Caco-2 permeability of weakly basic drugs predicted with the Double-Sink PAMPA method

Avdeef, Alex; Artursson, Per; Neuhoff, Sibylle; Lazorova, Lucia; Gråsjö, Johan; Tavelin, Staffan

doi:10.1016/j.ejps.2004.11.011

Cited by 206 publications

(235 citation statements)

References 37 publications

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“…These included three acidic (naproxen, warfarin, nimesulide), seven basic (lidocaine, propranolol, verapamil, diltiazem, amitriptyline, metoprolol, pindolol), and two neutral (caffeine, antipyrine) molecules. LogP and logD 6.8 (log 10 of distribution coefficient at pH 6.8, which corresponds to salivary pH) values were obtained either from literature or were estimated using ChemIDplus (8)(9)(10)(11)(12)(13)(14)(15). Drugs with a logD 6.8 value of greater than −1.0 and lower than +1.0 were selected as model compounds to minimize the effects of unstirred water layer and drug accumulation in the membrane.…”

Section: Drugs and Descriptorsmentioning

confidence: 99%

Effect of Drug Lipophilicity and Ionization on Permeability Across the Buccal Mucosa: A Technical Note

Kokate

Jasti

2008

AAPS PharmSciTech

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Section: Drugs and Descriptorsmentioning

confidence: 99%

Effect of Drug Lipophilicity and Ionization on Permeability Across the Buccal Mucosa: A Technical Note

Kokate

Jasti

2008

AAPS PharmSciTech

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“…A double-sink PAMPA consisting of a pH gradient (i.e., pH 6.5 and 7.4 for the donor and receiver compartments, respectively) and a lipophilic sink (i.e., a surfactant in the receiver solution) was utilized with cassette incubation of reference compounds in our studies. 8) Sample analysis was performed using selected reaction monitoring (SRM) with a triple quadrupole LC-MS/MS system. This sensitive and selective bioanalytical technique capable of simultaneous quantitation of all test compounds will allow for permeability screening of poorly soluble, lipophilic compounds that should be tested at low concentrations.…”

mentioning

confidence: 99%

Development of Cassette PAMPA for Permeability Screening

Lee

et al. 2017

Biological & Pharmaceutical Bulletin

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The parallel artificial membrane permeability assay (PAMPA) is widely used in early-stage drug discovery to discriminate compounds by intestinal permeability. The purpose of the current study was to establish a cassette (n-in-1) PAMPA to enable permeability screening of lipophilic compounds. A double-sink PAMPA consisting of a pH gradient (i.e., pH 6.5 and 7.4 for the donor and receiver compartments, respectively) and a lipophilic sink (i.e., a surfactant in the receiver solution) was utilized with cassette incubation of 10 reference compounds. Sample analysis was conducted using selected reaction monitoring (SRM) with a triple quadrupole LC-MS/MS system. Correlation between PAMPA permeability and human intestinal absorption (HIA) of the reference compounds yielded two false negatives, namely propranolol (PPN) and verapamil (VER); these two compounds showed a substantially lower recovery (ca. 10%) than other reference compounds (>69%). This cassette PAMPA was repeated subsequently with polysorbate 80 added to the donor compartments, which resulted in a significant increase in both the recovery and the permeability of the false negatives. Accordingly, the permeability class of all reference compounds could be unambiguously differentiated using this cassette PAMPA. Also, a strong linear correlation (r 0.9845) was observed between the cassette and discrete permeability of all reference compounds.

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“…PAMPA was carried out using a PAMPA Evolution instrument from pION Inc. (Woburn, MA) (Avdeef et al, 2005). The lipid solution consisted of a 20% (w/v) dodecane solution and lecithin mixture.…”

Section: Reductive Metabolism In Human Intestinementioning

confidence: 99%

Significance of Reductive Metabolism in Human Intestine and Quantitative Prediction of Intestinal First-Pass Metabolism by Cytosolic Reductive Enzymes

et al. 2013

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The number of new drug candidates that are cleared via noncytochrome P450 (P450) enzymes has increased. However, unlike oxidation by P450, the roles of reductive enzymes are less understood. The metabolism in intestine is especially not well known. The purposes of this study were to investigate the significance of reductive metabolism in human intestine, and to establish a quantitative prediction method of intestinal first-pass metabolism by cytosolic reductive enzymes, using haloperidol, mebendazole, and ziprasidone. First, we estimated the metabolic activities for these compounds in intestine and liver using subcellular fractions. Metabolic activities were detected in human intestinal cytosol (HIC) for all three compounds, and the intrinsic clearance values were higher than those in human liver cytosol for haloperidol and mebendazole. These metabolic activities in HIC were NADPH-and/or NADH-dependent. Furthermore, the metabolic activities for all three compounds in HIC were largely inhibited by menadione, which has been used as a carbonyl reductase (CBR)-selective chemical inhibitor. Therefore, considering subcellular location, cofactor requirement, and chemical inhibition, these compounds might be metabolized by CBRs in human intestine. Subsequently, we tried to quantitatively predict intestinal availability (F g ) for these compounds using human intestinal S9 (HIS9). Our prediction model using apparent permeability of parallel artificial membrane permeability assay and metabolic activities in HIS9 could predict F g in humans for the three compounds well. In conclusion, CBRs might have higher metabolic activities in human intestine than in human liver. Furthermore, our prediction method of human F g using HIS9 is applicable to substrates of cytosolic reductive enzymes.

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Caco-2 permeability of weakly basic drugs predicted with the Double-Sink PAMPA method

Cited by 206 publications

References 37 publications

Effect of Drug Lipophilicity and Ionization on Permeability Across the Buccal Mucosa: A Technical Note

Effect of Drug Lipophilicity and Ionization on Permeability Across the Buccal Mucosa: A Technical Note

Development of Cassette PAMPA for Permeability Screening

Significance of Reductive Metabolism in Human Intestine and Quantitative Prediction of Intestinal First-Pass Metabolism by Cytosolic Reductive Enzymes

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