![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 299, Issue 2, 620-628, November 2001
Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline,
Inc., Research Triangle Park, North Carolina
P-glycoprotein (Pgp) affects the absorption, distribution, and
clearance of a variety of compounds. Thus, identification of compounds
that are Pgp substrates can aid drug candidate selection and
optimization. Our goal was to evaluate three assays used to determine
whether compounds are Pgp substrates. Sixty-six compounds were tested
in monolayer efflux, ATPase, and calcein-AM assays. Assay results
yielded two categories of compounds. Category I (n = 35) exhibited concordance across the assays. Category II (n = 31) revealed differences among the assays that
related to the apparent permeability (Papp) of the
compounds. Within category II, two groups were discerned based on the
absence (group IIA, n = 10, nontransported
substrates) or presence (group IIB, n = 21, transported substrates) of monolayer efflux. Detection of efflux (group
IIB) was associated with compounds having low/moderate Papp
values (mean = 16.6 nm/s), whereas inability to detect efflux (group IIA) was associated with compounds having high Papp
values (mean = 535 nm/s). The calcein-AM and ATPase assays
revealed Pgp interactions for highly permeable group IIA compounds but
were less responsive than monolayer efflux for low/moderate
Papp compounds of group IIB. All assays detected substrates
across a broad range of Papp, but the efflux assay was more
prone to fail at high Papp, whereas the calcein-AM and
ATPase assays were more prone to fail at low Papp. When
Papp is low, efflux is a greater factor in the disposition
of Pgp substrates. The efflux assay is more reliable at low/moderate
Papp and is the method of choice for evaluating drug
candidates despite low throughput and reliance on liquid chromatography
with tandem mass spectrometry.
This article has been cited by other articles:
|
|
 |
|
  H. H. Usansky, P. Hu, and P. J. Sinko Differential Roles of P-Glycoprotein, Multidrug Resistance-Associated Protein 2, and CYP3A on Saquinavir Oral Absorption in Sprague-Dawley Rats Drug Metab. Dispos., May 1, 2008; 36(5): 863 - 869. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shirasaka, Y. Masaoka, M. Kataoka, S. Sakuma, and S. Yamashita Scaling of in Vitro Membrane Permeability to Predict P-glycoprotein-Mediated Drug Absorption in Vivo Drug Metab. Dispos., May 1, 2008; 36(5): 916 - 922. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Polli, J. E. Humphreys, K. A. Harmon, S. Castellino, M. J. O'Mara, K. L. Olson, L. St. John-Williams, K. M. Koch, and C. J. Serabjit-Singh The Role of Efflux and Uptake Transporters in N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, Lapatinib) Disposition and Drug Interactions Drug Metab. Dispos., April 1, 2008; 36(4): 695 - 701. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Feng, J. B. Mills, R. E. Davidson, R. J. Mireles, J. S. Janiszewski, M. D. Troutman, and S. M. de Morais In Vitro P-glycoprotein Assays to Predict the in Vivo Interactions of P-glycoprotein with Drugs in the Central Nervous System Drug Metab. Dispos., February 1, 2008; 36(2): 268 - 275. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Sun and K. S. Pang Permeability, Transport, and Metabolism of Solutes in Caco-2 Cell Monolayers: A Theoretical Study Drug Metab. Dispos., January 1, 2008; 36(1): 102 - 123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Shaik, N. Giri, G. Pan, and W. F. Elmquist P-glycoprotein-Mediated Active Efflux of the Anti-HIV1 Nucleoside Abacavir Limits Cellular Accumulation and Brain Distribution Drug Metab. Dispos., November 1, 2007; 35(11): 2076 - 2085. