Structural features determining the intestinal epithelial permeability and efflux of novel HIV-1 protease inhibitors

Journal of Pharmaceutical Sciences

Volumn 100, Issue 9, 2011, Pages 3763-3772

  Lazorova, Lucia ^a,c,d,e   Hubatsch, Ina ^a   Ekegren, Jenny K ^a   Gising, Johan ^a   Nakai, Daisuke ^a   Zaki, Noha M ^a   Bergström, Christel A S ^a   Norinder, Ulf ^a,b   Larhed, Mats ^a   Artursson, Per ^a  

^a UPPSALA UNIVERSITY   (Sweden)

^b Research and Development at Scania Technical Centre   (Sweden)

^c Octapharma AB   (Sweden)

^d DAIICHI SANKYO CO   (Japan)

^e Ain Shams University   (Egypt)

Author keywords

Absorption; ADME; Caco 2 cells; Drug design; Drug transport; HIV AIDS; Intestinal absorption; P glycoprotein; Passive diffusion transport; Permeability

Indexed keywords

AMPRENAVIR; ATAZANAVIR; HUMAN IMMUNODEFICIENCY VIRUS PROTEINASE INHIBITOR; INDINAVIR; LEUCINE; NELFINAVIR; VALINE;

ARTICLE; CELL CULTURE; CELL MEMBRANE PERMEABILITY; CELL STRAIN CACO 2; CELL STRUCTURE; CONTROLLED STUDY; DRUG ABSORPTION; DRUG PENETRATION; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TRANSPORT; HUMAN; HUMAN CELL; INTESTINE EPITHELIUM CELL;

EID: 79960156077     PISSN: 00223549     EISSN: 15206017     Source Type: Journal    
DOI: 10.1002/jps.22570     Document Type: Article

References (41)

