Permeability dominates in vivo intestinal absorption of P-gp substrate with high solubility and high permeability

Xianhua Cao, Lawrence X. Yu, Catalin Barbaciru, Christopher P. Landowski, Ho Chul Shin, Seth Gibbs, Heather A. Miller, Gordon L. Amidon, Duxin Sun

Research output: Contribution to journalArticleScientificpeer-review

63 Citations (Scopus)

Abstract

Three purposes are presented in this study: (1) to study the in vivo regional dependent intestinal absorption of a P-gp substrate with high solubility and high permeability, (2) to study the gene expression difference in the various regions of the intestine, and (3) to study the contributions of P-gp or any other transporters for the absorption of a P-gp substrate. The in vivo permeability of verapamil and propranolol were determined by single-pass in situ intestinal perfusion in rat. The gene expression profiles were measured using Affymetrix GeneChip. Correlation analysis between drug in vivo permeability and expression of 3500 genes was performed with nonparametric bootstrap and ANOVA analysis. The permeability of verapamil and propranolol did not demonstrate regional dependency even though significant differences in gene expression were observed in various regions of the intestine. Verapamil permeability significantly correlates with propranolol permeability in both jejunum and ileum, but did not correlate with the permeability of other hydrophilic compounds (valacyclovir, acyclovir, and phenylalanine). Four different regions (duodenum, jejunum, ileum, and colon) showed distinct gene expression patterns with more than 70-499 genes showing at least 5-fold expression differences. Interestingly, P-gp expression is gradually increased by 6-fold from the duodenum to colon. Despite the distinct gene expression patterns in the various regions of the intestine, verapamil permeability did not correlate with any gene expression from 3500 expressed genes in the intestine. A 2-6-fold P-gp expression difference did not seem to associate verapamil permeability in the various intestinal regions in vivo. These data suggest that P-gp plays a minimal role in the in vivo intestinal absorption process of verapamil with high water solubility and high membrane permeability. The intestinal absorption of verapamil in vivo is primarily dominated by its high permeability. However, it is important to note that the findings in this paper do not undermine the importance of P-gp in oral drug bioavailability, drug disposition from the liver, drug efflux from the blood-brain barrier, and drug-drug interaction.

Original languageEnglish
Pages (from-to)329-340
Number of pages12
JournalMolecular Pharmaceutics
Volume2
Issue number4
DOIs
Publication statusPublished - 1 Jul 2005
MoE publication typeA1 Journal article-refereed

Fingerprint

Intestinal Absorption
Solubility
Permeability
Verapamil
Gene Expression
Intestines
Propranolol
Pharmaceutical Preparations
valacyclovir
Jejunum
Ileum
Duodenum
Colon
Acyclovir
Blood-Brain Barrier
Phenylalanine
Drug Interactions
Transcriptome
Biological Availability
Genes

Keywords

  • Correlation
  • Gene expression
  • Intestine
  • Microarray
  • P-gp
  • Permeability
  • Verapamil

Cite this

Cao, Xianhua ; Yu, Lawrence X. ; Barbaciru, Catalin ; Landowski, Christopher P. ; Shin, Ho Chul ; Gibbs, Seth ; Miller, Heather A. ; Amidon, Gordon L. ; Sun, Duxin. / Permeability dominates in vivo intestinal absorption of P-gp substrate with high solubility and high permeability. In: Molecular Pharmaceutics. 2005 ; Vol. 2, No. 4. pp. 329-340.
@article{9c2b4308aebc4811bcb8a559eb0b8bc0,
title = "Permeability dominates in vivo intestinal absorption of P-gp substrate with high solubility and high permeability",
abstract = "Three purposes are presented in this study: (1) to study the in vivo regional dependent intestinal absorption of a P-gp substrate with high solubility and high permeability, (2) to study the gene expression difference in the various regions of the intestine, and (3) to study the contributions of P-gp or any other transporters for the absorption of a P-gp substrate. The in vivo permeability of verapamil and propranolol were determined by single-pass in situ intestinal perfusion in rat. The gene expression profiles were measured using Affymetrix GeneChip. Correlation analysis between drug in vivo permeability and expression of 3500 genes was performed with nonparametric bootstrap and ANOVA analysis. The permeability of verapamil and propranolol did not demonstrate regional dependency even though significant differences in gene expression were observed in various regions of the intestine. Verapamil permeability significantly correlates with propranolol permeability in both jejunum and ileum, but did not correlate with the permeability of other hydrophilic compounds (valacyclovir, acyclovir, and phenylalanine). Four different regions (duodenum, jejunum, ileum, and colon) showed distinct gene expression patterns with more than 70-499 genes showing at least 5-fold expression differences. Interestingly, P-gp expression is gradually increased by 6-fold from the duodenum to colon. Despite the distinct gene expression patterns in the various regions of the intestine, verapamil permeability did not correlate with any gene expression from 3500 expressed genes in the intestine. A 2-6-fold P-gp expression difference did not seem to associate verapamil permeability in the various intestinal regions in vivo. These data suggest that P-gp plays a minimal role in the in vivo intestinal absorption process of verapamil with high water solubility and high membrane permeability. The intestinal absorption of verapamil in vivo is primarily dominated by its high permeability. However, it is important to note that the findings in this paper do not undermine the importance of P-gp in oral drug bioavailability, drug disposition from the liver, drug efflux from the blood-brain barrier, and drug-drug interaction.",
keywords = "Correlation, Gene expression, Intestine, Microarray, P-gp, Permeability, Verapamil",
author = "Xianhua Cao and Yu, {Lawrence X.} and Catalin Barbaciru and Landowski, {Christopher P.} and Shin, {Ho Chul} and Seth Gibbs and Miller, {Heather A.} and Amidon, {Gordon L.} and Duxin Sun",
year = "2005",
month = "7",
day = "1",
doi = "10.1021/mp0499104",
language = "English",
volume = "2",
pages = "329--340",
journal = "Molecular Pharmaceutics",
issn = "1543-8384",
publisher = "American Chemical Society ACS",
number = "4",