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nishimura, N. Amano, Y. Kubo, M. Ono, Y. Kato, H. Fujita, Y. Kimura, and A. Tsuji Asymmetric Intestinal First-Pass Metabolism Causes Minimal Oral Bioavailability of Midazolam in Cynomolgus Monkey Drug Metab. Dispos., August 1, 2007; 35(8): 1275 - 1284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Venkatakrishnan, E. Tseng, F. R. Nelson, H. Rollema, J. L. French, I. V. Kaplan, W. E. Horner, and M. A. Gibbs Central Nervous System Pharmacokinetics of the Mdr1 P-Glycoprotein Substrate CP-615,003: Intersite Differences and Implications for Human Receptor Occupancy Projections from Cerebrospinal Fluid Exposures Drug Metab. Dispos., August 1, 2007; 35(8): 1341 - 1349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Okudaira, T. Kotegawa, H. Imai, K. Tsutsumi, S. Nakano, and K. Ohashi Effect of the Treatment Period With Erythromycin on Cytochrome P450 3A Activity in Humans J. Clin. Pharmacol., July 1, 2007; 47(7): 871 - 876. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Zhang, D. Zhang, W. Li, M. Yao, C. D'Arienzo, Y.-X. Li, W. R. Ewing, Z. Gu, Y. Zhu, N. Murugesan, et al. Reduction of Site-Specific CYP3A-Mediated Metabolism for Dual Angiotensin and Endothelin Receptor Antagonists in Various in Vitro Systems and in Cynomolgus Monkeys Drug Metab. Dispos., May 1, 2007; 35(5): 795 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Kalvass, E. R. Olson, and G. M. Pollack Pharmacokinetics and Pharmacodynamics of Alfentanil in P-Glycoprotein-Competent and P-Glycoprotein-Deficient Mice: P-Glycoprotein Efflux Alters Alfentanil Brain Disposition and Antinociception Drug Metab. Dispos., March 1, 2007; 35(3): 455 - 459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Balakrishnan, N. Hussainzada, P. Gonzalez, M. Bermejo, P. W. Swaan, and J. E. Polli Bias in Estimation of Transporter Kinetic Parameters from Overexpression Systems: Interplay of Transporter Expression Level and Substrate Affinity J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 133 - 144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Chang, P. M. Bahadduri, J. E. Polli, P. W. Swaan, and S. Ekins Rapid Identification of P-glycoprotein Substrates and Inhibitors Drug Metab. Dispos., December 1, 2006; 34(12): 1976 - 1984. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Sarkadi, L. Homolya, G. Szakacs, and A. Varadi Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System. Physiol Rev, October 1, 2006; 86(4): 1179 - 1236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Zamek-Gliszczynski, K. A. Hoffmaster, J. E. Humphreys, X. Tian, K.-i. Nezasa, and K. L. R. Brouwer Differential Involvement of Mrp2 (Abcc2) and Bcrp (Abcg2) in Biliary Excretion of 4-Methylumbelliferyl Glucuronide and Sulfate in the Rat J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 459 - 467. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhang, M. Huang, S. Guan, H.-C. Bi, Y. Pan, W. Duan, S. Y. Chan, X. Chen, Y.-H. Hong, J.