Physical and biological considerations for the use of nonaqueous solvents in oral bioavailability enhancement

Journal of Pharmaceutical Sciences

Volumn 97, Issue 3, 2008, Pages 1071-1088

  Pole, David L ^a  

^a PFIZER INC   (United States)

Author keywords

Absorption enhancer; Bioavailability; Biophysical models; Dissolution; Efflux pumps; Epithelial delivery permeability; excipients; Gastrointestinal transit; Metabolism; Permeation enhancers

Indexed keywords

ALCOHOL; ATENOLOL; CAPSAICIN; CIMETIDINE; CREMOPHOR; CYTOCHROME P450; DEXAMETHASONE; DIGOXIN; DIMETHYL SULFOXIDE; DODECYL SULFATE SODIUM; DOXORUBICIN; EXCIPIENT; FUROSEMIDE; HUMAN SERUM ALBUMIN; MACROGOL 400; MANNITOL; METHANOL; N METHYLPYRROLIDINONE; N,N DIMETHYLACETAMIDE; NONOXINOL; PACLITAXEL; PENETRATION ENHANCING AGENT; POLYSORBATE 80; PROPYLENE GLYCOL; PROTEIN ZO1; RANITIDINE; RHODAMINE 123; SOLVENT; TESTOSTERONE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG FORMULATION; DRUG SOLUBILITY; ENZYME ACTIVITY; GASTROINTESTINAL MOTILITY; GASTROINTESTINAL MUCOSA; GASTROINTESTINAL TRANSIT; HUMAN; NONHUMAN; ORAL DRUG FORMULATION; PHYSICAL CHEMISTRY; PRECIPITATION; SHORT SURVEY; SOLUBILIZATION; BIOAVAILABILITY; CHEMISTRY; ORAL DRUG ADMINISTRATION; REVIEW;

ADMINISTRATION, ORAL; BIOLOGICAL AVAILABILITY; SOLVENTS;

EID: 42949123477     PISSN: 00223549     EISSN: 15206017     Source Type: Journal    
DOI: 10.1002/jps.21060     Document Type: Short Survey

References (120)

1. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. 2001. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46:3-26.
2. Curatolo W. 1998. Physical chemical properties of oral drug candidates in the discovery and exploratory development settings. PSTT 1:387-393.
3. Amidon GL, Lennernaes H, Shah VP, Crison JR. 1995. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 12:413-420.
4. Sinko PJ. 1999. Drug selection in early drug development: Screening for acceptable pharmacokinetic properties using combined in vitro and computational approaches. Curr Opin Drug Discov Dev 2:42-48.
5. Smallwood IM. 1996. Handbook of organic solvent properties. 1st edition. London: Arnold.
6. Kim C-j. 2004. Advanced pharmaceutics. Physico-chemical principals. 1st edition. Boca Raton, FL: CRC Press. p 498.
7. Rowe RC, Sheskey PJ, Weller PJ. 2003. Handbook of pharmaceutical excipients. 4th edition. Washington, DC: Pharmaceutical Press.
8. Strickley R. 2004. Solubilizing excipients in oral and injectable formulations. Pharm Res 21:201-230.
9. Mottu F, Laurent A, Rufenacht DA, Doelker E. 2000. Organic solvents for pharmaceutical parent-erals and embolic liquids: A review of toxicity data. PDA J Pharm Sci Technol 54:456-469.
10. Yalkowsky SH. 1999. Solubilization by cosolvents. Solubility and solubilization in aqueous media. New York: Oxford University Press. p 180-235.
11. Yalkowsky SH. 1999. Solubility and solubilization in aqueous media. 1st edition. New York: Oxford University Press.
12. Yalkowsky SH, Roseman TJ. 1981. Solubilization of drugs by cosolvents. In: Yalkowsky SH, editor. Techniques of solubilization of drugs. New York: Dekker. p 91-134.
