Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model

Xianhua Cao, Seth T. Gibbs, Lanyan Fang, Heather A. Miller, Christopher P. Landowski, Ho Chul Shin, Hans Lennernas, Yanqiang Zhong, Gordon L. Amidon, Lawrence X. Yu, Duxin Sun

Research output: Contribution to journalArticleScientificpeer-review

240 Citations (Scopus)

Abstract

Purpose. To study the correlation of intestinal absorption for drugs with various absorption routes between human and rat, and to explore the underlying molecular mechanisms for the similarity in drug intestinal absorption and the differences in oral bioavailability between human and rat. Materials and Methods. The intestinal permeabilities of 14 drugs and three drug-like compounds with different absorption mechanisms in rat and human jejunum were determined by in situ intestinal perfusion. A total of 48 drugs were selected for oral bioavailability comparison. Expression profiles of transporters and metabolizing enzymes in both rat and human intestines (duodenum and colon) were measured using GeneChip analysis. Results. No correlation (r 2 = 0.29) was found in oral drug bioavailability between rat and human, while a correlation (r 2 = 0.8) was observed for drug intestinal permeability with both carrier-mediated absorption and passive diffusion mechanisms between human and rat small intestine. Moderate correlation (with r 2 > 0.56) was also found for the expression levels of transporters in the duodenum of human and rat, which provides the molecular mechanisms for the similarity and correlation of drug absorption between two species. In contrast, no correlation was found for the expressions of metabolizing enzymes between rat and human intestine, which indicates the difference in drug metabolism and oral bioavailability in two species. Detailed analysis indicates that many transporters (such as PepT1, SGLT-1, GLUT5, MRP2, NT2, and high affinity glutamate transporter) share similar expression levels in both human and rat with regional dependent expression patterns, which have high expression in the small intestine and low expression in the colon. However, discrepancy was also observed for several other transporters (such as MDR1, MRP3, GLUT1, and GLUT3) in both the duodenum and colon of human and rat. In addition, the expressions of metabolizing enzymes (CYP3A4/CYP3A9 and UDPG) showed 12 to 193-fold difference between human and rat intestine with distinct regional dependent expression patterns. Conclusions. The data indicate that rat and human show similar drug intestinal absorption profiles and similar transporter expression patterns in the small intestine, while the two species exhibit distinct expression levels and patterns for metabolizing enzymes in the intestine. Therefore, a rat model can be used to predict oral drug absorption in the small intestine of human, but not to predict drug metabolism or oral bioavailability in human.

Original languageEnglish
Pages (from-to)1675-1686
Number of pages12
JournalPharmaceutical Research
Volume23
Issue number8
DOIs
Publication statusPublished - 1 Aug 2006
MoE publication typeA1 Journal article-refereed

Fingerprint

Intestinal Absorption
Biological Availability
Rats
Pharmaceutical Preparations
Small Intestine
Intestines
Duodenum
Colon
Enzymes
Metabolism
Permeability
Uridine Diphosphate Glucose
Amino Acid Transport System X-AG
Cytochrome P-450 CYP3A
Jejunum

Keywords

  • Drug transporter
  • Gene expression
  • Inter-species correlation
  • Intestinal permeability
  • Metabolizing enzyme
  • Oral bioavailability

