Evaluation of rat intestinal absorption data and correlation with human intestinal absorption

Zhao, Yuan H.; Abraham, Michael H.; Le, Joelle; Hersey, Anne; Luscombe, Chris; Beck, Gordon; Sherborne, Brad; Cooper, Ian

doi:10.1016/s0223-5234(03)00015-1

Cited by 88 publications

(63 citation statements)

References 88 publications

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“…However, anatomical and physiological differences of the gastrointestinal tract exist, e.g., related to absorption [7] and permeability [21] and microsomal metabolism [42]. Despite such differences, a high predictive value of rats of absorption of pharmaceutical compounds for human has been established [45]. Nevertheless, important differences between rodents and humans exist, especially related to cell turnover.…”

Section: Discussionmentioning

confidence: 99%

Dietary modulation and structure prediction of rat mucosal pentraxin (Mptx) protein and loss of function in humans

et al. 2007

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Mucosal pentraxin (Mptx), identified in rats, is a short pentraxin of unknown function. Other subfamily members are Serum amyloid P component (SAP), Creactive protein (CRP) and Jeltraxin. Rat Mptx mRNA is predominantly expressed in colon and in vivo is strongly (30-fold) regulated by dietary heme and calcium, modulators of colon cancer risk. This renders Mptx a potential nutrient sensitive biomarker of gut health. To support a role as biomarker, we examined whether the pentraxin protein structure is conserved, whether Mptx protein is nutrientsensitively expressed and whether Mptx is expressed in mouse and human. Sequence comparison and 3D modelling showed that rat Mptx is highly homologous to the other pentraxins. The calcium-binding site and subunit interaction sites are highly conserved, while a loop deletion and charged residues contribute to a distinctive ''top'' face of the pentamer. In accordance with mRNA expression, Mptx protein is strongly down-regulated in rat colon mucosa in response to high dietary heme intake. Mptx mRNA is expressed in rat and mouse colon, but not in human colon. A stop codon at the beginning of human exon two indicates loss of function, which may be related to differences in intestinal cell turnover between man and rodents.

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Section: Discussionmentioning

confidence: 99%

Dietary modulation and structure prediction of rat mucosal pentraxin (Mptx) protein and loss of function in humans

et al. 2007

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“…A D o value of 1 implies that the expected highest GI concentration is similar to the solubility; a high D o implies low dissolution potential. Data for D o vs f a for these 73 high-P e compounds (Figure 2) clearly demonstrate the poor relationship between in-vitro solubility and in-vivo dissolution (Irvine et al 1999;Kataoka et al 2003;Zhao et al 2003;Kasim et al 2004;Peréz et al 2004;Willmann et al 2004;Yazdanian et al 2004;Yalkowsky et al 2006). In this extensive data set, drug products with very high aqueous D o were completely or near completely absorbed (telmisartan D o = 660 000; toremifene D o = 8700; oxatomide D o = 1500).…”

Section: Prediction Of Fraction Absorbed In Humans From Dissolution Amentioning

confidence: 92%

“…Solubility/dissolution-limited absorption was not fully investigated, and since animals were given the compounds as solutions or suspensions and humans were given tables/capsules, this could possibly have influenced the results. Zhao et al (2003) compared f a data for 98 substances in humans and rats. Compounds with suspected dissolution-ratelimited absorption were not included in the set, but those with active transport were.…”

Section: Prediction Of Fraction Absorbed In Humans From Fraction Absomentioning

confidence: 99%

“…D o data were taken from Yazdanian et al (2004), Kasim et al (2004) and Yalkowsky et al (2006), or calculated from dose and solubility data presented by Willmann et al (2004). F a data (and P e data for verifying high P e ) were taken from Irvine et al (1999), Kataoka et al (2003), Zhao et al (2003), Peréz et al (2004), Willmann et al (2004) and Yalkowsky et al (2006). Data by Zhao et al (2001) also demonstrate that substances with very high aqueous D o are well absorbed: 17 highly permeable compounds (D o > 20; 12 with D o ≥ 100) had f a values above 0.90.…”

Section: Prediction Of Fraction Absorbed In Humans From Dissolution Amentioning

confidence: 99%

“…It can be calculated using any of the following equations (Sun et al 2004): (2004) and Yalkowsky et al (2006), or calculated from dose and solubility data presented by Willmann et al (2004). F a data (and P e data for verifying high P e ) were taken from Irvine et al (1999), Kataoka et al (2003), Zhao et al (2003), Peréz et al (2004), Willmann et al (2004) and Yalkowsky et al (2006). The compound with low f a is danazol (D o = 2400; f a = 0.30).…”

Section: Maximum Absorbable Dose (Mad)mentioning

confidence: 99%

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Prediction of human pharmacokinetics —gastrointestinal absorption

Fagerholm

2007

Journal of Pharmacy and Pharmacology

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Permeability (P e ) and solubility/dissolution are two major determinants of gastrointestinal (GI) drug absorption. Good prediction of these is crucial for predicting doses, exposures and potential interactions, and for selecting appropriate candidate drugs. The main objective was to evaluate screening methods for prediction of GI P e , solubility/dissolution and fraction absorbed (f a ) in humans. The most accurate P e models for prediction of f a of passively transported and highly soluble compounds appear to be the 2/4/A1 rat small intestinal cell model (in-vitro and in-silico), a newly developed artificial-membrane method, and a semi-empirical approach based on in-vitro membrane affinity to immobilized lipid bilayers, effective molecular weight and physiological GI variables. The predictability of in-vitro Caco-2, in-situ perfusion and other artificial membrane methods seems comparably low. The P e and f a in humans for compounds that undergo mainly active transport were predicted poorly by all models investigated. However, the rat in-situ perfusion model appears useful for prediction of active uptake potential (complete active uptake is generally well predicted), and Caco-2 cells are useful for studying bidirectional active transport, respectively. Human intestinal in-vitro P e , which correlates well with f a for passively transported compounds, could possibly also have potential to improve/enable predictions of f a for actively transported substances. Molecular descriptor data could give an indication of the passive absorption potential. The 'maximum absorbable dose' and 'dose number' approaches, and solubility/dissolution data obtained in aqueous media, appear to underestimate in-vivo dissolution to a considerable extent. Predictions of in-vivo dissolution should preferably be done from in-vitro dissolution data obtained using either real or validated simulated GI fluids.

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Computational Prediction of Intestinal Absorption

Clark¹

1998

Encyclopedia of Computational Chemistry

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This review covers the in silico prediction of human intestinal permeability, fraction absorbed in humans, and Caco‐2 permeability, particularly focusing on recent developments and the current state of the art. It is suggested that the largest obstacle in the way of the development of improved predictive models is the current lack of suitable experimental data sets. Some likely future developments are outlined: notably the use of consensus models, the integration of absorption models with models for other absorption‐related processes, and the inclusion of better confidence estimates in the output of predictive models.

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Evaluation of rat intestinal absorption data and correlation with human intestinal absorption

Cited by 88 publications

References 88 publications

Dietary modulation and structure prediction of rat mucosal pentraxin (Mptx) protein and loss of function in humans

Dietary modulation and structure prediction of rat mucosal pentraxin (Mptx) protein and loss of function in humans

Prediction of human pharmacokinetics —gastrointestinal absorption

Computational Prediction of Intestinal Absorption

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