-S. Bian, et al. A Mechanistic Study of the Intestinal Absorption of Cryptotanshinone, the Major Active Constituent of Salvia miltiorrhiza J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1285 - 1294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Huang, Y. Wang, and S. Grimm ATP-DEPENDENT TRANSPORT OF ROSUVASTATIN IN MEMBRANE VESICLES EXPRESSING BREAST CANCER RESISTANCE PROTEIN Drug Metab. Dispos., May 1, 2006; 34(5): 738 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Rautio, J. E. Humphreys, L. O. Webster, A. Balakrishnan, J. P. Keogh, J. R. Kunta, C. J. Serabjit-Singh, and J. W. Polli IN VITRO P-GLYCOPROTEIN INHIBITION ASSAYS FOR ASSESSMENT OF CLINICAL DRUG INTERACTION POTENTIAL OF NEW DRUG CANDIDATES: A RECOMMENDATION FOR PROBE SUBSTRATES Drug Metab. Dispos., May 1, 2006; 34(5): 786 - 792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Taub, L. Podila, D. Ely, and I. Almeida FUNCTIONAL ASSESSMENT OF MULTIPLE P-GLYCOPROTEIN (P-GP) PROBE SUBSTRATES: INFLUENCE OF CELL LINE AND MODULATOR CONCENTRATION ON P-GP ACTIVITY Drug Metab. Dispos., November 1, 2005; 33(11): 1679 - 1687. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Zamek-Gliszczynski, K. A. Hoffmaster, X. Tian, R. Zhao, J. W. Polli, J. E. Humphreys, L. O. Webster, A. S. Bridges, J. C. Kalvass, and K. L. R. Brouwer MULTIPLE MECHANISMS ARE INVOLVED IN THE BILIARY EXCRETION OF ACETAMINOPHEN SULFATE IN THE RAT: ROLE OF MRP2 AND BCRP1 Drug Metab. Dispos., August 1, 2005; 33(8): 1158 - 1165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Liu, B. J. Smith, C. Chen, E. Callegari, S. L. Becker, X. Chen, J. Cianfrogna, A. C. Doran, S. D. Doran, J. P. Gibbs, et al. Use of a Physiologically Based Pharmacokinetic Model to Study the Time to Reach Brain Equilibrium: An Experimental Analysis of the Role of Blood-Brain Barrier Permeability, Plasma Protein Binding, and Brain Tissue Binding J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 1254 - 1262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Chen, R. J. Mireles, S. D. Campbell, J. Lin, J. B. Mills, J. J. Xu, and T. A. Smolarek DIFFERENTIAL INTERACTION OF 3-HYDROXY-3-METHYLGLUTARYL-COA REDUCTASE INHIBITORS WITH ABCB1, ABCC2, AND OATP1B1 Drug Metab. Dispos., April 1, 2005; 33(4): 537 - 546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Doran, R. S. Obach, B. J. Smith, N. A. Hosea, S. Becker, E. Callegari, C. Chen, X. Chen, E. Choo, J. Cianfrogna, 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., January 1, 2005; 33(1): 165 - 174. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. T. Tran, A. Mittal, T. Aldinger, J. W. Polli, A. Ayrton, H. Ellens, and J. Bentz The Elementary Mass Action Rate Constants of P-gp Transport for a Confluent Monolayer of MDCKII-hMDR1 Cells Biophys. J., January 1, 2005; 88(1): 715 - 738. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Milano, J. McKay, C. Dagenais, L. Foster-Brown, F. Pognan, R. Gadient, R. T. Jacobs, A. Zacco, B. Greenberg, and P. J. Ciaccio Modulation of Notch Processing by {gamma}-Secretase Inhibitors Causes Intestinal Goblet Cell Metaplasia and Induction of Genes Known to Specify Gut Secretory Lineage Differentiation Toxicol. Sci., November 1, 2004; 82(1): 341 - 358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Woodahl, Z. Yang, T. Bui, D. D. Shen, and R. J. Y. Ho Multidrug Resistance Gene G1199A Polymorphism Alters Efflux Transport Activity of P-Glycoprotein J. Pharmacol. Exp. Ther., September 1, 2004; 310(3): 1199 - 1207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Polli, T. M. Baughman, J. E. Humphreys, K. H. Jordan, A. L. Mote, L. O. Webster, R. J. Barnaby, G. Vitulli, L. Bertolotti, K. D. Read, et al. THE SYSTEMIC EXPOSURE OF AN N-METHYL-D-ASPARTATE RECEPTOR ANTAGONIST IS LIMITED IN MICE BY THE P-GLYCOPROTEIN AND BREAST CANCER RESISTANCE PROTEIN EFFLUX TRANSPORTERS Drug Metab. Dispos., July 1, 2004; 32(7): 722 - 