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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Passive Permeability and P-Glycoprotein-Mediated Efflux Differentiate Central Nervous System (CNS) and Non-CNS Marketed Drugs

Kelly M. Mahar Doan, Joan E. Humphreys, Lindsey O. Webster, Stephen A. Wring, Larry J. Shampine, Cosette J. Serabjit-Singh, Kimberly K. Adkison and Joseph W. Polli
Journal of Pharmacology and Experimental Therapeutics December 2002, 303 (3) 1029-1037; DOI: https://doi.org/10.1124/jpet.102.039255
Kelly M. Mahar Doan
Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina
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Joan E. Humphreys
Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina
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Lindsey O. Webster
Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina
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Stephen A. Wring
Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina
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Larry J. Shampine
Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina
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Cosette J. Serabjit-Singh
Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina
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Kimberly K. Adkison
Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina
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Joseph W. Polli
Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina
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Abstract

Membrane permeability and P-glycoprotein (Pgp) can be limiting factors for blood-brain barrier penetration. The objectives of this study were to determine whether there are differences in the in vitro permeability, Pgp substrate profiles, and physicochemical properties of drugs for central nervous system (CNS) and non-CNS indications, and whether these differences are useful criteria in selecting compounds for drug development. Apparent permeability (P app) and Pgp substrate profiles for 93 CNS (n = 48) and non-CNS (n = 45) drugs were determined by monolayer efflux. Calcein-AM inhibition assays were used to supplement the efflux results. The CNS set (2 of 48, 4.2%) had a 7-fold lower incidence of passive permeability values <150 nm/s compared with the non-CNS set (13 of 45, 28.9%). The majority of drugs (72.0%, 67 of 93) were not Pgp substrates; however, 49.5% (46 of 93) were positive in the calcein-AM assay when tested at 100 μM. The CNS drug set (n = 7 of 48, 14.6%) had a 3-fold lower incidence of Pgp-mediated efflux than the non-CNS drug set (n = 19 of 45, 42.2%). Analysis of 18 physicochemical properties revealed that the CNS drug set had fewer hydrogen bond donors, fewer positive charges, greater lipophilicity, lower polar surface area, and reduced flexibility compared with the non-CNS group (p < 0.05), properties that enhance membrane permeability. This study on a large, diverse set of marketed compounds clearly demonstrates that permeability, Pgp-mediated efflux, and certain physicochemical properties are factors that differentiate CNS and non-CNS drugs. For CNS delivery, a drug should ideally have an in vitro passive permeability >150 nm/s and not be a good (B → A/A → B ratio <2.5) Pgp substrate.

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Journal of Pharmacology and Experimental Therapeutics: 303 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 3
1 Dec 2002
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Passive Permeability and P-Glycoprotein-Mediated Efflux Differentiate Central Nervous System (CNS) and Non-CNS Marketed Drugs

Kelly M. Mahar Doan, Joan E. Humphreys, Lindsey O. Webster, Stephen A. Wring, Larry J. Shampine, Cosette J. Serabjit-Singh, Kimberly K. Adkison and Joseph W. Polli
Journal of Pharmacology and Experimental Therapeutics December 1, 2002, 303 (3) 1029-1037; DOI: https://doi.org/10.1124/jpet.102.039255

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Passive Permeability and P-Glycoprotein-Mediated Efflux Differentiate Central Nervous System (CNS) and Non-CNS Marketed Drugs

Kelly M. Mahar Doan, Joan E. Humphreys, Lindsey O. Webster, Stephen A. Wring, Larry J. Shampine, Cosette J. Serabjit-Singh, Kimberly K. Adkison and Joseph W. Polli
Journal of Pharmacology and Experimental Therapeutics December 1, 2002, 303 (3) 1029-1037; DOI: https://doi.org/10.1124/jpet.102.039255
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