Biomedical subjects

Paul R Seo

Publications and source records attributed to Paul R Seo.

3 recordsLinked to original sources

PubMed2006

Lipid composition effect on permeability across PAMPA.

The parallel artificial membrane permeability assay (PAMPA) system has promise to rapidly screen drug candidate passive permeability, but has been poorly described in terms of its lipid membrane structure and function. The objective was to investigate the role of PAMPA lipid composition on the permeability of five model compounds. PAMPA was used and employed individual phospholipids that varied in phosphate head group and acyl chain unsaturation. Transport of benzoic acid, taurocholic acid, metoprolol, sucrose, and mannitol was measured. Membrane fluidity was assessed by 1,3-diphenylhexatriene fluorescence anisotropy. Results indicate that compound permeability across PAMPA differed in their sensitivity to membrane lipid composition, where compounds with appreciable permeability (i.e. at least 0.2 x 10(-6)cm/s) were possibly sensitive to membrane fluidity and apparent ion pair effects. Benzoic acid permeability ranged 51-fold across membrane types, suggesting acyl chain effect on membrane fluidity. Mannitol, sucrose, and taurocholic acid permeabilities were low and independent of lipid composition. Metoprolol permeability ranged 17-fold and exhibited a markedly high permeability across 1,2-dioleoyl-sn-glycero-3-[phospho-L-serine] due to apparent ion pair-facilitated transport. Compound permeability was lowest across the phosphatidylcholines, which is consistent with phosphatidylcholine exhibiting relatively high membrane rigidity. In contrast to results from phosphatidylethanolamines and phosphatidylserines, acyl chain unsaturation had no effect on permeability across phosphatidylcholines. In conclusion, while much remains unknown about PAMPA structure and subsequent PAMPA permeability, results here from five solutes suggest that, for solutes with appreciable permeability, lipid composition modulated drug permeability through possible membrane fluidity and apparent ion pair influences.

Anisotropy↗

PubMed2002

Novel metrics to compare dissolution profiles.

PURPOSE: To evaluate four novel metrics that compare dissolution profiles and assess their performance characteristics by comparing dissolution profiles of FAST and SLOW immediate release metoprolol tartrate tablets. METHODS: The four novel metrics (rho, rho m, delta a, and delta s), along with f2, were applied to dissolution data from FAST and SLOW metoprolol tartrate tablets. For example, rho m is defined as: [formula: see text] where Rt is the percent dissolved of the reference product at time t, Tt the percent dissolved of the test product at time t, and RATIOt the larger of either Rt/Tt or Tt/Rt. The mean metric values, upper (or lower) confidence limits, and skewness values were calculated, in order to characterize the performance of each metric. RESULTS: The mean values of rho, rho m, delta a, delta s, and f2 were 1.80, 0.80, 0.47, 0.36, and 19.6, respectively. The novel metrics indicate that greater than a 50% relative difference exists between the FAST and SLOW profiles. The upper 95% confidence limits for rho, rho m, delta a, and delta s were 1.84, 0.83, 0.48, and 0.38, respectively, with f2 having a lower limit of 19.1. Skewness values for ln-transformed rho, rho m, delta a, delta s, and f2 were 0.81, 0.71, 0.86, 0.47, and -0.94, respectively, suggesting favorable metric distribution properties. CONCLUSIONS: The direct curve comparison metrics rho, rho m, delta a, and delta s appear to be viable methods to compare dissolution profiles, particularly rho m.

Mathematics↗

PubMedDate not supplied

Chemical substituent effect on pyridine permeability and mechanistic insight from computational molecular descriptors.

The objective was (1) to evaluate the chemical substituent effect on Caco-2 permeability, using a congeneric series of pyridines, and (2) compare molecular descriptors from a computational chemistry approach against molecular descriptors from the Hansch approach for their abilities to explain the chemical substituent effect on pyridine permeability. The passive permeability of parent pyridine and 14 monosubstituted pyridines were measured across Caco-2 monolayers. Computational chemistry analysis was used to obtain the following molecular descriptions: solvation free energies, solvent accessible surface area, polar surface area, and cavitation energy. Results indicate that the parent pyridine was highly permeable and that chemical substitution was able to reduce pyridine permeability almost 20-fold. The substituent effect on permeability provided the following rank order: 3-COO- < 4-NH2 < 3-CONH2 < 3-Cl < 3-CHO < 3-OH < 3-CH2OH < 3-C6H5 < 3-NH2 < 3-CH2C6H5 < 3-C2H5 < 3-H < 3-CH3 < 3-F < 4-C6H5. This substituent effect was better explained via molecule descriptors from the computational chemistry approach than explained by classic descriptors from Hansch. Computational descriptors indicate that aqueous desolvation, but not membrane partitioning per se, dictated substituent effect on permeability.

Caco-2 Cells↗