrophilic Organic Cation Ranitidine in Caco-2 Cells: Role of pH-Dependent Organic Cation Uptake System and P-Glycoprotein. Pharm Res 23, 1165–1177 (2006). https://doi.org/10.1007/s11095-006-0251-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-006-0251-4

Key Words

Search

Navigation