Pharmacological Reviews
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lin, J. H.
Right arrow Articles by Baillie, T. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lin, J. H.
Right arrow Articles by Baillie, T. A.

Vol. 51, Issue 2, 135-158, June 1999

Is the Role of the Small Intestine in First-Pass Metabolism Overemphasized?

Jiunn H. Lin1, Masato Chiba and Thomas A. Baillie

Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania

I. Introduction
II. Physiological and Biochemical Factors Affecting Intestinal Metabolism
    A. Anatomy and Circulation of the Small Intestine
    1. Mucosal Blood Flow
    2. Countercurrent Exchange
    B. Localization of Drug-Metabolizing Enzymes in the Small Intestine
    1. Cytochromes P-450
    2. UDP Glucosyltransferases and Sulfotransferases
    C. Intestinal Enzyme Induction
    1. Cytochromes P-450
    2. UDP Glucosyltransferases
    3. Effect of Route and Dose on Enzyme Induction
    D. p-Glycoprotein
    1. Intestinal p-Glycoprotein
    2. Cytochromes P-450 and p-Glycoprotein
    3. p-Glycoprotein and Intracellular Residence Time
III. Drug Absorption and Intestinal First-Pass Metabolism
    A. Drug Absorption and Concentration Gradient
    B. Saturable First-Pass Metabolism
    C. Hepatic and Intestinal Organ Clearance
IV. Relative Contribution of Hepatic and Intestinal First-Pass Metabolism
V. Conceptions and Misconceptions
VI. Conclusions
Acknowledgment
References

1   Address for correspondence: Jiunn H. Lin, Ph.D., WP42-2, MerckResearch Laboratories, West Point, PA 19486. E-mail: jiunn_lin{at}merck.com

0031-6997/99/5102-0135$03.00/0
PHARMACOLOGICAL REVIEWS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
A. Watanabe, T. Fukami, M. Nakajima, M. Takamiya, Y. Aoki, and T. Yokoi
Human Arylacetamide Deacetylase Is a Principal Enzyme in Flutamide Hydrolysis
Drug Metab. Dispos., July 1, 2009; 37(7): 1513 - 1520.
[Abstract] [Full Text] [PDF]

Home page
 JNMHome page
C. Bolzati, M. Cavazza-Ceccato, S. Agostini, S. Tokunaga, D. Casara, and G. Bandoli
Subcellular Distribution and Metabolism Studies of the Potential Myocardial Imaging Agent [99mTc(N)(DBODC)(PNP5)]+
J. Nucl. Med., August 1, 2008; 49(8): 1336 - 1344.
[Abstract] [Full Text] [PDF]

Home page
 Am J Health Syst PharmHome page
W. Song and W. A. Miller
Diffuse exanthema in a patient receiving varenicline
Am. J. Health Syst. Pharm., July 1, 2008; 65(13): 1239 - 1241.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
L. X. Garmire and C. A. Hunt
In Silico Methods for Unraveling the Mechanistic Complexities of Intestinal Absorption: Metabolism-Efflux Transport Interactions
Drug Metab. Dispos., July 1, 2008; 36(7): 1414 - 1424.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
W. Meinl, B. Ebert, H. Glatt, and A. Lampen
Sulfotransferase Forms Expressed in Human Intestinal Caco-2 and TC7 Cells at Varying Stages of Differentiation and Role in Benzo[a]pyrene Metabolism
Drug Metab. Dispos., February 1, 2008; 36(2): 276 - 283.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
K. Masaki, M. Hashimoto, and T. Imai
Intestinal First-Pass Metabolism via Carboxylesterase in Rat Jejunum and Ileum
Drug Metab. Dispos., July 1, 2007; 35(7): 1089 - 1095.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
E. G. van de Kerkhof, A.-L. B. Ungell, A. K. Sjoberg, M. H. de Jager, C. Hilgendorf, I. A. M. de Graaf, and G. M. M. Groothuis
Innovative Methods to Study Human Intestinal Drug Metabolism in Vitro: Precision-Cut Slices Compared with Ussing Chamber Preparations
Drug Metab. Dispos., November 1, 2006; 34(11): 1893 - 1902.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Microbiol. Rev.Home page
J. Meletiadis, S. Chanock, and T. J. Walsh
Human Pharmacogenomic Variations and Their Implications for Antifungal Efficacy
Clin. Microbiol. Rev., October 1, 2006; 19(4): 763 - 787.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
S. Liu, D. Tam, X. Chen, and K. S. Pang
P-Glycoprotein and an Unstirred Water Layer Barring Digoxin Absorption in the Vascularly Perfused Rat Small Intestine Preparation: Induction Studies with Pregnenolone-16{alpha}-carbonitrile
Drug Metab. Dispos., September 1, 2006; 34(9): 1468 - 1479.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
T. Sten, S. Qvisen, P. Uutela, L. Luukkanen, R. Kostiainen, and M. Finel
Prominent but Reverse Stereoselectivity in Propranolol Glucuronidation by Human UDP-Glucuronosyltransferases 1A9 and 1A10
Drug Metab. Dispos., September 1, 2006; 34(9): 1488 - 1494.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
A. Galetin and J. B. Houston
Intestinal and Hepatic Metabolic Activity of Five Cytochrome P450 Enzymes: Impact on Prediction of First-Pass Metabolism
J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 1220 - 1229.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
K. Masaki, M. Taketani, and T. Imai
FIRST-PASS HYDROLYSIS OF A PROPRANOLOL ESTER DERIVATIVE IN RAT SMALL INTESTINE
Drug Metab. Dispos., March 1, 2006; 34(3): 398 - 404.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
B. A. Graf, C. Ameho, G. G. Dolnikowski, P. E. Milbury, C.-Y. Chen, and J. B. Blumberg
Rat Gastrointestinal Tissues Metabolize Quercetin
J. Nutr., January 1, 2006; 136(1): 39 - 44.
[Abstract] [Full Text] [PDF]