13. Aungst BJ. 2000. Intestinal permeation enhancers. J Pharm Sci 89:429-442.
14. Aungst BJ, Blake JA, Hussain MA. 1990. Contributions of drug solubilization, partitioning, barrier disruption, and solvent permeation to the enhancement of skin permeation of various compounds with fatty acids and amines. Pharm Res 7:712-718.
15. Humberstone AJ, Charman WN. 1997. Lipid-based vehicles for the oral delivery of poorly water soluble drugs. Adv Drug Deliv Rev 25:103-128.
16. Kim C-K, Park J-S. 2004. Solubility enhancers for oral drug delivery: Can chemical structure manipulation be avoided? Am J Drug Deliv 2:113-130.
17. Constantinides PP. 1995. Lipid microemulsions for improving drug dissolution and oral absorption: Physical and biopharmaceutical aspects. Pharm Res 12:1561-1572.
18. Yalkowsky SH, Flynn GL, Amidon GL. 1972. Solubility of nonelectrolytes in polar solvents. J Pharm Sci 61:983-984.
19. Yalkowsky SH, Valvani SC, Amidon GL. 1976. Solubility of nonelectrolytes in polar solvents. IV. Nonpolar drugs in mixed solvents. J Pharm Sci 65:1488-1494.
20. Millard JW, Alvarez-Nunez FA, Yalkowsky SH. 2002. Solubilization by cosolvents establishing useful constants for the log-linear model. Int J Pharm 245:153-166.
21. Li A, Yalkowsky SH. 1994. Solubility of organic solutes in ethanol/water mixtures. J Pharm Sci 83:1735-1740.
22. Machatha SG, Yalkowsky SH. 2004. Estimation of the ethanol/water solubility profile from the octanol/water partition coefficient. Int J Pharm 286: 111-115.
23. Machatha SG, Yalkowsky SH. 2005. Bilinear model for the prediction of drug solubility in ethanol/water mixtures. J Pharm Sci 94:2731-2734.
24. Yalkowsky SH, Valvani SC. 1977. Precipitation of solubilized drugs due to injection or dilution. Drug Intell Clin Pharm 11:417-419.
25. Agoram B, Woltosz WS, Bolger MB. 2001. Predicting the impact of physiological and biochemical processes on oral drug bioavailability. Adv Drug Deliv Rev 50:S41-S67.
26. Johnson KC. 2003. Dissolution and absorption modeling: Model expansion to simulate the effects of precipitation, water absorption, longitudinally changing intestinal permeability, and controlled release on drug absorption. Drug Dev Ind Pharm 29:833-842.
27. Amidon GL, Sinko PJ, Fleisher D. 1988. Estimating human oral fraction dose absorbed: A correlation using rat intestinal membrane permeability for passive and carrier-mediated compounds. Pharm Res 5:651-654.
28. Sinko PJ, Leesman GD, Amidon GL. 1991. Predicting fraction dose absorbed in humans using a macroscopic mass balance approach. Pharm Res 8:979-988.
29. Vertzoni M, Fotaki N, Kostewicz E, Stippler E, Leuner C, Nicolaides E, Dressman J, Reppas C. 2004. Dissolution media simulating the intralumenal composition of the small intestine: Physiological issues and practical aspects. J Pharm Pharmacol 56:453-462.
30. Galia E, Nicolaides E, Horter D, Lobenberg R, Reppas C, Dressman JB. 1998. Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs. Pharm Res 15:698-705.
31. Nicolaides E, Symillides M, Dressman JB, Reppas C. 2001. Biorelevant dissolution testing to predict the plasma profile of lipophilic drugs after oral administration. Pharm Res 18:380-388.
32. Gu C-H, Gandhi RB, Tay LK, Zhou S, Raghavan K. 2004. Importance of using physiologically relevant volume of dissolution medium to correlate the oral exposure of formulations of BMS-480188 mesy-late. Int J Pharm 269:195-202.
