title: Structural determinants of drug partitioning in surrogates of phosphatidylcholine bilayer strata.
abstract: The knowledge of drug concentrations in bilayer headgroups, core, and at the interface between them is a prerequisite for quantitative modeling of drug interactions with many membrane-bound transporters, metabolizing enzymes and receptors, which have the binding sites located in the bilayer. This knowledge also helps understand the rates of trans-bilayer transport because balanced interactions of drugs with the bilayer strata lead to high rates, while excessive affinities for any stratum cause a slowdown. Experimental determination of bilayer location is so tedious and costly that the data are only available for some fifty compounds. To extrapolate these valuable results to more compounds at a higher throughput, surrogate phases have been used to obtain correlates of the drug affinities for individual strata. We introduced a novel system, consisting of a diacetyl phosphatidylcholine (DAcPC) solution with the water content of the fluid bilayer as the headgroup surrogate and n-hexadecane (C16) representing the core. The C16/DAcPC partition coefficients were measured for 113 selected compounds, containing structural fragments that are frequently occurring in approved drugs. The data were deconvoluted into the ClogP-based fragment solvation characteristics and processed using a solvatochromic correlation. Increased H-bond donor ability and excess molar refractivity of compounds promote solvation in the DAcPC phase as compared to bulk water, contrary to H-bond acceptor ability, dipolarity/polarizability, and volume. The results show that aromates have more balanced distribution in bilayer strata, and thus faster trans-bilayer transport, than similar alkanes. This observation is in accordance with the frequent occurrence of aromatic rings in approved drugs and with the role of rigidity of drug molecules in promoting intestinal absorption. Bilayer locations, predicted using the C16/DAcPC system, are in excellent agreement with available experimental data, in contrast to other surrogate systems.
authors: College of Pharmacy, North Dakota State University , Fargo, North Dakota 58102, United States.
authors: Viera
authors: V
authors: Lukacova
authors: Senthil
authors: S
authors: Natesan
authors: Ming
authors: M
authors: Peng
authors: Roman
authors: R
authors: Tandlich
authors: Zhanbin
authors: Z
authors: Wang
authors: Sandra
authors: S
authors: Lynch
authors: Rajesh
authors: R
authors: Subramaniam
authors: Stefan
authors: S
authors: Balaz
mesh_terms: D000473:Alkanes / Q000737:chemistry; D008051:Lipid Bilayers / Q000737:chemistry; D008962:Models, Theoretical; D010713:Phosphatidylcholines / Q000737:chemistry*; D010743:Phospholipids / Q000737:chemistry
chemical_list: D000473:Alkanes; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D010743:Phospholipids; C007932:n-hexadecane
references: Biophys J. 2005 Apr;88(4):2626-37
references: 15665131
references: J Pharm Sci. 1994 Oct;83(10):1511-8
references: 7884677
references: Biophys J. 2001 Jun;80(6):2536-45
references: 11371432
references: J Chem Inf Comput Sci. 2000 Jan;40(1):71-80
references: 10661552
references: Chem Phys Lipids. 2008 Oct;155(2):114-9
references: 18691565
references: J Invest Dermatol. 1969 Jan;52(1):63-70
references: 5761930
references: J Med Chem. 2006 Jul 27;49(15):4568-73
references: 16854061
references: Langmuir. 2006 Feb 14;22(4):1869-74
references: 16460120
references: Biochim Biophys Acta. 1977 Mar 1;465(2):173-8
references: 16250332
references: J Pharm Sci. 1994 Aug;83(8):1085-100
references: 7983591
references: PLoS Comput Biol. 2011 Aug;7(8):e1002152
references: 21852944
references: Biochemistry. 1995 Sep 12;34(36):11460-6
references: 7547874
references: Biochim Biophys Acta. 1997 Nov 21;1331(3):235-70
references: 9512654
references: J Chem Inf Model. 2011 Apr 25;51(4):930-46
references: 21438606
references: J Med Chem. 2002 Jun 6;45(12):2615-23
references: 12036371
references: Nat Struct Biol. 1996 Nov;3(11):927-33
references: 8901870
references: Biochemistry. 1994 Jul 5;33(26):8082-8
references: 8025114
references: Chem Phys Lipids. 2002 Jun;116(1-2):135-51
references: 12093539
references: J Org Chem. 2001 May 18;66(10):3484-91
references: 11348133
references: J Lipid Res. 1974 Mar;15(2):103-8
references: 4832752
references: J Chem Inf Model. 2011 Apr 25;51(4):918-29
references: 21438609
references: Biophys J. 1993 Sep;65(3):1207-18
references: 8241401
references: J Mol Biol. 1982 May 5;157(1):105-32
references: 7108955
references: Biochim Biophys Acta. 2001 May 2;1512(1):40-52
references: 11334623
references: J Phys Chem B. 2007 Aug 30;111(34):10160-5
references: 17683135
references: Nature. 1982 Sep 23;299(5881):371-4
references: 7110359
references: Biochem J. 1987 Jul 15;245(2):455-62
references: 3663172
references: Biochemistry. 1989 Apr 18;28(8):3421-37
references: 2742845
references: Trends Biochem Sci. 2011 Dec;36(12):653-62
references: 21930386
references: Biochem Pharmacol. 1983 Jul 15;32(14):2175-80
references: 6307314
references: Chem Rev. 2009 May;109(5):1793-899
references: 19265398
references: Annu Rev Biophys Biophys Chem. 1986;15:321-53
references: 3521657
references: J Med Chem. 1996 Jul 19;39(15):2887-93
references: 8709122
references: Biochemistry. 1987 Dec 1;26(24):7535-41
references: 3322401
references: Nat Struct Biol. 1996 Oct;3(10):842-8
references: 8836100
references: J Am Chem Soc. 2002 Dec 18;124(50):15085-93
references: 12475354
references: Mini Rev Med Chem. 2005 Feb;5(2):135-51
references: 15720284
references: J Chem Inf Model. 2013 Jun 24;53(6):1424-35
references: 23641957
references: Pharm Res. 1994 Mar;11(3):412-9
references: 8008709
references: Biophys J. 1998 May;74(5):2419-33
references: 9591668
references: Biophys J. 1988 Sep;54(3):535-43
references: 3207838
references: Fresenius J Anal Chem. 2000 May;367(1):1-7
references: 11227426
references: Biophys J. 2004 Aug;87(2):768-79
references: 15298886
references: J Chem Phys. 2010 Oct 14;133(14):145103
references: 20950050
references: J Med Chem. 1977 Feb;20(2):304-6
references: 836503
references: Biochemistry. 1996 Feb 13;35(6):1803-9
references: 8639661
references: Acta Physiol Scand. 1947 Jun 20;13(4):363-81
references: 20273351
references: Drug Discov Today. 2011 Feb;16(3-4):164-71
references: 21129497