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Species differences in size discrimination in the paracellular pathway reflected by oral bioavailability of poly(ethylene glycol) and D-peptides

Species differences in size discrimination in the paracellular pathway reflected by oral bioavailability of poly(ethylene glycol) and D-peptides
Species differences in size discrimination in the paracellular pathway reflected by oral bioavailability of poly(ethylene glycol) and D-peptides
Animal models are frequently used to aid prediction of intestinal absorption in humans. However, there is little comparative quantitative information on species differences in paracellular permeation, which is an important route for oral absorption of small to medium-sized hydrophilic drug molecules. This study addresses this issue by comparing the molecular mass (MM) dependency in oral bioavailability between rat and dog of poly(ethylene glycol) (PEG), a polydispersed model mixture commonly used to characterize paracellular absorption, and of a series of eight D-peptides (based on D-phenylalanine). Fasted rats and dogs received PEG (400/900) and the D-peptides (MM 236-406 Da), orally and intravenously, with total 24-48 h urine collection to estimate oral bioavailability. After HPLC separation, the individual PEG oligomers and D-peptides were determined using radiometric detection, for radiolabeled material, and LC-MS, for unlabeled (PEG) material. All compounds were predominantly excreted unchanged following intravenous administration. After oral administration, the predominant peak in the radiochromatogram was unchanged material, indicating stability of the compounds in the gastrointestinal tract. A clear molecular mass dependency in oral bioavailability was seen with both series, but with absorption much greater in dog than rat. Thus, for PEG in rat, bioavailability decreased sharply from 79 to around 2% with increasing MM between 282 and 591 Da, and then tapered to around 1. 5% up to 1295 Da. Whereas in dog, bioavailability remained around 100% for oligomers up to 600 Da and then decreased quite sharply with increasing MM, tending to plateau around 13% beyond 900 Da. Likewise, for the d-peptides in rat, bioavailability decreased from 30 to 1% with increasing MM between 236 and 406 Da, whereas in dog it was 100%, declining to 16% over the same molecular range. This species difference appears to be due to a larger pore size and greater frequency of pores in the paracellular pathway of dog compared to rat. Furthermore, on the basis of comparison with literature data for PEG and selected drugs, rat would appear to be a better predictor than dog of absorption of hydrophilic compounds in human.
0022-3549
626-633
He, Yan-Ling
c93f2f78-35e9-4bfe-85f3-681e5f6b653a
Murby, Susan
9f9ebf0b-63ba-481a-8a2f-7f8c17953839
Warhurst, Geoffrey
74a5cea0-c1b9-4086-a780-0b4c5595ad0e
Gifford, Larry
a09ed207-e97e-4a0c-ba0a-37f70dc76c31
Walker, David
b94e6f46-ec02-4b5b-a726-67c0aafc9f94
Ayrton, John
1d0921cc-3d7c-4b4e-aea3-4b3129f97d56
Eastmond, Richard
ad9167f1-b5f1-42ee-857d-f35522f4d4dd
Rowland, Malcolm
680cad77-67d7-4b71-a794-c745e64def7c
He, Yan-Ling
c93f2f78-35e9-4bfe-85f3-681e5f6b653a
Murby, Susan
9f9ebf0b-63ba-481a-8a2f-7f8c17953839
Warhurst, Geoffrey
74a5cea0-c1b9-4086-a780-0b4c5595ad0e
Gifford, Larry
a09ed207-e97e-4a0c-ba0a-37f70dc76c31
Walker, David
b94e6f46-ec02-4b5b-a726-67c0aafc9f94
Ayrton, John
1d0921cc-3d7c-4b4e-aea3-4b3129f97d56
Eastmond, Richard
ad9167f1-b5f1-42ee-857d-f35522f4d4dd
Rowland, Malcolm
680cad77-67d7-4b71-a794-c745e64def7c

He, Yan-Ling, Murby, Susan, Warhurst, Geoffrey, Gifford, Larry, Walker, David, Ayrton, John, Eastmond, Richard and Rowland, Malcolm (1998) Species differences in size discrimination in the paracellular pathway reflected by oral bioavailability of poly(ethylene glycol) and D-peptides. Journal of Pharmaceutical Sciences, 87 (5), 626-633. (doi:10.1021/js970120d). (PMID:9572915)

Record type: Article

Abstract

Animal models are frequently used to aid prediction of intestinal absorption in humans. However, there is little comparative quantitative information on species differences in paracellular permeation, which is an important route for oral absorption of small to medium-sized hydrophilic drug molecules. This study addresses this issue by comparing the molecular mass (MM) dependency in oral bioavailability between rat and dog of poly(ethylene glycol) (PEG), a polydispersed model mixture commonly used to characterize paracellular absorption, and of a series of eight D-peptides (based on D-phenylalanine). Fasted rats and dogs received PEG (400/900) and the D-peptides (MM 236-406 Da), orally and intravenously, with total 24-48 h urine collection to estimate oral bioavailability. After HPLC separation, the individual PEG oligomers and D-peptides were determined using radiometric detection, for radiolabeled material, and LC-MS, for unlabeled (PEG) material. All compounds were predominantly excreted unchanged following intravenous administration. After oral administration, the predominant peak in the radiochromatogram was unchanged material, indicating stability of the compounds in the gastrointestinal tract. A clear molecular mass dependency in oral bioavailability was seen with both series, but with absorption much greater in dog than rat. Thus, for PEG in rat, bioavailability decreased sharply from 79 to around 2% with increasing MM between 282 and 591 Da, and then tapered to around 1. 5% up to 1295 Da. Whereas in dog, bioavailability remained around 100% for oligomers up to 600 Da and then decreased quite sharply with increasing MM, tending to plateau around 13% beyond 900 Da. Likewise, for the d-peptides in rat, bioavailability decreased from 30 to 1% with increasing MM between 236 and 406 Da, whereas in dog it was 100%, declining to 16% over the same molecular range. This species difference appears to be due to a larger pore size and greater frequency of pores in the paracellular pathway of dog compared to rat. Furthermore, on the basis of comparison with literature data for PEG and selected drugs, rat would appear to be a better predictor than dog of absorption of hydrophilic compounds in human.

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Published date: May 1998
Organisations: Medical Education

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Local EPrints ID: 359213
URI: https://eprints.soton.ac.uk/id/eprint/359213
ISSN: 0022-3549
PURE UUID: eec86843-50e2-468a-b07f-1b3488a949a9

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Date deposited: 23 Oct 2013 12:35
Last modified: 18 Jul 2017 03:22

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Author: Yan-Ling He
Author: Susan Murby
Author: Geoffrey Warhurst
Author: Larry Gifford
Author: David Walker
Author: John Ayrton
Author: Richard Eastmond
Author: Malcolm Rowland

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