33. Dressman JB, Reppas C. 2000. In vitro-in vivo correlations for lipophilic, poorly water-soluble drugs. Eur J Pharm Sci 11:S73-S80.
34. Noyes AA, Whitney WR. 1897. The rate of solution of solid substances in their own solutions. J Am Chem Soc 19:930-934.
35. Rodríguez-Hornedo N, Murphy D. 1999. Significance of controlling crystallization mechanisms and kinetics in pharmaceutical systems. J Pharm Sci 88:651-660.
36. Blanquet S, Zeijdner E, Beyssac E, Meunier J-P, Denis S, Havenaar R, Alric M. 2004. A dynamic artificial gastrointestinal system for studying the behavior of orally administered drug dosage forms under various physiological conditions. Pharm Res 21:585-591.
37. Carino SR, Sperry DC, Hawley M. 2006. Relative bioavailability estimation of carbamazepine crystal forms using an artificial stomach-duodenum model. J Pharm Sci 95:116-125.
38. Vatier J, Harman A, Castela N, Droy-Lefaix MT, Farinotti R. 1994. Interactions of cimetidine and ranitidine with aluminum-containing antacids and a clay-containing gastric-protective drug in an "artificial stomach-duodenum" model. J Pharm Sci 83:962-966.
39. Gu C-H, Rao D, Gandhi RB, Hilden J, Raghavan K. 2005. Using a novel multicompartment dissolution system to predict the effect of gastric pH on the oral absorption of weak bases with poor intrinsic solubility. J Pharm Sci 94:199-208.
40. Kostewicz ES, Wunderlich M, Brauns U, Becker R, Bock T, Dressman JB. 2004. Predicting the precipitation of poorly soluble weak bases upon entry in the small intestine. J Pharm Pharmacol 56: 43-51.
41. Gao P, Guyton M, Huang T, Bauer J, Stefanski K, Lu Q. 2004. Enhanced oral bioavailability of a poorly water soluble drug PNU-91325 by super-saturatable formulations. Drug Dev Ind Pharm 30:221-229.
42. Gao P, Rush BD, Pfund WP, Huang T, Bauer JM, Morozowich W, Kuo M-S, Hageman MJ. 2003. Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability. J Pharm Sci 92: 2386-2398.
43. Wiedmann TS, Kamel L. 2002. Examination of the solubilization of drugs by bile salt micelles. J Pharm Sci 91:1743-1764.
44. Ostwald W. 1897. Studien uber die bildung und umwandlung fester korper. Z Phys Chem 22:289-302.
45. Bartsch W, Sponer G, Dietmann K, Fuchs G. 1976. Acute toxicity of various solvents in the mouse and rat. LD50 of ethanol, diethylacetamide, dimethylformamide, dimethylsulfoxide, glycerine, N-methylpyrrolidone, polyethylene glycol 400, 1,2-propanediol, and Tween 20. Arzneimittel-forschung 26:1581-1583.
46. Beck IT, Dinda PK. 1981. Acute exposure of small intestine to ethanol. Dig Dis Sci 26:817-838.
47. Kalant H. 1971. Absorption, diffusion, distribution, and elimination of ethanol: Effects on biological membranes. In: Kissin B, Begleiter H, editors. The biology of alcoholism, Vol 1. Biochemistry. 1st edition. New York: Plenum Press. p 1-62.
48. v Wartburg JP, Aebi H. 1970. Stoffwechsel von Aethanol. In: Lang K, editor. Alkohol und Caffeine. Darmstadt: Steikopff Verlag. p 1-14.
49. Lehman AJ, Newman HW. 1937. Propylene glycol: Rate of metabolism, absorption, and excretion, with a method for estimation in body fluids. J Pharmacol Exp Ther 60:312-322.
50. Newman HW, Van Winkle WJ, Kennedy NK, Morton MC. 1940. Comparative effects of propylene glycol, other glycols, and alcohol on the liver directly. J Pharmacol Exp Ther 68:194-200.
