Passive Permeability and P-Glycoprotein-Mediated Efflux Differentiate Central Nervous System (CNS) and Non-CNS Marketed Drugs
- Kelly M. Mahar Doan1,
- Joan E. Humphreys,
- Lindsey O. Webster,
- Stephen A. Wring,
- Larry J. Shampine,
- Cosette J. Serabjit-Singh,
- Kimberly K. Adkison and
- Joseph W. Polli
- Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina
- Dr. Joseph W. Polli, Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Inc., P.O. Box 13398, Room: MAI.A3666.3E, Research Triangle Park, NC 27709. E-mail: joseph.w.polli{at}gsk.com
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 (Papp) 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.
Footnotes
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↵1 Current address: Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Inc., Mail Stop-UW2720, 709 Swedeland Rd., King of Prussia, PA 19406.
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K.M.M.D. was a GlaxoSmithKline postdoctoral fellow in Preclinical Drug Metabolism and Pharmacokinetics.
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DOI: 10.1124/jpet.102.039255
- Abbreviations:
- CNS
- central nervous system
- BBB
- blood-brain barrier
- Pgp
- P-glycoprotein
- MDCK
- Madin Darby canine kidney cells
- PSA
- polar surface area
- MDR
- multidrug resistance protein
- DMSO
- dimethyl sulfoxide
- A → B
- apical to basolateral
- B → A
- basolateral to apical
- B → A/A → B ratio
- Papp B → A/Papp A → B
- LC
- liquid chromatography
- MS
- mass spectrometry
- Papp
- apparent permeability
- AM
- acetoxymethyl ester
- clogP
- calculated octagonal/water partition coefficient
- cmr
- calculated molar refraction
- HBD
- count of hydrogen bond donor groups
- RFU
- relative fluorescence unit
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- Received May 21, 2002.
- Accepted July 15, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