Cite this

Cao, Xianhua ; Gibbs, Seth T. ; Fang, Lanyan ; Miller, Heather A. ; Landowski, Christopher P. ; Shin, Ho Chul ; Lennernas, Hans ; Zhong, Yanqiang ; Amidon, Gordon L. ; Yu, Lawrence X. ; Sun, Duxin. / Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model. In: Pharmaceutical Research. 2006 ; Vol. 23, No. 8. pp. 1675-1686.
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abstract = "Purpose. To study the correlation of intestinal absorption for drugs with various absorption routes between human and rat, and to explore the underlying molecular mechanisms for the similarity in drug intestinal absorption and the differences in oral bioavailability between human and rat. Materials and Methods. The intestinal permeabilities of 14 drugs and three drug-like compounds with different absorption mechanisms in rat and human jejunum were determined by in situ intestinal perfusion. A total of 48 drugs were selected for oral bioavailability comparison. Expression profiles of transporters and metabolizing enzymes in both rat and human intestines (duodenum and colon) were measured using GeneChip analysis. Results. No correlation (r 2 = 0.29) was found in oral drug bioavailability between rat and human, while a correlation (r 2 = 0.8) was observed for drug intestinal permeability with both carrier-mediated absorption and passive diffusion mechanisms between human and rat small intestine. Moderate correlation (with r 2 > 0.56) was also found for the expression levels of transporters in the duodenum of human and rat, which provides the molecular mechanisms for the similarity and correlation of drug absorption between two species. In contrast, no correlation was found for the expressions of metabolizing enzymes between rat and human intestine, which indicates the difference in drug metabolism and oral bioavailability in two species. Detailed analysis indicates that many transporters (such as PepT1, SGLT-1, GLUT5, MRP2, NT2, and high affinity glutamate transporter) share similar expression levels in both human and rat with regional dependent expression patterns, which have high expression in the small intestine and low expression in the colon. However, discrepancy was also observed for several other transporters (such as MDR1, MRP3, GLUT1, and GLUT3) in both the duodenum and colon of human and rat. In addition, the expressions of metabolizing enzymes (CYP3A4/CYP3A9 and UDPG) showed 12 to 193-fold difference between human and rat intestine with distinct regional dependent expression patterns. Conclusions. The data indicate that rat and human show similar drug intestinal absorption profiles and similar transporter expression patterns in the small intestine, while the two species exhibit distinct expression levels and patterns for metabolizing enzymes in the intestine. Therefore, a rat model can be used to predict oral drug absorption in the small intestine of human, but not to predict drug metabolism or oral bioavailability in human.",
keywords = "Drug transporter, Gene expression, Inter-species correlation, Intestinal permeability, Metabolizing enzyme, Oral bioavailability",
author = "Xianhua Cao and Gibbs, {Seth T.} and Lanyan Fang and Miller, {Heather A.} and Landowski, {Christopher P.} and Shin, {Ho Chul} and Hans Lennernas and Yanqiang Zhong and Amidon, {Gordon L.} and Yu, {Lawrence X.} and Duxin Sun",
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Cao, X, Gibbs, ST, Fang, L, Miller, HA, Landowski, CP, Shin, HC, Lennernas, H, Zhong, Y, Amidon, GL, Yu, LX & Sun, D 2006, 'Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model', Pharmaceutical Research, vol. 23, no. 8, pp. 1675-1686. https://doi.org/10.1007/s11095-006-9041-2

Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model. / Cao, Xianhua; Gibbs, Seth T.; Fang, Lanyan; Miller, Heather A.; Landowski, Christopher P.; Shin, Ho Chul; Lennernas, Hans; Zhong, Yanqiang; Amidon, Gordon L.; Yu, Lawrence X.; Sun, Duxin.

In: Pharmaceutical Research, Vol. 23, No. 8, 01.08.2006, p. 1675-1686.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model

AU - Cao, Xianhua

AU - Gibbs, Seth T.

AU - Fang, Lanyan

AU - Miller, Heather A.

AU - Landowski, Christopher P.

AU - Shin, Ho Chul

AU - Lennernas, Hans

AU - Zhong, Yanqiang

AU - Amidon, Gordon L.

AU - Yu, Lawrence X.