51. Borgstrom B, Dahlqvist A, Lundh G, Sjovall J. 1957. Studies of intestinal digestion and absorption in the human. J Clin Invest 36:1521-1536.
52. Chadwick VS, Phillips SF, Hofmann AF. 1977. Measurements of intestinal permeability using low molecular weight polyethylene glycols (PEG 400). I. chemical analysis and biological properties of PEG 400. Gastroenterology 73:241-246.
53. He Y-L, Murby S, Warhurst G, Gifford L, Walker D, Ayrton J, Eastmond R, Rowland M. 1998. Species differences in size discrimination in the para-cellular pathway reflected by oral bioavailability of poly(ethylene glycol) and D-peptides. J Pharm Sci 87:626-633.
54. Krasny HC, de Miranda P, Blum MR, Elion GB. 1981. Pharmacokinetics and bioavailability of acyclovir in the dog. J Pharmacol Exp Ther 216:281-288.
55. Dreyfuss J, Shaw JM, Ross JJ Jr. 1978. Absorption of the beta-adrenergic-blocking agent, nadolol, by mice, rats, hamsters, rabbits, dogs, monkeys, and man: An unusual species difference. Xenobiotica 8:503-508.
56. Nerurkar MM, Burton PS, Borchardt RT. 1996. The use of surfactants to enhance the permeability of peptides through Caco-2 cells by inhibition of an apically polarized efflux system. Pharm Res 13: 528-534.
57. Alvarez-Nunez FA, Yalkowsky SH. 2000. Relationship between Polysorbate 80 solubilization descriptors and octanol-water partition coefficients of drugs. Int J Pharm 200:217-222.
58. Daher CF, Baroody GM, Howland RJ. 2003. Effect of a surfactant, Tween 80, on the formation and secretion of chylomicrons in the rat. Food Chem Toxicol 41:575-582.
59. Uch AS, Hesse U, Dressman JB. 1999. Use of 1-methyl-pyrrolidone as a solubilizing agent for determining the uptake of poorly soluble drugs. Pharm Res 16:968-971.
60. Sartor O. 2003. Eligard: Leuprolide acetate in a novel sustained-release delivery system. Urology 61:25-31.
61. R: Pharmacokinetics, effect on testosterone and PSA levels and tolerability. Eur Urol Suppl 4:20-25.
62. Enomoto N, Ikejima K, Bradford B, Rivera C, Kono H, Brenner DA, Thurman RG. 1998. Alcohol causes both tolerance and sensitization of rat Kupffer cells via mechanisms dependent on endotoxin. Gastroenterology 115:443-451.
63. Enomoto N, Ikejima K, Yamashina S, Hirose M, Shimizu H, Kitamura T, Takei Y, Sato N, Thurman RG. 2001. Kupffer cell sensitization by alcohol involves increased permeability to gut-derived endotoxin. Alcohol Clin Exp Res 25:51-54.
64. Rivera CA, Bradford BU, Seabra V, Thurman RG. 1998. Role of endotoxin in the hypermetabolic state after acute ethanol exposure. Am J Physiol Gastrointest Liver Physiol 275:G1252-1258.
65. Curatolo W, Ochoa R. 1994. Safety assessment of intestinal permeability enhancers. In: Boer AGd, editor. Drug absorption enhancement concepts, possibilities, limitations, and trends. 1st edition. Reading: Harwood Academic Publishers. p 367-389.
66. Swenson ES, Milisen WB, Curatolo W. 1994. Intestinal permeability enhancement: Efficacy, acute local toxicity, and reversibility. Pharmaceutical Research 11:1132-1142.
67. Beck IT. 1995. Small bowel injury by ethanol. In: Preedy VR, Watson RR, editors. Alcohol and Gastrointestinal Tract. 1st edition. Boca Raton, FL: CRC. p 163-202.
