Similarity in the linear and non-linear oral absorption of drugs between human and rat

Chiou, Win L.; Ma, Chein; Chung, Sung Kee; Wu, Ta C.; Jeong, Hyunyoung

doi:10.5414/cpp38532

Cited by 46 publications

(18 citation statements)

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“…The dose of AZT used here in drinking water was 0.6 mg/ml, equivalent to 70 mg/kg body weight/day. This dose corresponds to human treatment regimens, i.e., 8 to 12 mg/kg/day, or to 50 to 75 mg/kg/day in rats after correction for the metabolic and drug disposal rate in rats being five-to sevenfold higher than that in humans (7).…”

Section: Methodsmentioning

confidence: 99%

Site-Specific Reduction of Oxidative and Lipid Metabolism in Adipose Tissue of 3′-Azido-3′-Deoxythymidine-Treated Rats

Deveaud

Beauvoit

Reynaud

et al. 2007

Antimicrob Agents Chemother

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Although it is well accepted that treatment with some nucleoside reverse transcriptase inhibitors modifies both fat metabolism and fat distribution in humans, the mechanisms underlying these modifications are not yet known. The present investigation examined whether a decrease in oxidative capacity, induced by a chronic oral administration of 3-azido-3-deoxythymidine (AZT) in rats, could be associated with an alteration of the lipogenic capacity of white adipose tissues. The impact of obesity as a factor was then evaluated. Results showed that AZT treatment induced differential effects depending on anatomical localization. Indeed, in the inguinal adipose tissue, the specific activities of cytochrome c oxidase and fatty acid synthase, two ratecontrolling enzymes in energy and lipogenic metabolisms, respectively, both decreased under AZT treatment, thus leading to a lowered cell lipid accumulation. Moreover, the AMP-activated protein kinase phosphorylation level tended to increase, thus implying that AZT causes an energy imbalance. Furthermore, the inguinal tissue of obese rats presented a sensitivity to AZT treatment that was higher than that of lean rats. In contrast, for epididymal tissue, no significant change in all these parameters could be detected under AZT treatment, regardless of the nutritional status of the animals. Taken together, these data demonstrate differential effects of AZT on subcutaneous adipose tissue and visceral white adipose tissue. It could be considered that the chronic decreases in energy and lipogenic metabolism of inguinal adipocyte, consecutive to AZT treatment, may lead, in the long term, to adipose tissue atrophy.

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Section: Methodsmentioning

confidence: 99%

Site-Specific Reduction of Oxidative and Lipid Metabolism in Adipose Tissue of 3′-Azido-3′-Deoxythymidine-Treated Rats

Deveaud

Beauvoit

Reynaud

et al. 2007

Antimicrob Agents Chemother

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“…Building on this, a strong overall correlation (R 2 =0.97) was reported between rat and human F a for 64 drugs with varying physico-chemical properties and absolute F oral (42). Further work showed that rats may serve as a good in vivo model for predicting dose-dependent (when dose was normalised to body weight) as well as dose-independent oral absorption properties in humans (16,33). Some may consider this surprising given that the rat small intestine has ca.…”

Section: Can Human Oral Absorption Be Accurately Predicted From Pre-cmentioning

confidence: 99%

“…Despite its considerable complexity, a number of qualitative as well as quantitative approaches have been successfully employed for estimation of human F a , either from animal models (33,34) or from IVIVE of data from in vitro systems such as Caco-2 monolayers or Ussing chamber preparations (14,(35)(36)(37). Perhaps suited to late stage discovery compounds, due to the level of compound-specific information required, commercial software such as Simcyp® and GastroPlus TM are available to facilitate predictions of F a through integration of permeability and solubility data into mathematical models alongside appropriate physiological parameters (38)(39)(40).…”

Section: Can Human Oral Absorption Be Accurately Predicted From Pre-cmentioning

confidence: 99%

Gut Wall Metabolism. Application of Pre-Clinical Models for the Prediction of Human Drug Absorption and First-Pass Elimination

Jones

Hatley

Ungell

et al. 2016

AAPS J

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Abstract. Quantifying the multiple processes which control and modulate the extent of oral bioavailability for drug candidates is critical to accurate projection of human pharmacokinetics (PK). Understanding how gut wall metabolism and hepatic elimination factor into first-pass clearance of drugs has improved enormously. Typically, the cytochrome P450s, uridine 5′-diphosphate-glucuronosyltransferases and sulfotransferases, are the main enzyme classes responsible for drug metabolism. Knowledge of the isoforms functionally expressed within organs of first-pass clearance, their anatomical topology (e.g. zonal distribution), protein homology and relative abundances and how these differ across species is important for building models of human metabolic extraction. The focus of this manuscript is to explore the parameters influencing bioavailability and to consider how well these are predicted in human from animal models or from in vitro to in vivo extrapolation. A unique retrospective analysis of three AstraZeneca molecules progressed to first in human PK studies is used to highlight the impact that species differences in gut wall metabolism can have on predicted human PK. Compared to the liver, pharmaceutical research has further to go in terms of adopting a common approach for characterisation and quantitative prediction of intestinal metabolism. A broad strategy is needed to integrate assessment of intestinal metabolism in the context of typical DMPK activities ongoing within drug discovery programmes up until candidate drug nomination.

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“…Chiou et al (Chiou et al 2000) demonstrated that there is a good correlation between absorption rates in humans and rats with a slope near unity. One limitation of the MAD calculation is that only the aqueous solubility in pH 6.5 buffer is taken into consideration, and no considerations are made for possible solubility enhancement by bile salts, surfactants, lypolytic products, etc., present in GI fluids.…”

Section: Tier 1 -Discovery and Early Preclinical Development: Assessimentioning

confidence: 99%

In Vitro–In Vivo Correlation in Dosage Form Development: Case Studies

Li¹,

Royce²,

Serajuddin³

2008

Biopharmaceutics Applications in Drug Development

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Similarity in the linear and non-linear oral absorption of drugs between human and rat

Cited by 46 publications

References 0 publications

Site-Specific Reduction of Oxidative and Lipid Metabolism in Adipose Tissue of 3′-Azido-3′-Deoxythymidine-Treated Rats

Site-Specific Reduction of Oxidative and Lipid Metabolism in Adipose Tissue of 3′-Azido-3′-Deoxythymidine-Treated Rats

Gut Wall Metabolism. Application of Pre-Clinical Models for the Prediction of Human Drug Absorption and First-Pass Elimination

In Vitro–In Vivo Correlation in Dosage Form Development: Case Studies

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