Experimental and computational models to investigate intestinal drug permeability and metabolism

Chen, Jinyuan; Yuan, Ziyun; Tu, Yifan; Hu, Wanyu; Xie, Cong; Ye, Ling

doi:10.1080/00498254.2023.2180454

Cited by 3 publications

(2 citation statements)

References 198 publications

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“…Most new drug modalities are within the category of middle-to-large molecules, and thus, they tend to lack oral bioavailability, which is one of the greatest advantages of small-molecule drugs. Considering that oral administration is superior to other dosing routes (e.g., intravenous and subcutaneous) given its noninvasiveness and safety [ 11 ], parenteral administration of new drug modalities limits their potential use by patients. The reason for the poor oral bioavailability of new drug modalities can be explained by Lipinski’s rule of five [ 12 ] defining the necessary properties for oral absorption as follows: molecular weight (MW) ≤ 500, number of hydrogen bond donors (HBDs) ≤ 5, number of hydrogen bond acceptors (HBAs) ≤ 10, and octanol-water partition coefficient (LogP) ≤ 5.…”

Section: Introductionmentioning

confidence: 99%

Oral Absorption of Middle-to-Large Molecules and Its Improvement, with a Focus on New Modality Drugs

Asano,

Takakusa,

Nakai

2023

Pharmaceutics

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To meet unmet medical needs, middle-to-large molecules, including peptides and oligonucleotides, have emerged as new therapeutic modalities. Owing to their middle-to-large molecular sizes, middle-to-large molecules are not suitable for oral absorption, but there are high expectations around orally bioavailable macromolecular drugs, since oral administration is the most convenient dosing route. Therefore, extensive efforts have been made to create bioavailable middle-to-large molecules or develop absorption enhancement technology, from which some successes have recently been reported. For example, Rybelsus® tablets and Mycapssa® capsules, both of which contain absorption enhancers, were approved as oral medications for type 2 diabetes and acromegaly, respectively. The oral administration of Rybelsus and Mycapssa exposes their pharmacologically active peptides with molecular weights greater than 1000, namely, semaglutide and octreotide, respectively, into systemic circulation. Although these two medications represent major achievements in the development of orally absorbable peptide formulations, the oral bioavailability of peptides after taking Rybelsus and Mycapssa is still only around 1%. In this article, we review the approaches and recent advances of orally bioavailable middle-to-large molecules and discuss challenges for improving their oral absorption.

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Section: Introductionmentioning

confidence: 99%

Oral Absorption of Middle-to-Large Molecules and Its Improvement, with a Focus on New Modality Drugs

Asano,

Takakusa,

Nakai

2023

Pharmaceutics

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“…According to the International Coordination Committee for the Registration of Pharmaceutical Products for Human Use (ICH) guidelines and the M9 Bioequivalence Exemptions Based on the Biopharmaceutical Classification System [1][2][3][4] permeability is closely related to the rate and extent of drug absorption in the body and is one of the key factors in the transport of drugs in the body through expanded membranes and is relevant to drug development. Pharmaceutical excipients are non-physiologically active substances in pharmaceuticals that affect their absorption and bioavailability in the body [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Decreased Penetration Mechanism of Ranitidine Due to Application of Sodium Sulfobutyl Ether-β-Cyclodextrin

Yang,

Zhang,

Huang

et al. 2023

Pharmaceutics

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Permeability has an important effect on drug absorption. In this study, the effect of different concentrations of sodium sulfobutyl ether-β-cyclodextrin (SBE-β-CD) on the absorption of ranitidine was investigated to examine the mechanism of permeability changes. The results of a parallel artificial membrane permeability assay (PAMPA) showed that increasing the concentration of sodium sulfobutyl ether-β-cyclodextrin, 0, 0.12% (w/v), 0.36% (w/v) and 3.6% (w/v), respectively, caused the apparent permeability coefficient of ranitidine to decrease to 4.62 × 10−5, 4.5 × 10−5, 3.61 × 10−5 and 1.08 × 10−5 in Caco-2 cells, respectively. The same results were obtained from an oral pharmacokinetic study in rats. Further studies indicated that SBE-β-CD significantly increased the zeta potential of ranitidine. SBE-β-CD interacted with ranitidine charges to form a complex that reduced ranitidine permeability, and SBE-β-CD should be chosen with caution for drugs with poor permeability.

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Decreased Penetration Mechanism of Ranitidine Due to Application of Sodium Sulfobutyl Ether-β-Cyclodextrin

Rui,

Jing,

Jia-Qi

et al. 2023

Preprint

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Permeability has an important effect on drug absorption. In this study, the effect of different concentrations of sodium sulfobutyl ether-β-cyclodextrin (SBE-β-CD) on the absorption of ranitidine was investigated to examine the mechanism of permeability changes. The results of parallel artificial membrane permeability assay (PAMPA) showed that increasing the concentration of sodium sulfobutyl ether-β-cyclodextrin, 0, 0.12% (w/v), 0.36% (w/v) and 3.6% (w/v), respectively, the apparent permeability coefficient of ranitidine decreased to 4.62×10-5 , 4.5×10-5 , 3.61×10-5 and 1.08×10-5 in Caco-2 cells, respectively. The same results were obtained from oral pharmacokinetic study in rats; Further studies indicated that SBE-β-CD significantly increased the zeta potential of ranitidine. SBE-β-CD interacted with ranitidine charges to form a complex that reduced ranitidine permeability, and SBE-β-CD should be chosen with caution for drugs with poor permeability.

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Experimental and computational models to investigate intestinal drug permeability and metabolism

Cited by 3 publications

References 198 publications

Oral Absorption of Middle-to-Large Molecules and Its Improvement, with a Focus on New Modality Drugs

Oral Absorption of Middle-to-Large Molecules and Its Improvement, with a Focus on New Modality Drugs

Decreased Penetration Mechanism of Ranitidine Due to Application of Sodium Sulfobutyl Ether-β-Cyclodextrin

Decreased Penetration Mechanism of Ranitidine Due to Application of Sodium Sulfobutyl Ether-β-Cyclodextrin

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