68. Swenson ES, Milisen WB, Curatolo W. 1994. Intestinal permeability enhancement: Structure-activity and structure-toxicity relationships for nonylphenoxypolyoxyethylene surfactant permeability enhancers. Pharm Res 11:1501-1504.
69. Nakanishi K, Masada M, Nadai T. 1983. Effect of pharmaceutical adjuvants on the rectal permeability of drugs. III. Effect of repeated administration and recovery of the permeability. Chem Pharm Bull (Tokyo) 31:4161-4166.
70. Ito S, Lacy ER. 1988. Morphology of rat gastric mucosal damage, defense, and restitution in the presence of luminal ethanol. Gastroenterology 88: 250-260.
71. Ito S, Lacy ER, Rutten MJ, Critchlow J, Silen W. 1984. Rapid repair of injured gastric mucosa. Scand J Gastroenterol Suppl 101:87-95.
72. Takeuchi K, Okabe S. 1983. Role of luminal alka-linization in repair process of ethanol-induced mucosal damage in rat stomach. Dig Dis Sci 28: 993-1000.
73. Ingels FM, Augustijns PF. 2003. Biological, pharmaceutical, and analytical considerations with respect to the transport media used in the absorption screening system, Caco-2. J Pharm Sci 92: 1545-1558.
74. Jacob SW, Herschler R. 1986. Pharmacology of DMSO. Cryobiology 23:14-27.
75. Tavelin S, Hashimoto K, Malkinson J, Lazorova L, Toth I, Artursson P. 2003. A new principle for tight junction modulation based on occludin peptides. Mol Pharmacol 64:1530-1540.
76. Aungst BJ, Nguyen NH, Bulgarelli JP, Oates-Lenz K. 2000. The influence of donor and reservoir additives on Caco-2 permeability and secretory transport of HIV protease inhibitors and other lipophilic compounds. Pharm Res 17:1175-1180.
77. Krishna G, Chen K-j, Lin C-c, Nomeir AA. 2001. Permeability of lipophilic compounds in drug discovery using in vitro human absorption model, Caco-2. Int J Pharm 222:77-89.
78. Demirbas S, Stavchansky S. 2003. Effects of citicholine and dimethylsulfoxide on transepithe-lial transport of passively diffused drugs in the Caco-2 cell culture model. Int J Pharm 251:107-112.
79. Chan OH, Schmid HL, Kuo B-S, Wright DS, How-son W, Stewart BH. 1996. Absorption of Cam-2445, an NK1 neurokinin receptor antagonist: In vivo, in situ, and in vitro evaluations. J Pharm Sci 85:253-257.
80. Rege BD, Yu LX, Hussain AS, Polli JE. 2001. Effect of common excipients on Caco-2 transport of low-permeability drugs. J Pharm Sci 90:1776-1786.
81. Takahashi Y, Kondo H, Yasuda T, Watanabe T, Kobayashi S-I, Yokohama S. 2002. Common solubilizers to estimate the Caco-2 transport of poorly water-soluble drugs. Int J Pharm 246: 85-94.
82. Salama NN, Eddington ND, Fasano A. 2006. Tight junction modulation and its relationship to drug delivery. Adv Drug Deliv Rev 58:15-28.
83. Ma TY, Nguyen D, Bui V, Nguyen H, Hoa N. 1999. Ethanol modulation of intestinal epithelial tight junction barrier. Am J Physiol Gastrointest Liver Physiol 276:G965-974.
84. Saha P, Kou JH. 2000. Effect of solubilizing exci-pients on permeation of poorly water-soluble compounds across Caco-2 cell monolayers. Eur J Pharm Biopharm 50:403-411.
85. Flynn GL, Smith RW. 1972. Membrane diffusion. 3. Influence of solvent composition and permeant solubility on membrane transport. J Pharm Sci 61:61-66.
