Simulation Modelling of Human Intestinal Absorption using Caco-2 Permeability and Kinetic Solubility Data for Early Drug Discovery

Thomas, Shl; Brightman, Frances A.; Gill, Helen; Lee, Sally; Pufong, Boris

doi:10.1002/jps.21305

Cited by 49 publications

(32 citation statements)

References 18 publications

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“…PTX solubility increased from 0.0003 mg/mL (35, 36) to 3.50 mg/mL, DCTX solubility increased from 0.0055 mg/mL (35)to 4.27 mg/mL. ETO solubility also increased from 0.0580 mg/mL (37) to 3.17 mg/mL. 17-AAG solubility increased from 0.1000 gm/mL (38)to 4.21 mg/mL.…”

Section: Resultsmentioning

confidence: 94%

Multi-drug loaded polymeric micelles for simultaneous delivery of poorly soluble anticancer drugs

Shin

Alani

Rao

et al. 2009

Journal of Controlled Release

234

155

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Current clinical and preclinical anticancer formulations are limited by their use of toxic excipients and stability issues upon combining different drug formulations. We have found that poly(ethylene glycol)-block-poly(d,l lactic acid) (PEG-b-PLA) micelles can deliver multiple poorly water-soluble drugs at clinically relevant doses. Paclitaxel (PTX), etoposide (ETO), docetaxel (DCTX) and 17-AAG were solubilized individually in PEG-b-PLA micelles. Combinations of PTX/17-AAG, ETO/ 17-AAG, DCTX/17-AAG and PTX/ETO/17-AAG were also solubilized in PEG-b-PLA micelles. PEG-b-PLA micelles were characterized in terms of drug loading, size, stability and drug release. All anticancer agents in all combinations were all solubilized at the level of mg/mL and were stable for 24 hours in the 2 and 3 drug combination PEG-b-PLA micelles. The stability of the 2 and 3 drug combination PEG-b-PLA micelles was due to the presence of 17-AAG. In vitro, t 1/2 values for 2 and 3 drug combination PEG-b-PLA micelles spanned 1-5 hrs. PEG-b-PLA micelles offer a promising alternative for combination drug therapy without formulation related side effects.

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Section: Resultsmentioning

confidence: 94%

Multi-drug loaded polymeric micelles for simultaneous delivery of poorly soluble anticancer drugs

Shin

Alani

Rao

et al. 2009

Journal of Controlled Release

234

155

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“…Larregieu and Benet [59] recently reviewed some of the problems in using Caco-2 as a surrogate for human permeability measurements. Thomas et al [60] recently published a compilation of results for 120 drugs determined in their lab by the same method and these values were compared with the AM values for the drugs studied by both methods (Additional file 1: Table 2). In addition, Additional file 1: Table 2 was filled in with Caco-2 results from other labs.…”

Section: Discussionmentioning

confidence: 99%

Quantitation of small intestinal permeability during normal human drug absorption

Levitt

2013

BMC Pharmacol Toxicol

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BackgroundUnderstanding the quantitative relationship between a drug’s physical chemical properties and its rate of intestinal absorption (QSAR) is critical for selecting candidate drugs. Because of limited experimental human small intestinal permeability data, approximate surrogates such as the fraction absorbed or Caco-2 permeability are used, both of which have limitations.MethodsGiven the blood concentration following an oral and intravenous dose, the time course of intestinal absorption in humans was determined by deconvolution and related to the intestinal permeability by the use of a new 3 parameter model function (“Averaged Model” (AM)). The theoretical validity of this AM model was evaluated by comparing it to the standard diffusion-convection model (DC). This analysis was applied to 90 drugs using previously published data. Only drugs that were administered in oral solution form to fasting subjects were considered so that the rate of gastric emptying was approximately known. All the calculations are carried out using the freely available routine PKQuest Java (http://www.pkquest.com) which has an easy to use, simple interface.ResultsTheoretically, the AM permeability provides an accurate estimate of the intestinal DC permeability for solutes whose absorption ranges from 1% to 99%. The experimental human AM permeabilities determined by deconvolution are similar to those determined by direct human jejunal perfusion. The small intestinal pH varies with position and the results are interpreted in terms of the pH dependent octanol partition. The permeability versus partition relations are presented separately for the uncharged, basic, acidic and charged solutes. The small uncharged solutes caffeine, acetaminophen and antipyrine have very high permeabilities (about 20 x 10-4 cm/sec) corresponding to an unstirred layer of only 45 μm. The weak acid aspirin also has a large AM permeability despite its low octanol partition at pH 7.4, suggesting that it is nearly completely absorbed in the first part of the intestine where the pH is about 5.4.ConclusionsThe AM deconvolution method provides an accurate estimate of the human intestinal permeability. The results for these 90 drugs should provide a useful benchmark for evaluating QSAR models.

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“…Based on a single parameter such as the intestinal effective permeability,96 the absorption potential97 or Caco‐2‐cells monolayer permeability,98 previous studies have proposed a method for the prediction of the extent of drug absorption ( F abs ). More recently, methods incorporating two parameters such as apparent permeability coefficients and solubility51, 99 have been used to estimate the extent of absorption for a wide drug selection. In the present work, based on the ACAT approach, dynamic processes for the GIT transit rate, drug dissolution, solubility in fassif medium, and diffusion velocity of the nonionized drug through the gut membrane have been included in the WB‐PBPK model and used as a predictive tool for the extent of drug absorption.…”

Section: Discussionmentioning

confidence: 99%

Physiologically Based Predictions of the Impact of Inhibition of Intestinal and Hepatic Metabolism on Human Pharmacokinetics of CYP3A Substrates

Fenneteau

Poulin

Nekka

2010

Journal of Pharmaceutical Sciences

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Simulation Modelling of Human Intestinal Absorption using Caco-2 Permeability and Kinetic Solubility Data for Early Drug Discovery

Cited by 49 publications

References 18 publications

Multi-drug loaded polymeric micelles for simultaneous delivery of poorly soluble anticancer drugs

Multi-drug loaded polymeric micelles for simultaneous delivery of poorly soluble anticancer drugs

Quantitation of small intestinal permeability during normal human drug absorption

Physiologically Based Predictions of the Impact of Inhibition of Intestinal and Hepatic Metabolism on Human Pharmacokinetics of CYP3A Substrates

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