AU - Sun, Duxin

PY - 2006/8/1

Y1 - 2006/8/1

N2 - Purpose. To study the correlation of intestinal absorption for drugs with various absorption routes between human and rat, and to explore the underlying molecular mechanisms for the similarity in drug intestinal absorption and the differences in oral bioavailability between human and rat. Materials and Methods. The intestinal permeabilities of 14 drugs and three drug-like compounds with different absorption mechanisms in rat and human jejunum were determined by in situ intestinal perfusion. A total of 48 drugs were selected for oral bioavailability comparison. Expression profiles of transporters and metabolizing enzymes in both rat and human intestines (duodenum and colon) were measured using GeneChip analysis. Results. No correlation (r 2 = 0.29) was found in oral drug bioavailability between rat and human, while a correlation (r 2 = 0.8) was observed for drug intestinal permeability with both carrier-mediated absorption and passive diffusion mechanisms between human and rat small intestine. Moderate correlation (with r 2 > 0.56) was also found for the expression levels of transporters in the duodenum of human and rat, which provides the molecular mechanisms for the similarity and correlation of drug absorption between two species. In contrast, no correlation was found for the expressions of metabolizing enzymes between rat and human intestine, which indicates the difference in drug metabolism and oral bioavailability in two species. Detailed analysis indicates that many transporters (such as PepT1, SGLT-1, GLUT5, MRP2, NT2, and high affinity glutamate transporter) share similar expression levels in both human and rat with regional dependent expression patterns, which have high expression in the small intestine and low expression in the colon. However, discrepancy was also observed for several other transporters (such as MDR1, MRP3, GLUT1, and GLUT3) in both the duodenum and colon of human and rat. In addition, the expressions of metabolizing enzymes (CYP3A4/CYP3A9 and UDPG) showed 12 to 193-fold difference between human and rat intestine with distinct regional dependent expression patterns. Conclusions. The data indicate that rat and human show similar drug intestinal absorption profiles and similar transporter expression patterns in the small intestine, while the two species exhibit distinct expression levels and patterns for metabolizing enzymes in the intestine. Therefore, a rat model can be used to predict oral drug absorption in the small intestine of human, but not to predict drug metabolism or oral bioavailability in human.

AB - Purpose. To study the correlation of intestinal absorption for drugs with various absorption routes between human and rat, and to explore the underlying molecular mechanisms for the similarity in drug intestinal absorption and the differences in oral bioavailability between human and rat. Materials and Methods. The intestinal permeabilities of 14 drugs and three drug-like compounds with different absorption mechanisms in rat and human jejunum were determined by in situ intestinal perfusion. A total of 48 drugs were selected for oral bioavailability comparison. Expression profiles of transporters and metabolizing enzymes in both rat and human intestines (duodenum and colon) were measured using GeneChip analysis. Results. No correlation (r 2 = 0.29) was found in oral drug bioavailability between rat and human, while a correlation (r 2 = 0.8) was observed for drug intestinal permeability with both carrier-mediated absorption and passive diffusion mechanisms between human and rat small intestine. Moderate correlation (with r 2 > 0.56) was also found for the expression levels of transporters in the duodenum of human and rat, which provides the molecular mechanisms for the similarity and correlation of drug absorption between two species. In contrast, no correlation was found for the expressions of metabolizing enzymes between rat and human intestine, which indicates the difference in drug metabolism and oral bioavailability in two species. Detailed analysis indicates that many transporters (such as PepT1, SGLT-1, GLUT5, MRP2, NT2, and high affinity glutamate transporter) share similar expression levels in both human and rat with regional dependent expression patterns, which have high expression in the small intestine and low expression in the colon. However, discrepancy was also observed for several other transporters (such as MDR1, MRP3, GLUT1, and GLUT3) in both the duodenum and colon of human and rat. In addition, the expressions of metabolizing enzymes (CYP3A4/CYP3A9 and UDPG) showed 12 to 193-fold difference between human and rat intestine with distinct regional dependent expression patterns. Conclusions. The data indicate that rat and human show similar drug intestinal absorption profiles and similar transporter expression patterns in the small intestine, while the two species exhibit distinct expression levels and patterns for metabolizing enzymes in the intestine. Therefore, a rat model can be used to predict oral drug absorption in the small intestine of human, but not to predict drug metabolism or oral bioavailability in human.

KW - Drug transporter

KW - Gene expression

KW - Inter-species correlation

KW - Intestinal permeability

KW - Metabolizing enzyme

KW - Oral bioavailability

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DO - 10.1007/s11095-006-9041-2

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