}

Permeability dominates in vivo intestinal absorption of P-gp substrate with high solubility and high permeability. / Cao, Xianhua; Yu, Lawrence X.; Barbaciru, Catalin; Landowski, Christopher P.; Shin, Ho Chul; Gibbs, Seth; Miller, Heather A.; Amidon, Gordon L.; Sun, Duxin.

In: Molecular Pharmaceutics, Vol. 2, No. 4, 01.07.2005, p. 329-340.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Permeability dominates in vivo intestinal absorption of P-gp substrate with high solubility and high permeability

AU - Cao, Xianhua

AU - Yu, Lawrence X.

AU - Barbaciru, Catalin

AU - Landowski, Christopher P.

AU - Shin, Ho Chul

AU - Gibbs, Seth

AU - Miller, Heather A.

AU - Amidon, Gordon L.

AU - Sun, Duxin

PY - 2005/7/1

Y1 - 2005/7/1

N2 - Three purposes are presented in this study: (1) to study the in vivo regional dependent intestinal absorption of a P-gp substrate with high solubility and high permeability, (2) to study the gene expression difference in the various regions of the intestine, and (3) to study the contributions of P-gp or any other transporters for the absorption of a P-gp substrate. The in vivo permeability of verapamil and propranolol were determined by single-pass in situ intestinal perfusion in rat. The gene expression profiles were measured using Affymetrix GeneChip. Correlation analysis between drug in vivo permeability and expression of 3500 genes was performed with nonparametric bootstrap and ANOVA analysis. The permeability of verapamil and propranolol did not demonstrate regional dependency even though significant differences in gene expression were observed in various regions of the intestine. Verapamil permeability significantly correlates with propranolol permeability in both jejunum and ileum, but did not correlate with the permeability of other hydrophilic compounds (valacyclovir, acyclovir, and phenylalanine). Four different regions (duodenum, jejunum, ileum, and colon) showed distinct gene expression patterns with more than 70-499 genes showing at least 5-fold expression differences. Interestingly, P-gp expression is gradually increased by 6-fold from the duodenum to colon. Despite the distinct gene expression patterns in the various regions of the intestine, verapamil permeability did not correlate with any gene expression from 3500 expressed genes in the intestine. A 2-6-fold P-gp expression difference did not seem to associate verapamil permeability in the various intestinal regions in vivo. These data suggest that P-gp plays a minimal role in the in vivo intestinal absorption process of verapamil with high water solubility and high membrane permeability. The intestinal absorption of verapamil in vivo is primarily dominated by its high permeability. However, it is important to note that the findings in this paper do not undermine the importance of P-gp in oral drug bioavailability, drug disposition from the liver, drug efflux from the blood-brain barrier, and drug-drug interaction.

AB - Three purposes are presented in this study: (1) to study the in vivo regional dependent intestinal absorption of a P-gp substrate with high solubility and high permeability, (2) to study the gene expression difference in the various regions of the intestine, and (3) to study the contributions of P-gp or any other transporters for the absorption of a P-gp substrate. The in vivo permeability of verapamil and propranolol were determined by single-pass in situ intestinal perfusion in rat. The gene expression profiles were measured using Affymetrix GeneChip. Correlation analysis between drug in vivo permeability and expression of 3500 genes was performed with nonparametric bootstrap and ANOVA analysis. The permeability of verapamil and propranolol did not demonstrate regional dependency even though significant differences in gene expression were observed in various regions of the intestine. Verapamil permeability significantly correlates with propranolol permeability in both jejunum and ileum, but did not correlate with the permeability of other hydrophilic compounds (valacyclovir, acyclovir, and phenylalanine). Four different regions (duodenum, jejunum, ileum, and colon) showed distinct gene expression patterns with more than 70-499 genes showing at least 5-fold expression differences. Interestingly, P-gp expression is gradually increased by 6-fold from the duodenum to colon. Despite the distinct gene expression patterns in the various regions of the intestine, verapamil permeability did not correlate with any gene expression from 3500 expressed genes in the intestine. A 2-6-fold P-gp expression difference did not seem to associate verapamil permeability in the various intestinal regions in vivo. These data suggest that P-gp plays a minimal role in the in vivo intestinal absorption process of verapamil with high water solubility and high membrane permeability. The intestinal absorption of verapamil in vivo is primarily dominated by its high permeability. However, it is important to note that the findings in this paper do not undermine the importance of P-gp in oral drug bioavailability, drug disposition from the liver, drug efflux from the blood-brain barrier, and drug-drug interaction.

KW - Correlation

KW - Gene expression

KW - Intestine

KW - Microarray

KW - P-gp

KW - Permeability

KW - Verapamil

UR - http://www.scopus.com/inward/record.url?scp=23944475593&partnerID=8YFLogxK

U2 - 10.1021/mp0499104

DO - 10.1021/mp0499104

M3 - Article

C2 - 16053336

AN - SCOPUS:23944475593

VL - 2

SP - 329

EP - 340

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 4

ER -