86. Higuchi T. 1960. Physical chemical analysis of percutaneous absorption process from creams and ointments. J Soc Cosmet Chem 11:85-97.
87. Yamashita S, Furubayashi T, Kataoka M, Sakane T, Sezaki H, Tokuda H. 2000. Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells. Eur J Pharm Sci 10:195-204.
88. Hugger ED, Audus KL, Borchardt RT. 2002. Effects of poly(ethylene glycol) on efflux transporter activity in Caco-2 cell monolayers. J Pharm Sci 91:1980-1990.
89. Nerurkar MM, Ho NFH, Burton PS, Vidmar TJ, Borchardt RT. 1997. Mechanistic roles of neutral surfactants on concurrent polarized and passive membrane transport of a model peptide in Caco-2 cells. J Pharm Sci 86:813-821.
90. Cornaire G, Woodley JF, Saivin S, Legendre J-Y, Decourt S, Cloarec A, Houin G. 2000. Effect of polyoxyl 35 castor oil and polysorbate 80 on the intestinal absorption of digoxin in vitro. Arznei-mittelforschung 50:576-579.
91. Woodcock DM, Linsenmeyer ME, Chojnowski G, Kriegler AB, Nink V, Webster LK, Sawyer WH. 1992. Reversal of multidrug resistance by surfactants. Br J Cancer 66:62-68.
92. Woodcock DM. 1990. Reversal of the multidrug resistance phenotype with cremophor EL, a common vehicle for water-insoluble vitamins and drugs. Cancer Res 50:4199-4203.
93. Drori S, Eytan GD, Assaraf YG. 1995. Potentiation of anticancer-drug cytotoxicity by multidrug-resistance chemosensitizers involves alterationsin membrane fluidity leading to increased membrane permeability. Eur J Biochem 228:1020-1029.
94. Dudeja PK, Anderson KM, Harris JS, Buckingham L, Coon JS. 1995. Reversal of multidrug-resistance phenotype by surfactants: Relationship to membrane lipid fluidity. Arch Biochem Biophys 319:309-315.
95. Venkatakrishnan K, Von Moltke LL, Greenblatt DJ. 2001. Human drug metabolism and the cyto-chromes P450: Application and relevance of in vitro models. J Clin Pharmacol 41:1149-1179.
96. Venkatakrishnan K, von Moltke LL, Obach RS, Greenblatt DJ. 2003. Drug metabolism and drug interactions: Application and clinical value of in vitro models. Curr Drug Metab 4:423-459.
97. Chauret N, Gauthier A, Nicoll-Griffith DA. 1998. Effect of common organic solvents on in vitro cytochrome P450-mediated metabolic activities in human liver microsomes. Drug Metab Dispos 26:1-4.
98. Busby WF Jr, Ackermann JM, Crespi CL. 1999. Effect of methanol, ethanol, dimethyl sulfoxide, and acetonitrile on in vitro activities of cDNA-expressed human cytochromes P-450. Drug Metab Dispos 27:246-249.
99. Hickman D, Wang JP, Wang Y, Unadkat JD. 1998. Evaluation of the selectivity of in vitro probes and suitability of organic solvents for the measurement of human cytochrome P450 monooxygenase activities. Drug Metab Dispos 26:207-215.
100. Easterbrook J, Lu C, Sakai Y, Li AP. 2001. Effects of organic solvents on the activities of cytochrome P450 isoforms, UDP-dependent glucuronyl transferase, and phenol sulfotransferase in human hepatocytes. Drug Metab Dispos 29:141-144.
101. Watkins PB. 1997. The barrier function of CYP3A4 and P-glycoprotein in the small bowel. Adv Drug Deliv Rev 27:161-170.
102. Mountfield RJ, Senepin S, Schleimer M, Walter I, Bittner B. 2000. Potential inhibitory effects of formulation ingredients on intestinal cytochrome P450. Int J Pharm 211:89-92.