Home page
 J Clin PharmacolHome page
N. Baririan, Y. Horsmans, J.-P. Desager, R. Verbeeck, R. Vanbinst, P. Wallemacq, and L. Van Obbergh
Alfentanil-Induced Miosis Clearance as a Liver CYP3A4 and 3A5 Activity Measure in Healthy Volunteers: Improvement of Experimental Conditions
J. Clin. Pharmacol., December 1, 2005; 45(12): 1434 - 1441.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
E. G. van de Kerkhof, I. A. M. de Graaf, M. H. de Jager, D. K. F. Meijer, and G. M. M. Groothuis
CHARACTERIZATION OF RAT SMALL INTESTINAL AND COLON PRECISION-CUT SLICES AS AN IN VITRO SYSTEM FOR DRUG METABOLISM AND INDUCTION STUDIES
Drug Metab. Dispos., November 1, 2005; 33(11): 1613 - 1620.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
R. J. Riley, D. F. McGinnity, and R. P. Austin
A UNIFIED MODEL FOR PREDICTING HUMAN HEPATIC, METABOLIC CLEARANCE FROM IN VITRO INTRINSIC CLEARANCE DATA IN HEPATOCYTES AND MICROSOMES
Drug Metab. Dispos., September 1, 2005; 33(9): 1304 - 1311.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
T. Imai, M. Imoto, H. Sakamoto, and M. Hashimoto
IDENTIFICATION OF ESTERASES EXPRESSED IN CACO-2 CELLS AND EFFECTS OF THEIR HYDROLYZING ACTIVITY IN PREDICTING HUMAN INTESTINAL ABSORPTION
Drug Metab. Dispos., August 1, 2005; 33(8): 1185 - 1190.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
B. A. Graf, W. Mullen, S. T. Caldwell, R. C. Hartley, G. G. Duthie, M. E. J. Lean, A. Crozier, and C. A. Edwards
DISPOSITION AND METABOLISM OF [2-14C]QUERCETIN-4'-GLUCOSIDE IN RATS
Drug Metab. Dispos., July 1, 2005; 33(7): 1036 - 1043.
[Abstract] [Full Text] [PDF]