1. Sugano K, Kansy M, Artursson P, Avdeef A, Bendels S, Di L, Ecker GF, Faller B, Fischer H, Gerebtzoff G, Lennernaes H, Senner F. 2010. Coexistence of passive and carrier-mediated processes in drug transport. Nat Rev Drug Discov 9(8):597-614.
2. Kansy M, Senner F, Gubernator K. 1998. Physicochemical high throughput screening: Parallel artificial membrane permeation assay in the description of passive absorption processes. J Med Chem 41(7):1007-1010.
3. Avdeef A. 2005. The rise of PAMPA. Expert Opin Drug Metab Toxicol 1(2):325-342.
4. Tavelin S, Taipalensuu J, Soderberg L, Morrison R, Chong S, Artursson P. 2003. Prediction of the oral absorption of low-permeability drugs using small intestine-like 2/4/A1 cell monolayers. Pharm Res 20(3):397-405.
5. Linnankoski J, Makela J, Palmgren J, Mauriala T, Vedin C, Ungell AL, Lazorova L, Artursson P, Urtti A, Yliperttula M. 2010. Paracellular porosity and pore size of the human intestinal epithelium in tissue and cell culture models. J Pharm Sci 99(4):2166-2175.
6. Tavelin S, Milovic V, Ocklind G, Olsson S, Artursson P. 1999. A conditionally immortalized epithelial cell line for studies of intestinal drug transport. J Pharmacol Exp Ther 290(3):1212-1221.
7. Matsson P, Bergstrom CAS, Nagahara N, Tavelin S, Norinder U, Artursson P. 2005. Exploring the role of different drug transport routes in permeability screening. J Med Chem 48(2):604-613.
8. Tavelin S, Taipalensuu J, Hallbook F, Vellonen KS, Moore V, Artursson P. 2003. An improved cell culture model based on 2/4/A1 cell monolayers for studies of intestinal drug transport: Characterization of transport routes. Pharm Res 20(3):373-381.
9. Hidalgo IJ, Raub TJ, Borchardt RT. 1989. Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology 96(3):736-749.
10. Artursson P, Karlsson J. 1991. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem Biophys Res Commun 175(3):880-885.
11. Tavelin S, Grasjo J, Taipalensuu J, Ocklind G, Artursson P. 2002. Applications of epithelial cell culture in studies of drug transport. Methods Mol Biol 188:233-272.
12. Englund G, Rorsman F, Ronnblom A, Karlbom U, Lazorova L, Grasjo J, Kindmark A, Artursson P. 2006. Regional levels of drug transporters along the human intestinal tract: Co-expression of ABC and SLC transporters and comparison with Caco-2 cells. Eur J Pharm Sci 29(3-4):269-277.
13. Hubatsch I, Ragnarsson EGE, Artursson P. 2007. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat Protoc 2(9):2111-2119.
14. Ritchie TJ, Ertl P, Lewis R. 2011. The graphical representation of ADME-related molecule properties for medicinal chemists. Drug Discov Today 16(1-2):65-72.
15. Clavel F, Hance AJ. 2004. HIV drug resistance. N Engl J Med 350(10):1023-1035.
16. Menéndez-Arias L. 2002. Targeting HIV: Antiretroviral therapy and development of drug resistance. Trends Pharmacol Sci 23(8):381-388.
17. Rodriguez-Barrios F, Gago F. 2004. HIV protease inhibition: Limited recent progress and advances in understanding current pitfalls. Curr Top Med Chem 4(9):991-1007.
18. Ekegren JK, Unge T, Safa MZ, Wallberg H, Samuelsson B, Hallberg A. 2005. A new class of HIV-1 protease inhibitors containing a tertiary alcohol in the transition-state mimicking scaffold. J Med Chem 48(25):8098-8102.
19. Ekegren JK, Gising J, Wallberg H, Larhed M, Samuelsson B, Hallberg A. 2006. Variations of the P2 group in HIV-1 protease inhibitors containing a tertiary alcohol in the transition-state mimicking scaffold. Org Biomol Chem 4(16):3040-3043.
20. Wu X, Ohrngren P, Ekegren JK, Unge J, Unge T, Wallberg H, Samuelsson B, Hallberg A, Larhed M. 2008. Two-carbon-elongated HIV-1 protease inhibitors with a tertiary-alcohol-containing transition-state mimic. J Med Chem 51(4):1053-1057.
21. Mahalingam AK, Axelsson L, Ekegren JK, Wannberg J, Kihlstrom J, Unge T, Wallberg H, Samuelsson B, Larhed M, Hallberg A. 2010. HIV-1 protease inhibitors with a transition-state mimic comprising a tertiary alcohol: Improved antiviral activity in cells. J Med Chem 53(2):607-615.
22. Gray RA, Vander Velde DG, Burke CJ, Manning MC, Middaugh CR, Borchardt RT. 1994. Delta-sleep-inducing peptide: Solution conformational studies of a membrane-permeable peptide. Biochemistry 33(6):1323-1331.
23. Conradi RA, Hilgers AR, Burton PS, Hester JB. 1994. Epithelial cell permeability of a series of peptidic HIV protease inhibitors: aminoterminal substituent effects. J Drug Target 2(2):167-171.
24. Ashwood VA, Field MJ, Horwell DC, Julien-Larose C, Lewthwaite RA, McCleary S, Pritchard MC, Raphy J, Singh L. 2001. Utilization of an intramolecular hydrogen bond to increase the CNS penetration of an NK(1) receptor antagonist. J Med Chem 44(14):2276-2285.
25. Bergstrom CA, Strafford M, Lazorova L, Avdeef A, Luthman K, Artursson P. 2003. Absorption classification of oral drugs based on molecular surface properties. J Med Chem 46(4):558-570.
26. Neuhoff S, Artursson P, Zamora I, Ungell AL. 2006. Impact of extracellular protein binding on passive and active drug transport across Caco-2 cells. Pharm Res 23(2):350-359.
27. Palm K, Luthman K, Ros J, Grasjo J, Artursson P. 1999. Effect of molecular charge on intestinal epithelial drug transport: pH-dependent transport of cationic drugs. J Pharmacol Exp Ther 291(2):435-443.
28. Ekegren JK, Ginman N, Johansson A, Wallberg H, Larhed M, Samuelsson B, Unge T, Hallberg A. 2006. Microwave-accelerated synthesis of P1'-extended HIV-1 protease inhibitors encompassing a tertiary alcohol in the transition-state mimicking scaffold. J Med Chem 49(5):1828-1832.
29. Palm K, Stenberg P, Luthman K, Artursson P. 1997. Polar molecular surface properties predict the intestinal absorption of drugs in humans. Pharm Res 14(5):568-571.
30. Kelder J, Grootenhuis PD, Bayada DM, Delbressine LP, Ploemen JP. 1999. Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs. Pharm Res 16(10):1514-1519.
31. Pai VB, Nahata MC. 1999. Nelfinavir mesylate: A protease inhibitor. Ann Pharmacother 33(3):325-339.
32. Kim RB, Fromm MF, Wandel C, Leake B, Wood AJ, Roden DM, Wilkinson GR. 1998. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 101(2):289-294.
33. Bergstrom CA, Bolin S, Artursson P, Ronn R, Sandstrom A. 2009. Hepatitis C virus NS3 protease inhibitors: Large, flexible molecules of peptide origin show satisfactory permeability across Caco-2 cells. Eur J Pharm Sci 38(5):556-563.
34. Raub TJ. 2006. P-glycoprotein recognition of substrates and circumvention through rational drug design. Mol Pharm 3(1):3-25.
35. Hallifax D, Houston JB. 2007. Saturable uptake of lipophilic amine drugs into isolated hepatocytes: Mechanisms and consequences for quantitative clearance prediction. Drug Metab Dispos 35(8):1325-1332.
36. Neuhoff S, Ungell AL, Zamora I, Artursson P. 2003. pH-dependent bidirectional transport of weakly basic drugs across Caco-2 monolayers: Implications for drug-drug interactions. Pharm Res 20(8):1141-1148.
37. Mahar Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, Adkison KK, Polli JW. 2002. Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J Pharmacol Exp Ther 303(3):1029-1037.
38. Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, Serabjit-Singh CS. 2001. Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther 299(2):620-628.
39. Hayeshi R, Hilgendorf C, Artursson P, Augustijns P, Brodin B, Dehertogh P, Fisher K, Fossati L, Hovenkamp E, Korjamo T, Masungi C, Maubon N, Mols R, Mullertz A, Monkkonen J, O'Driscoll C, Oppers-Tiemissen HM, Ragnarsson EGE, Rooseboom M, Ungell AL. 2008. Comparison of drug transporter gene expression and functionality in Caco-2 cells from 10 different laboratories. Eur J Pharm Sci 35(5):383-396.
40. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L. 2010. Membrane transporters in drug development. Nat Rev Drug Discov 9(3):215-236.
41. Ahlin G, Hilgendorf C, Karlsson J, Szigyarto CA, Uhlen M, Artursson P. 2009. Endogenous gene and protein expression of drug-transporting proteins in cell lines routinely used in drug discovery programs. Drug Metab Dispos 37(12):2275-2283.