Rapid Screening of Drug Absorption Potential Using the Immobilized Artificial Membrane Phosphatidylcholine Column and Molar Volume

Yoon, Chi Ho; Shin, Beomsu; Chang, Hyuk Soo; Kwon, L. S.; Kim, H. Y.; Yoo, Sun-Dong; Yoo, Sun Dong

doi:10.1365/s10337-004-0410-x

Cited by 17 publications

(13 citation statements)

References 30 publications

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“…The absorption potential of apicidin by passive diffusion was evaluated by the immobilized artificial membrane (IAM) chromatographic assay described previously elsewhere (Yoon et al, 2004). Briefly, high-performance liquid chromatography (HPLC) analysis was performed using a Waters 2695 separations module and Waters 2996 photo diode array detector (Waters Corporation, Milford, MA).…”

Section: Methodsmentioning

confidence: 99%

Quantitative Determination of Absorption and First-Pass Metabolism of Apicidin, a Potent Histone Deacetylase Inhibitor

et al. 2014

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Apicidin, a potential oral chemotherapeutic agent, possesses potent anti-histone-deacetylase activity. After oral administration, the total bioavailability of apicidin is known to be low (14.2%-19.3%). In the present study, we evaluated the factors contributing to the low bioavailability of apicidin by means of quantitative determination of absorption fraction and first-pass metabolism after oral administration. Apicidin was given to rats by five different routes: into the femoral vein, duodenum, superior mesenteric artery, portal vein, and carotid artery. Especially, the fraction absorbed (F X ) and the fraction that is not metabolized in the gut wall (F G ) were separated by injection of apicidin via superior mesenteric artery, which enables bypassing the permeability barrier. The F X was 45.9% 6 9.7%, the F G was 70.9% 6 8.1% and the hepatic bioavailability (F H ) was 70.6% 6 12.3%, while the pulmonary firstpass metabolism was minimal (F L = 102.8% 6 7.4%), indicating that intestinal absorption was the rate-determining step for oral absorption of apicidin. The low F X was further examined in terms of passive diffusion and transporter-mediated efflux by in vitro immobilized artificial membrane (IAM) chromatographic assay and in situ single-pass perfusion method, respectively. Although the passive diffusion potential of apicidin was high (98.01%) by the IAM assay, the in situ permeability was significantly enhanced by the presence of the P-glycoprotein (P-gp) inhibitor elacrider. These data suggest that the low bioavailability of apicidin was mainly attributed to the P-gp efflux consistent with the limited F X measured in vivo experiment.

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Section: Methodsmentioning

confidence: 99%

Quantitative Determination of Absorption and First-Pass Metabolism of Apicidin, a Potent Histone Deacetylase Inhibitor

et al. 2014

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“…A mobile phase pH of 5.5 may be useful in predicting the BBB penetration, especially when a simultaneous rapid screening of intestinal absorption potential is needed as the prediction of intestinal absorption was most successful at this pH. 28 A mobile phase pH of 7.0 may also be used in predicting the BBB penetration with relatively high success. These pH values were within the pH range recommended by the column manufacturer.…”

Section: Prediction Of Cns Penetration Potential Based On Iam Partitimentioning

confidence: 99%

“…27 The IAM chromatography has been used in predicting the drug transport across biological barriers. 25,26,28 This study examined the utility of the IAM phosphatidylcholine column chromatography for the prediction of BBB penetration potential using a set of 23 structurally unrelated drugs. The developed method was validated for a set of 7 newly synthesized PDE-4 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Rapid Screening of Blood-Brain Barrier Penetration of Drugs Using the Immobilized Artificial Membrane Phosphatidylcholine Column Chromatography

Yoon¹,

Kim²,

Shin³

et al. 2006

SLAS Discovery

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The chromatographic capacity factors (k IAM ) of 23 structurally diverse drugs were measured by the immobilized artificial membrane (IAM) phosphatidylcholine chromatography for the prediction of blood-brain barrier (BBB) penetration. The k IAM was determined using the mobile phase consisting of acetonitrile:DPBS (20:80 v/v) and corrected for the molar volume of the solutes (k IAM /MW n ). The correlation between k IAM /MW n and CNS penetration was highest when measured at pH 5.5 with the power function of n = 4. This in vitro prediction method was validated with 7 newly synthesized PDE-4 inhibitors. The relationship between in vivo plasma-to-brain concentration ratios and in vitro CNS penetration was excellent (r = 0.959). The developed in vitro prediction method may be used as a rapid screening tool for BBB penetration of drugs with passive transport mechanism, with high success, low cost, and reproducibility. (Journal of Biomolecular

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“…The human fraction absorbed (F a ) was calculated for all 15 commercial drugs using the following equation obtained previously in our laboratory (Yoon et al, 2004):…”

Section: Discussionmentioning

confidence: 99%

“…The above equation was derived based on the measurement of IAM capacity factors (k IAM ) for 40 test compounds with excellent correlation (r = 0.925; Yoon et al, 2004). The IAM capacity factor was calculated as shown below:…”

Section: Discussionmentioning

confidence: 99%

Prediction of drug bioavailability in humans using immobilized artificial membrane phosphatidylcholine column chromatography and in vitro hepatic metabolic clearance

Shin

Yoon

Balthasar

et al. 2009

Biomedical Chromatography

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This study reports a rapid screening method for the prediction of oral drug bioavailability in humans based on combined immobilized artificial membrane (IAM) chromatographic capacity factor (k(IAM)) and in vitro stability in hepatic microsomes. The fraction of drug absorbed (F(a)) in humans was predicted for a set of 15 structurally diverse commercial drugs based on k(IAM) values using a mobile phase consisting of acetonitrile: Dulbecco's phosphate-buffered saline. The hepatic intrinsic clearance (CL'(int)) was calculated from in vitro disappearance half-life, and the oral bioavailability was predicted using in vitro hepatic clearance (CL(h)) and F(a). Significant correlations were observed for the relationships between predicted hepatic extraction ratios (ER(h)) and actual presystemic metabolism (r = 0.854) and between predicted and observed oral bioavailabilities (r = 0.805; p < 0.01). The IAM capacity factor together with the hepatic microsomal disappearance half-life may be useful in identifying compounds with high oral absorption potential in early drug discovery processes.

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Rapid Screening of Drug Absorption Potential Using the Immobilized Artificial Membrane Phosphatidylcholine Column and Molar Volume

Cited by 17 publications

References 30 publications

Quantitative Determination of Absorption and First-Pass Metabolism of Apicidin, a Potent Histone Deacetylase Inhibitor

Quantitative Determination of Absorption and First-Pass Metabolism of Apicidin, a Potent Histone Deacetylase Inhibitor

Rapid Screening of Blood-Brain Barrier Penetration of Drugs Using the Immobilized Artificial Membrane Phosphatidylcholine Column Chromatography

Prediction of drug bioavailability in humans using immobilized artificial membrane phosphatidylcholine column chromatography and in vitro hepatic metabolic clearance

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