103. Moes AJ. 1993. Gastroretentive dosage forms. Crit Rev Ther Drug Carrier Syst 10:143-195.
104. Talukder R, Fassihi R. 2004. Gastroretentive delivery systems: A mini review. Drug Dev Ind Pharm 30:1019-1028.
105. Lee JW, Park JH, Robinson JR. 2000. Bio-adhesive-based dosage forms: The next generation. J Pharm Sci 89:850-866.
106. Rouge N, Buri P, Doelker E. 1996. Drug absorption sites in the gastrointestinal tract and dosage forms for site-specific delivery. Int J Pharm 136:117-139.
107. Wilding IR, Coupe AJ, Davis SS. 1991. The role of g-scintigraphy in oral drug delivery. Adv Drug Deliv Rev 7:87-117.
108. Newman SP, Hirst PH, Wilding IR. 2003. New developments in radionuclide imaging for assessing drug delivery in man. Eur J Pharm Sci 18: 19-22.
109. Scroggs R, Abruzzo M, Advokat C. 1986. Effects of ethanol on gastrointestinal transit in mice. Alcohol Clin Exp Res 10:452-456.
110. Izbeki F, Wittmann T, Csati S, Jeszenszky E, Lonovics J. 2001. Opposite effects of acute and chronic administration of alcohol on gastric emptying and small bowel transit in rat. Alcohol Alcohol 36:304-308.
111. Jian R, Cortot A, Ducrot F, Jobin G, Chayvialle JA, Modigliani R. 1986. Effect of ethanol ingestion on postprandial gastric emptying and secretion, bilio-pancreatic secretions, and duodenal absorption in man. Dig Dis Sci 31:604-614.
112. Knight LC, Maurer AH, Wikander R, Krevsky B, Malmud LS, Fisher RS. 1992. Effect of ethyl alcohol on motor function in canine stomach. Am J Physiol 262:G223-G230.
113. Izbéki F, Wittmann T, Jancsó G, Csáti S, Lonovics J. 2002. Inhibition of gastric emptying and small intestinal transit by ethanol is mediated by capsaicin-sensitive afferent nerves. Naunyn Schmiedebergs Arch Pharmacol 365:17-21.
114. Izbeki F, Wittmann T, Csati S, Lonovics J. 2004. The mechanisms of the inhibitory effect of ethanol on gastric emptying involve type A CCK receptors. Regul Pept 117:101-105.
115. Basit AW, Newton JM, Short MD, Waddington WA, Ell PJ, Lacey LF. 2001. The effect of polyethylene glycol 400 on gastrointestinal transit: Implications for the formulation of poorly-water soluble drugs. Pharm Res 18:1146-1150.
116. Basit AW, Podczeck F, Newton JM, Waddington WA, Ell PJ, Lacey LF. 2002. Influence of polyethylene glycol 400 on the gastrointestinal absorption of ranitidine. Pharm Res 19:1368-1374.
117. Schulze JDR, Waddington WA, Ell PJ, Parsons GE, Coffin MD, Basit AW. 2003. Concentration-dependent effects of polyethylene glycol 400 on gastrointestinal transit and drug absorption. Pharm Res 20:1984-1988.
118. Schulze JDR, Peters EE, Vickers AW, Staton JS, Coffin MD, Parsons GE, Basit AW. 2005. Excipient effects on gastrointestinal transit and drug absorption in beagle dogs. Int J Pharm 300:67-75.
119. Swenson SE, Curatolo WJ. 1992. (C) Means to enhance penetration: (2) Intestinal permeability enhancement for proteins, peptides and other polar drugs: mechanisms and potential toxicity. Adv Drug Deliv Rev 8:39-92.
120. Kruijtzer CMF, Beijnen JH, Schellens JHM. 2002. Improvement of oral drug treatment by temporary inhibition of drug transporters and/or cytochrome P450 in the gastrointestinal tract and liver: An overview. Oncologist 7:516-530.