726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. D. Kharasch, C. Hoffer, T. G. Altuntas, and D. Whittington Quinidine as a Probe for the Role of P-Glycoprotein in the Intestinal Absorption and Clinical Effects of Fentanyl J. Clin. Pharmacol., March 1, 2004; 44(3): 224 - 233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. W. Ward, G. J. Stelman, J. A. Morgan, K. S. Zeigler, L. M. Azzarano, J. R. Kehler, J. E. McSurdy-Freed, J. W. Proksch, and B. R. Smith DEVELOPMENT OF AN IN VIVO PRECLINICAL SCREEN MODEL TO ESTIMATE ABSORPTION AND FIRST-PASS HEPATIC EXTRACTION OF XENOBIOTICS. II. USE OF KETOCONAZOLE TO IDENTIFY P-GLYCOPROTEIN/CYP3A-LIMITED BIOAVAILABILITY IN THE MONKEY Drug Metab. Dispos., February 1, 2004; 32(2): 172 - 177. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Cummins, W. Jacobsen, U. Christians, and L. Z. Benet CYP3A4-Transfected Caco-2 Cells as a Tool for Understanding Biochemical Absorption Barriers: Studies with Sirolimus and Midazolam J. Pharmacol. Exp. Ther., January 1, 2004; 308(1): 143 - 155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Siccardi, L. E. Kandalaft, M. Gumbleton, and C. McGuigan Stereoselective and Concentration-Dependent Polarized Epithelial Permeability of a Series of Phosphoramidate Triester Prodrugs of d4T: An in Vitro Study in Caco-2 and Madin-Darby Canine Kidney Cell Monolayers J. Pharmacol. Exp. Ther., December 1, 2003; 307(3): 1112 - 1119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Johnson, W. N. Charman, and C. J. H. Porter APPLICATION OF COMPARTMENTAL MODELING TO AN EXAMINATION OF IN VITRO INTESTINAL PERMEABILITY DATA: ASSESSING THE IMPACT OF TISSUE UPTAKE, P-GLYCOPROTEIN, AND CYP3A Drug Metab. Dispos., September 1, 2003; 31(9): 1151 - 1160. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Mizuno, T. Niwa, Y. Yotsumoto, and Y. Sugiyama Impact of Drug Transporter Studies on Drug Discovery and Development Pharmacol. Rev., September 1, 2003; 55(3): 425 - 461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. D. Bjornsson, J. T. Callaghan, H. J. Einolf, V. Fischer, L. Gan, S. Grimm, J. Kao, S. P. King, G. Miwa, L. Ni, et al. THE CONDUCT OF IN VITRO AND IN VIVO DRUG-DRUG INTERACTION STUDIES: A PHARMACEUTICAL RESEARCH AND MANUFACTURERS OF AMERICA (PhRMA) PERSPECTIVE Drug Metab. Dispos., July 1, 2003; 31(7): 815 - 832. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. D. Bjornsson, J. T. Callaghan, H. J. Einolf, V. Fischer, L. Gan, S. Grimm, J. Kao, S. P. King, G. Miwa, L. Ni, et al. The Conduct of In Vitro and In Vivo Drug-Drug Interaction Studies: A PhRMA Perspective J. Clin. Pharmacol., May 1, 2003; 43(5): 443 - 469. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Johnson, W. Chen, R. T. Borchardt, W. N. Charman, and C. J. H. Porter A Kinetic Evaluation of the Absorption, Efflux, and Metabolism of Verapamil in the Autoperfused Rat Jejunum J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 151 - 158. [Abstract] [Full Text]
|
|
|
|
|
|
C. Chen, E. Hanson, J. W. Watson, and J. S. Lee P-Glycoprotein Limits the Brain Penetration of Nonsedating but not Sedating H1-Antagonists Drug Metab. Dispos., March 1, 2003; 31(3): 312 - 318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. M. Doan, J. E. Humphreys, L. O. Webster, S. A. Wring, L. J. Shampine, C. J. Serabjit-Singh, K. K. Adkison, and J. W. Polli Passive Permeability and P-Glycoprotein-Mediated Efflux Differentiate Central Nervous System (CNS) and Non-CNS Marketed Drugs J. Pharmacol. Exp. Ther., December 1, 2002; 303(3): 1029 - 1037. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