Home page
 International Journal of ToxicologyHome page
A. Ramesh, S. A. Walker, D. B. Hood, M. D. Guillen, K. Schneider, and E. H. Weyand
Bioavailability and Risk Assessment of Orally Ingested Polycyclic Aromatic Hydrocarbons
International Journal of Toxicology, September 1, 2004; 23(5): 301 - 333.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
K. S. Pang
MODELING OF INTESTINAL DRUG ABSORPTION: ROLES OF TRANSPORTERS AND METABOLIC ENZYMES (FOR THE GILLETTE REVIEW SERIES)
Drug Metab. Dispos., December 1, 2003; 31(12): 1507 - 1519.
[Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
L. S. Kaminsky and Q.-Y. Zhang
THE SMALL INTESTINE AS A XENOBIOTIC-METABOLIZING ORGAN
Drug Metab. Dispos., December 1, 2003; 31(12): 1520 - 1525.
[Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
D. Tam, H. Sun, and K. S. Pang
INFLUENCE OF P-GLYCOPROTEIN, TRANSFER CLEARANCES, AND DRUG BINDING ON INTESTINAL METABOLISM IN CACO-2 CELL MONOLAYERS OR MEMBRANE PREPARATIONS: A THEORETICAL ANALYSIS
Drug Metab. Dispos., October 1, 2003; 31(10): 1214 - 1226.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
J. P. E. Spencer
Metabolism of Tea Flavonoids in the Gastrointestinal Tract
J. Nutr., October 1, 2003; 133(10): 3255S - 3261.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
H. Jinno, M. Saeki, T. Tanaka-Kagawa, N. Hanioka, Y. Saito, S. Ozawa, M. Ando, K. Shirao, H. Minami, A. Ohtsu, et al.
Functional Characterization of Wild-type and Variant (T202I and M59I) Human UDP-glucuronosyltransferase 1A10
Drug Metab. Dispos., May 1, 2003; 31(5): 528 - 532.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. G. Soars, B. Burchell, and R. J. Riley
In Vitro Analysis of Human Drug Glucuronidation and Prediction of in Vivo Metabolic Clearance
J. Pharmacol. Exp. Ther., April 1, 2002; 301(1): 382 - 390.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
T. Hashizume, S. Imaoka, M. Mise, Y. Terauchi, T. Fujii, H. Miyazaki, T. Kamataki, and Y. Funae
Involvement of CYP2J2 and CYP4F12 in the Metabolism of Ebastine in Human Intestinal Microsomes
J. Pharmacol. Exp. Ther., January 1, 2002; 300(1): 298 - 304.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
D. Cong, A. K. Y. Fong, R. Lee, and K. S. Pang
Absorption of Benzoic Acid in Segmental Regions of the Vascularly Perfused Rat Small Intestine Preparation
Drug Metab. Dispos., December 1, 2001; 29(12): 1539 - 1547.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
T. Hashizume, M. Mise, S. Matsumoto, Y. Terauchi, T. Fujii, S. Imaoka, Y. Funae, T. Kamataki, and H. Miyazaki
A Novel Cytochrome P450 Enzyme Responsible for the Metabolism of Ebastine in Monkey Small Intestine
Drug Metab. Dispos., June 1, 2001; 29(6): 798 - 805.
[Abstract] [Full Text]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
A. D. Mottino, T. Hoffman, L. Jennes, J. Cao, and M. Vore
Expression of multidrug resistance-associated protein 2 in small intestine from pregnant and postpartum rats
Am J Physiol Gastrointest Liver Physiol, June 1, 2001; 280(6): G1261 - G1273.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
J. C. Stevens, J. L. Fayer, and K. C. Cassidy

Drug Metab. Dispos., March 1, 2001; 29(3): 289 - 295.
[Abstract] [Full Text]

Home page
 Drug Metab. Dispos.Home page
Z. Desta, N. Soukhova, S. K. Mahal, and D. A. Flockhart
Interaction of Cisapride with the Human Cytochrome P450 System: Metabolism and Inhibition Studies
Drug Metab. Dispos., July 1, 2000; 28(7): 789 - 800.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
A. D. Mottino, T. Hoffman, L. Jennes, and M. Vore
Expression and Localization of Multidrug Resistant Protein mrp2 in Rat Small Intestine
J. Pharmacol. Exp. Ther., June 1, 2000; 293(3): 717 - 723.
[Abstract] [Full Text]

Home page
 Drug Metab. Dispos.Home page
D. Cong, M. Doherty, and K. S. Pang
A New Physiologically Based, Segregated-Flow Model to Explain Route-Dependent Intestinal Metabolism
Drug Metab. Dispos., February 1, 2000; 28(2): 224 - 235.
[Abstract] [Full Text]

Home page
 Drug Metab. Dispos.Home page
J. H. Lin, M. Chiba, I-W. Chen, J. A. Nishime, F. A. deLuna, M. Yamazaki, and Y. J. Lin
Effect of Dexamethasone on the Intestinal First-Pass Metabolism of Indinavir in Rats: Evidence of Cytochrome P-450 A and p-Glycoprotein Induction
Drug Metab. Dispos., October 1, 1999; 27(10): 1187 - 1193.
[Abstract] [Full Text]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition