Is the role of the small intestine in first-pass metabolism overemphasized?

Pharmacological Reviews

Volumn 51, Issue 2, 1999, Pages 135-157

  Lin, Jiunn H ^a   Chiba, Masato ^a   Baillie, Thomas A ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOCHROME P450; DRUG;

DRUG ABSORPTION; DRUG CLEARANCE; DRUG METABOLISM; ENZYME INDUCTION; ENZYME LOCALIZATION; FIRST PASS EFFECT; HUMAN; INTESTINE BLOOD FLOW; NONHUMAN; PRIORITY JOURNAL; REVIEW;

ANIMALS; HUMANS; INTESTINAL ABSORPTION; INTESTINE, SMALL; LIVER; PHARMACEUTICAL PREPARATIONS;

EID: 0033009998     PISSN: 00316997     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (154)

1. Augustijns PF, Bradshaw P, Gan LSL, Hendren RW and Thakker DR (1993) Evidence for a polarized efflux system in Caco-2 cells capable of modulating cyclosporine A transport. Biochem Biophys Res Commun 197:360-365.
2. Back DJ and Rogers SM (1987) First-pass metabolism by gastrointestinal mucosa. Aliment Pharmacol Ther 227:339-357.
3. Benet LZ, Wu CY, Hebert MF and Wacher VJ (1996) Intestinal drug metabolism and antitransport process: A potential shift in oral drug delivery. J Control Release 39:139-143.
4. Bertalanffy FD and Nagy KP (1961) Mitotic activity and renewal rate of the epithelial cells of human duodenum. Acta Anat 45:362-370.
5. Biber B, Lundgren O and Svanvik J (1973) The influence of blood flow on the rate of absorption of 85 Kr from the small intestine of the cat. Acta Physiol Scand 89:227-238.
6. Bock KW and Bock-Hennig BS (1987) Differential induction of human liver UDP-glucuronosyl-transferase activities by phenobarbital-type inducer. Biochem Pharmacol 36:4137-4144.
7. Bock KW, Lilienblum W and von Bahr C (1984) Studies of UDP-glucuronyltransferase activities in human liver microsomes. Drug Metab Dispos 12:93-97.
8. Bock KW, Wiltfang J, Blume R, Ullrich D and Bircher J (1987) Paracetamol as a test drug to determine glucuronide formation in man. Effect of inducers and of smoking. Eur J Clin Pharmacol 31:677-683.
9. Bond JH and Levitt MD (1979) Use of microsphere to measure small intestinal villus blood flow in the dog. Am J Physiol 236:E577-E583.
10. Bond JH, Levitt DG and Levitt MD (1977) Quantitation of countercurrent exchange during passive absorption from the dog small intestine. J Clin Invest 59:308-310.
11. Bond JH, Prenfiss RA and Levitt MD (1979) The effects of feeding on blood flow to the stomach, small bowel and colon of the conscious dog. J Lab Clin Med 93:594-599.
12. Bonkovsky HL, Hauri HP, Marti U, Gasser R and Meyer UA (1985) Cytochrome P450 of small intestinal epithelial cells: Immunochemical characterization of the increase in cytochrome P450 caused by phenobarbital. Gastroenterology 88:458-467.
13. Borm PJA, Frankhuyzen-Sierevogel AC, Weller EBC and Noordhoek J (1985) Absorption and metabolism of hexamethylmelamine and pentamethylmelamine in rat everted perfused gut segments: Correction with in-vitro data. J Pharm Pharmacol 37:629-636.
14. Buchthal J, Grund KE, Buchman A, Schrenk D, Beaune P and Bock KW (1995) Induction of cytochrome P-4501A by smoking or omeprazole in comparison with UDP-glucuronosyl-transferase in biopsies of human duodenal mucosa. Eur J Clin Pharmacol 47:431-435.
15. Burt RK and Thorgeirsson SS (1988) Coinduction of MDR-1 multidrug resistance and cytochrome P450 genes in rat liver by xenobiotics. J Natl Cancer Inst 80:1383-1386.
16. Caldwell J and Marsh MV (1982) Metabolism of drugs by the gastrointestinal tract, in Clinical Pharmacology and Therapeutics: Presystemic Drug Elimination (George CF, Shand DG and Renwick AG eds) pp 29-42, Butterworths, London.
17. Callen DF, Baker E, Simmers RN, Seshadri R and Roninsum IB (1987) Localization of the human multiple drug resistance gene, MDR1 to 7g21.1. Hum Genet 77:142-144.
18. Campa JL and Reynolds TB (1988) The hepatic circulation, in The Liver -Biology and Pathology (Arias IM, Jakoby WB, Popper U, Schachter D and Shafritz DA eds) pp 911-930, Raven Press, New York.
19. Cappiello M, Franchi M, Giuliani L and Pacifici GM (1989) Distribution of 2-naphthol sulphotransferase and its endogenous substrate adenosine 3′-phosphate 5′-phosphosurphate in human tissues. Eur J Clin Pharmacol 37:317-320.
20. Cappiello M, Giuliani L and Pacifici GM (1991) Distribution of UDP-glucuronosyltransferase and its endogenous substrate uridine 5′-diphosphoglucuronic acid in human tissues. Eur J Clin Pharmacol 41:345-350.
21. Chen J and Pang KS (1997) Effect of flow on first-pass metabolism of drugs: Single pass studies on 4-methylum-belliferone conjugation in the serially perfused rat intestine and liver preparations. J Pharmacol Exp Ther 280:24-31.
22. Chiba M, Hensleigh M and Lin JH (1997) Hepatic and intestinal metabolism of indinavir, an HIV protease inhibitor, in rat and human microsomes. Biochem Pharmacol 53:1187-1195.
23. Clarks DJ and Burchell B (1994) The uridine diphosphate glucuronosyltransferase multigene family: Function and regulation, in Conjugation-Deconjugation Reactions in Drug Metabolism and Toxicity (Kauffman FC ed) pp 3-34, Springer-Verlag, Berlin.
24. Colburn WA (1979) A pharmacokinetic model to differentiate preabsorptive, gut, epithelial, and hepatic first-pass metabolism: J Pharmacokinet Biopharm 7:407-415.
25. Correia MA (1995) Rat and human liver cytochromes P450, in Cytochrome P450: Structure, Mechanism, and Biochemistry (Ortiz de Montellano PR ed), pp 473-535, Plenum Press, New York.
26. Creamer B (1967) The turnover of the epithelium of the small intestine. Br Med Bull 23:226-230.
27. de Vries MH, Hofman GA, Koster ASJ and Noordhoek J (1989) Systemic intestinal metabolism of 1-naphthol. A study in the isolated vascularly perfused rat small intestine. Drug Metab Dispos 17:573-578.
28. Debri K, Boobis AR, Davies DS and Edwards RJ (1995) Distribution and induction of CYP3A1 and CYP3A2 in rat liver and extrahepatic tissues. Biochem Pharmacol 50:2047-2056.
29. de Waziers I, Cugenec PH, Yang CS, Lerous JP and Beaune PH (1990) Cytochrome P450 isoenzymes, epoxide hydrolase and glutathione transferase in rat and human hepatic and extrahepatic tissues. J Pharmacol Exp Ther 253:387-394.
30. Dubey RK and Singh J (1988) Localization and characterization of drug-metabolizing enzymes along the villus-crypt surface of the rat small intestine II. Conjugates. Biochem Pharmacol 37:177-184.
31. Eichelbaum M, Albrecht M, Kliems G, Schäfer K and Somogyi A (1980) Influence of meso-caval shunt surgery on verapamil kinetics, bioavailability and response. Br J Clin Pharmacol 10:527-530.
32. Eichelbaum M, Dengler HJ, Somogyi A and Van Unruh GE (1981a) Superiority of stable isotope techniques in the assessment of the bioavailability of drugs undergoing extensive first-pass elimination: Studies of the relative bioavailability of verapamil tablets. Eur J Clin Pharmacol 19:127-131.
33. Eichelbaum M, Somogyi A, Van Unruh GE and Dengler HJ (1981b) Simultaneous determination of the intravenous and oral pharmacokinetic parameters of D, L-verapamil using isotope-labelled verapamil. Eur J Clin Pharmacol 19:133-137.
34. Fardel O, Lecureur V, Daval S, Corlu A and Guillouzo A (1997) Up-regulation of p-glycoprotein expression in rat liver cells by acute doxorubicin treatment. Eur J Biochem 246:186-192.
35. Fardel O, Lecureur V and Guillouzo A (1993) Regulation by dexamethasone of p-glycoprotein expression cultured rat hepatocytes. FEBS Lett 327:189-193.
36. Floren LC, Bekersky I, Benet LZ, Mekki Q, Dressier D, Lee JH, Roberts JP and Hebert MR (1997) Tacrolimus oral bioavailability doubles with coadministration with ketoconazole. Clin Pharmacol Ther 62:41-49.
37. Fojo AT, Ueda K, Slamon DJ, Poplack DG, Gottesman MM and Pastan I (1987) Expression of a multidrug resistance gene in human tumors and tissues. Proc Natl Acad Sci USA 84:265-269.
38. Fricker G, Drewe J, Huwyler J, Gutmann H and Beglinger C (1996) Relevance of p-glycoprotein for the enterai absorption of cyclosporin A: In vitro-in vivo correlation. Br J Pharmacol 118:1841-1847.
39. Fromm MF, Busse D, Kroemer HK and Eichelbaum M (1996) Differential induction of prehepatic and hepatic metabolism of verapamil by rifampin Hepatology 24: 796-801.
40. Gan LS, Moseley MA, Khosla B, Augustijins PF, Bradshaw TP, Hendren RW and Thakker DR (1996) CYP3A-like cytochrome P450-mediated metabolism and polarized efflux of cyclosporin A in Caco-2 cells. Drug Metab Dispos 24:344-349.
41. Gant TW, O'Connor CK, Corbitt R, Thorgeirsson U and Thorgeirsson SS (1995) In vivo induction of liver p-glycoprotein expression by xenobiotics in monkeys. Toxicol Appi Pharmacol 133:269-276.
42. Ged C, Rouillon JM, Pichard L, Combalbert J, Bressot N, Bories P, Michel H., Beaune P. and Maurel P (1989) The increase in urinary excretion of 6β-hydroxycortisol as a marker of human hepatic cytochrome P450IIIA induction. Br J Clin Pharmacol 28:373-387.
43. George CF, Blackwell EW and Davies DS (1974) Metabolism of isoprenaline in the intestine. J Pharm Pharmacol 26:265-267.
44. Gillette JR and Pang KS (1977) Theoretic aspects of pharmacokinetic drug interaction. Clin Pharmacol Ther 22:27-638.
45. Goon D and Klassen CD (1992) Effects of microsomal enzyme inducers upon UDP-glucuronic acid concentration and UDP-glucuronosyltransferase activity in the rat intestine and liver. Toxicol Appl Pharmacol 115:253-260.
46. Gore RW and Bohlen HG (1977) Microvascular pressures in rat intestinal muscle and mucosal villi. Am J Physiol 233:H685-H693.
47. Guengerich FP (1995) Cytochrome P450 enzymes, in Cytochrome P450: Structure, Mechanism and Biochemistry (Ortiz de Montellano PR ed) pp 473-535, Plenum Press, New York.
48. Gupta S, Kim J and Gollapudi S (1991) Reversal of daunorubicin resistance in p388/ADR cells by itraconazole. J Clin. Invest 87:1467-1469.
49. Guyton AC (1991) General principles of gastrointestinal function - mortality, nervous control, and blood circulation, in Textbook of Medical Physiology, pp 698-708, WB Saunders, Philadelphia.
50. Hallback DA, Hulten L, Jodal M, Lindhagen J and Lundgren D (1978) Evidence for the existence of a countercurrent exchanger in the small intestine in man. Gastroenterology 74:683-690.
51. Hebert, MF, Roberts JP, Prueksaritanont T and Benet LZ (1992) Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther 52:453-457.
52. Higgins CF (1992) ABC transporters: From microorganism to man. Annu Rev Cell Biol 8:67-113.
53. Higuchi WI, Ho NF, Park JY and Komiya I (1981) Rate-limiting steps and factors in drug absorption, in Drug Absorption (Prescott LF and Nimmo WS eds) pp 35-60, ADIS Press, New York.
54. Hirayama H and Pang KS (1990) First-pass metabolism of gentisamide: Influence of intestinal metabolism on hepatic formation of conjugates: Studies in the once-through vascularly perfused rat intestine-liver preparation. Drug Metab Dispos 18:580-587.
55. Ho NF, Park JY, Ni PF and Higuchi WI (1983) Advancing quantitative and mechanistic approaches in interfacing gastrointestinal drug absorption studies in animals and humans, in Animal Models for Oral Drug Delivery in Man: In Situ and In Vivo Approaches (Crouthamel W and Sarapu AC eds) pp 27-106, American Pharmaceutics Association, Washington, DC.
56. Hoensch H, Woo CH, Raffin SB and Schmid R (1976) Oxidative metabolism of foreign compounds in rat small intestine: Cellular localization and dependence on dietary iron. Gastroenterology 70:1063-1070.
57. Hofsli E and Nissen-Meyer J (1989) Reversal of drug resistance by erythromycin: Erythromycin increases the accumulation of actinomycin D and toxorubicin in multidrug-resistant cells. Int J Cancer 44:149-154.
58. Holtbecker N, Fromm MF, Kroemer HK, Ohnhms EF and Heidemann H (1996) The nifedipine-rifampin interaction: Evidence for induction of gut wall metabolism. Drug Metab Dispos 24:1121-1123.
59. Hsing S, Gatmaitan Z and Arias IM (1992) The function of gp170, the multidrug-resistance gene product, in the brush border of rat intestinal mucosa. Gastroenterology 102:879-885.
60. Hulten L, Lindhagen J and Lundgren O (1977) Sympathetic nervous control of intramural blood flow in the feline and human intestines. Gastroenterology 72:41-48.
61. Hunter J, Jepson MA, Tsuruo T, Simmons NL and Hirst BH (1993) Functional expression of p-glycoprotein in apical membrane of human intestinal Caco-2 cells. Kinetics of vinblastine secretion and interactions with modulators. J Biol Chem 268:14991-14997.
62. Ilett KF (1990) In vivo studies of gut wall metabolism, in Clinical Pharmacology and Therapeutics: Presystemic Drug Elimination (George CF, Shand DG and Renwick AG eds) pp 26-53, Butterworths, London.
63. Ilett KF, Dollery CT and Davis DS (1980) Isoprenaline conjugation: A "true first-pass effect" in the dog intestine. J Pharm Pharmacol 32:362-366.
64. Ilett KF, Tee LBG, Reeves PT and Minchin RF (1990) Metabolism of drugs and other xenobiotics in the gut lumen wall. Pharmacol Ther 48:67-93.
65. Inoue K, Inazawa J and Nakagawa H (1992) Assignment of the human cytochrome P450 nifedipine oxidase gene (CYP3A4) to chromosome 7 at band g22.1 by fluoresence in situ hybridization. Jpn J Hum Genet 37:133-138.
66. Juliano RL and Ling V (1976) A surface glycoprotein modulating drug permeability in chinese hamster ovary cell mutants. Biochem Biophys Acta 455:152-162.
67. Kaminsky LS and Fasco MJ (1992) Small intestinal cytochrome P450. Crit Rev Toxicol 21:407-422.
68. Karlson J, Kuo SM, Ziemniak J and Artursson P (1993) Transports of celiprolol across human intestinal epithelial (Caco-2) cells: Mediation of secretion by multiple transports including p-glycoprotein. Br J Pharmacol 110:1009-1016.
69. Kleinbloesem CH, Van Hartan J, Wilson JPH, Danhof M, Van Brummek P and Breimer DD (1986) Nifedipine: Kinetics and hemodynamic effects in patients with liver cirrhosis after intravenous and oral administration. Clin Pharmacol Ther 40:21-28.
70. Klippert P, Borm P and Noordhoek J (1982) Prediction of intestinal first-pass effect of phenacetin in the rat from enzyme kinetic data -Correlation with in vivo data using mucosal blood flow. Biochem Pharmacol 31:2545-2548.
71. Klippert PJM, Hulshoff A, Mingels M-JJ, Hofman G and Noordhoek J (1983) Low bioavailability of hexamethylmelamine in the rat due to simultaneous hepatic and intestinal metabolism. Cancer Res 43:3160-3164.
72. Klippert PJM and Noordhoek J (1983) Influence of administration route and blood sampling site on the area under the curve: Assessment of gut wall, liver and lung metabolism from a physiological model. Drug Metab Dispos 11:62-66.
73. 1-adduct formation in rat and human small bowel. Gastroenterology 106:433-439.
74. Kolars JC, Schmiedlin-Ren P, Schuetz JD, Fang C and Watkins PB (1992) Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest 90:1874-1878.
75. Koster AS, Schirmer G and Bock KW (1986) Immunochemical and functional characterization of UDP-glucuronosyltransferases from rat liver, intestine and kidney. Biochem Pharmacol 35:3971-3975.
76. Krishna DR and Klotz U (1994) Extrahepatic metabolism of drugs in humans. Clin Pharmacokinet 26:144-160.
77. Kusuhara H, Suzuki H and Sugiyama Y (1987) The role of p-glycoprotein in the liver. Nippon Rinsho 55:1069-1076.
78. Lampen A, Christians U, Guengerich FP, Watkins PB, Kolars JC, Bader A, Gonschior AK, Dralle H, Hackbarth I and Sewing KF (1995) Metabolism of the immunosuppressant tacrolimus in the small intestine: Cytochrome P450, drug interactions, and interindividual variability. Drug Metab Dispos 23:1315-1324.
79. Lecureur V, Guillouzo A and Fardel O (1996) Differential regulation of mdr genes in response to 2-acetylaminofluorene treatment in cultured rat and human hepatocytes. Carcinogenesis (Lond) 17:1157-1160.
80. Leu BL and Huang JD (1995) Inhibition of intestinal p-glycoprotein and effects on etoposide absorption. Cancer Chemother Pharmacol 35:432-436.
81. Lin JH (1994) Dose-dependent pharmacokinetics: Experimental observations and theoretical considerations. Biopharm Drug Dispos 15:1-31.
82. Lin JH, Chiba M and Baillie TA (1997) In vivo assessment of intestinal metabolism. Drug Metab Dispos 25:1107-1109.
83. Lin JH, Chiba M, Balani SK, Chen IW, Kwei G, Vastag KJ and Nishime JA (1996) Species-differences in the pharmacokinetics and metabolism of indinavir, a potent human-immunodeficiency-virus protease inhibitor. Drug Metab Dispos 24:1111-1120.
84. Lipkin M, Sherlock P and Bell B (1963) Cell proliferation kinetics in the gastrointestinal tract of man II. Gastroenterology 45:721-729.
85. Lown KS, Kolars JC, Thummel KE, Barnett JL, Kunze KL, Wrighton SA and Watkins PB (1994) Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel: Lack of prediction by the erythromycin breath test. Drug Metab Dispos 22:947-955.
86. Lown KS, Mayo RR, Leichtman AB, Hsiao HL, Turgeon K, Schmiedlin-Ren P, Brown MB, Guo W, Rossi SJ, Benet LZ and Watkins PB (1997) Role of intestinal p-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther 62:248-260.
87. Macey RI (1978) Mathematical models of membrane transport processes, in Physiology of Membrane Disorders (Andreoli R ed) pp 125-146, Plenum Press, New York.
88. Mackenzie PI, Owens IS, Burchell B, Bock KW, Bairock A, Belanger A, Fournel-Gigleux S, Green M, Hum DW, Iyanagi T, Lancet D, Louisot P, Magdalou J, Chowdhury JR, Ritter JK, Schachter H, Tephly TR, Tipton KF and Nebert DW (1997) The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics 7:255-269.
89. Mayer U, Wagenaar E, Beijnen JH, Smit JW, Meijer DKF, van Asperen J, Borst P and Schinkel AH (1996) Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdr1a p-glycoprotein. Br J Pharmacol 119:1038-1044.
90. McDanell RE and McLean AEM (1984) Differences between small and large intestine and liver in the inducibility of microsomal enzymes in response to stimulation by phenobarbitone and β-naphthoflavone in the diet. Biochem Pharmacol 33: 1977-1980.
91. McKinnon RA, Burgess WM, Hall P, deLa M, Roberts-Thompson SJ, Gonzalez FJ and McManus ME (1995) Characterization of CYP3A gene subfamily expression in human gastrointestinal tissues. Gut 36:259-267.
92. Melander A, Danielson K, Hanson DA, Rudell B, Schersten B, Thulin T and Wahlin E (1977a) Enhancement of hydralazine bioavailability by food. Clin Pharmacol Ther 22:104-107.
93. Melander A, Danielson K, Scherstein B and Wahlin E (1977b) Enhancement of the bioavailability of propranolol and metoprolol by food. Clin Pharmacol Ther 22: 108-112.
94. Melander A and McLean A (1983) Influence of food intake on presystemic clearance of drugs. Clin Pharmacokinet 8:286-296.
95. Minchin RF and Ilett KF (1982) Presystemic elimination of drugs: Theoretical considerations for quantifying the relative contribution of gut and liver. J Pharm Sci 71:458-460.
96. Miranda CL and Chhabra RS (1979) Species differences in stimulation of intestinal and hepatic microsomal mixed-function oxidase enzymes. Biochem Pharmacol 29:1161-1165.
97. Mistry M and Houston JB (1987) Glucuronidation in vitro and in vivo. Comparison of intestinal and hepatic conjugation of morphine, naloxone and buprenorphine. Drug Metab Dispos 15:710-717.
98. Morse MA and Stoner GD (1993) Cancer chemoprevention: principles and prospects. Carcinogenesis (Lond) 14:1737-1746.
99. Murray GI, Barnes TS, Swell HF, Ewen SW, Melvin WT and Burk MD (1988) The immunochemical localization and distribution of cytochrome P450 in normal human hepatic and extrahepatic tissues with a monoclonal antibody to human cytochrome P450. Br J Clin Pharmacol 25:465-475.
100. Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, Waterman MR, Gotoh O, Coon MJ, Estabrook RW, Gunsalus IC and Nebert DW (1996) The P450 superfamily, update on new sequences, gene mapping, accession number and nomenclature. Pharmacogenetics, 6:1-42.
101. Olanoff LS, Walle T, Cowart TD, Walle UK, Oexmann MJ and Conradi EC (1986) Food effects on propranolol systemic and oral clearance: Support for a blood flow hypothesis. Clin Pharmacol Ther 40:408-414.
102. Pacifici GM, Eligi M and Giuliani L (1993) (+) and (-) terbutaline are sulfated at a higher rate in human intestine than in liver. Eur J Clin Pharmacol 45:483-487.
103. Pacifici GM, Franchi M and Bencini F (1988) Tissue distribution of drug metabolizing enzymes in human. Xenabiotica 18:849-856.
104. Pade V and Stavchansky S (1997) Estimation of the relative contribution of the transcellular and paracellular pathway to the transport of passively absorbed drugs in the Caco-2 cell culture model. Pharmacol Res 14:1210-1215.
105. Paine MF, Khalighi M. Fisher JM, Shen DD, Kunze KL, March CL, Perkins JD and Thummel KE (1997) Characterization of interintestinal and intraintestinal differences in human CYP3A-dependent metabolism. J Pharmacol Exp Ther 283:1552-1562.
106. Paine MF, Shen DD, Kunze KL, Perkins JD, Marsh CL, McVicar JP, Barr DM, Gillies BS and Thummel KE (1996) First-pass metabolism of midazolam by the human intestine. Clin Pharmacol Ther 60:14-24.
107. Parks DA and Jacobson ED (1987) Mesenteric circulation, in Physiology of the Gastrointestinal Tract (Johnson LR, Christensen J, Jackson MJ, Jacobson ED and Walsh JH eds) pp 1649-1670, Raven Press, New York.
108. Pelkonen O, Pasanen M, Kuha H, Gachalyi B, Kaivraluoma M, Sotaniem EA, Park SS, Friedman FK and Gelboin HV (1986) The effect of cigarette smoking on 7-ethoxyresorfin O-deethylase and other monooxygenase activities in human liver: Analyses with monoclonal antibodies. Br J Clin Pharmacol 22:125-134.
109. Pesola GR and Walle T (1993) Stereoselective sulfate conjugation of isoproterenol in humans: Comparison of hepatic, intestinal and platelet activity. Chirality 5:602-609.
110. Peters WH and Kremers PG (1989) Cytochromes P450 in the intestinal mucosa of man. Biochem Pharmacol 38:1535-1538.
111. Peters WHM and Jansen PLM (1988) Immunocharacterization of UDP-glucuronyltransferase isoenzymes in human liver, intestine and kidney. Biochem Pharmacol 37:564-567.
112. Peters WHM, Kock L, Nagengast FM and Kremers PG (1991) Biotransformation enzymes in human intestine: Critical low levels in the colon? Gut 32:408-412.
113. Pichard L, Fabre I, Danjat M, Domergue J, Joyeux H and Maurel P (1992) Effect of corticosteroids on the expression of cytochrome P450 and on cyclosporin A oxidase activity in primary cultured human hepatocytes. Mol Pharmacol 41:1047-1055.
114. Prueksaritanont T, Dwyer LM and Cribb AE (1995) (+)-Bufuralol 1′-hydroxylation activity in human and rhesus monkey intestine and liver. Biochem Pharmacol 50:1521-1525.
115. Renwick AG and George CF (1989) Metabolism of xenobiotics in the gastro-intestinal tract, in Intermediary Xenobiotic Metabolism in Animals: Methodology, Mechanisms and Significance (Huston DH, Caldwell J and Paulson GD eds) pp 13-40, Taylor and Francis, London.
116. Romiti P, Giullian L and Pacifici GM (1992) Interindividual variability in the N-sulfation of desipramine in human liver and platelets. Br J Clin Pharmacol 33:17-23.
117. Salphati L and Benet LZ (1998) Modulation of p-glycoprotein expression by cytochrome P450 3A inducers in male and female rat livers. Biochem Pharmacol 55:387-395.
118. Schinkel AH, Smit JJM, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, Mol CAAM, van der Valk MA, Robaans-Maandag EC, te Riele HPJ, Berns AJM and Borst P (1994) Disruption of mouse mdrla p-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77:491-502.
119. Schinkel AH, Wagenaar E, van Deemter L, Mol CAAM and Borst P (1995) Absence of mdrla p-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin and cyclosporine A. J Clin Invest 96:1698-1705.
120. Schuetz EG, Beck WT and Schuetz JD (1996) Modulation and substrates of p-glycoprotein and cytochrome P450 3A coordinately up-regulated these proteins in human colon carcinoma cells. Mol Pharmacol 49:311-318.
121. Schuetz EG, Furuya KN and Schuetz JD (1995a) Interindividual variation in expression of p-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther 275:1011-1018.
122. Schuetz EG, Schuetz JD, Thompson MT, Fisher RA, Madariage JR and Strom SC (1995b) Phenotypic variability in induction of p-glycoprotein mRNA by aromatic hydrocarbons in primary human hepatocytes. Mol Carcinog 12:61-65.
123. Segel IH (1975) Kinetics of unireactant enzymes, in Enzyme Kinetics (Segel IH ed) pp 18-99, John Wiley and Sons, New York.
124. Sesardic D, Boobis AR, Edwards RJ and Davis DS (1988) A form of cytochrome P450 in man, orthologus to form d in the rat, catalyses the O-deethylation of phenacetin and is inducible by cigarette smoking. Br J Clin Pharmacol 26:363-372.
125. Sesardic D, Cole KJ, Edwards RJ, Davies DS, Thomoas PE, Levin W and Boobis AR (1990) The inducibility and catalytic activity of cytochrome P450e (P450 1A1) and P450d (P4501A2) in rat tissues. Biochem Pharmacol 39:499-506.
126. Shimada T, Yamazaki H, Mumura M, Inui Y and Guengerich FP (1994) Interindividual variations in human liver cytochrome P450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: Studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270:414-423.
127. Shiner M (1995) Anatomy of the small intestine, in Gastroenterology (Haubrich WS ed) vol 5, pp 885-898, WB Saunders Company, Philadelphia.
128. Shirkey RS, Chakraborty J and Bridges JW (1979) Comparison of the drug metabolizing ability of rat intestinal mucosal microsomes with that of liver. Biochem Pharmacol 28:2835-2839.
129. Siegsmund MJ, Cardarell C, Aksentijevich I, Sugimoto Y, Pasten I and Gottesman MM (1994) Ketoconazole effectively reverses multidrug resistance in highly resistant KB cells. J Urol 151:485-491.
130. Silverman JA and Schrenk D (1997) Expression of multidrug resistance genes in the liver. FASEB J 11:308-313.
131. Sparreboom A, van Asperen J, Mayer U, Schinkel AH, Smit JW, Meijer DKF, Borst P, Nooijen WJ, Beijen JH and van Tellingen O (1997) Limited oral bioavailability and active excretion of paclitaxel (Taxol) caused by p-glycoprotein in the intestine. Proc Natl Acad Sci USA 94:2031-2035.
132. Strömberg C, Vanakoski J, Olkkola KT, Lindgvist A, Seppäläö T and Laitinen LA (1992) Exercise alters the pharmacokinetics of midazolam. Clin Pharmacol Ther 51:527-532.
133. Su SF and Huang JD (1996) Inhibition of the intestinal digoxin absorption and exsorption by quinidine. Drug Metab Dispos 24:142-147.
134. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I and Willingham MC (1987) Cellular localization of the multidrug resistance gene product in normal human tissues. Proc Natl Acad Sci USA 84:7735-7738.
135. Thomas ABR (1988) Relationship between physiology and clinical disorders of the small intestine, in Principles and Practice of Gastroenterology and Hepatology (Gitnick G, Hollander D, Kaplowitz N, Samloff LM and Schoenfield LJ eds) pp 281-289, Elsevier, Amsterdam.
136. Thummel KE, Kunze KL and Shen DD (1997) Enzyme-catalyzed process of first-pass hepatic and intestinal drug extraction. Adv Drug Delivery Rev 27: 99-127.
137. Thummel KE, O'Shea D, Paine MF, Shen DD, Kunze KL, Perkins JD and Wilkinson GR (1995) Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther 59:491-502.
138. Traber PG, Chianale J, Florence R, Kim K, Wojcik E and Gumucio JJ (1988) Expression of cytochrome P450c genes in small intestinal mucosa of rats following treatment with phenobarbital, polyhalogenated biphenyls, and organochlorine pesticide. J Biol Chem 263:9449-9455.
139. Vargas M and Franklin MR (1997) Intestinal UDP-glucuronosyltransferase activities in rats and rabbits. Xenobiotica 37:413-421.
140. Vickers AEM, Alegret M, Meyer E, Smiley S and Guerter J (1996) Hydroxyethyl cyclosporin A induces and decreases P450 3A and p-glycoprotein level in rat livers. Xenobiotica 26:27-39.
141. Wacher VJ, Wu CY and Benet LZ (1995) Overlapping substrate specificities and tissue distribution of cytochrome P4503A and p-glycoprotein: Implications for drug delivery and activity in cancer chemotherapy. Mol Pharmacol 13:129-134.
142. Walle T, Walle UK, Cowart TD, Conrad EC and Gaffney T (1987) Selective induction of propranolol metabolism by smoking. Additional effects on renal clearance of metabolites. J Pharmacol Exp Ther 241:928-933.
143. Wang SX, Sutfin TA, Bäärnhielm C and Regardh CG (1989) Contribution of intestine to the first-pass metabolism of felodipine in the rat. J Pharmacol Exp Ther 250:632-636.
144. Watkins PB (1997) The barrier function of CYP3A4 and p-glycoprotein in the small bowel. Acta Drug Delivery Rev 27:161-170.
145. Watkins PB, Murray SA, Winkelman LG, Heuman DM, Wrighton SA and Guzelian PS (1989) Erythromycin breath test as an assay of glucocorticoid-induced liver cytochrome P450. J Clin Invest 83:688-697.
146. Watkins PB, Wrighton SA, Schuetz EG, Molowa DT and Guzelian PS (1987) Identification of glucocorticoid cytochrome P450 in the intestinal mucosa of rats and man. J Clin Invest 80:1029-1036.
147. Weinshilboum R and Otterness D (1994) Sulfotransferase enzymes, in Conjugation-Deconjugation Reactions in Drug Metabolism and Toxicity (Kauffman FC ed) pp 45-78, Springer-Verlag, Berlin.
148. Weisbradt NW (1987) Motility of the small intestine, in Physiology of the Gastrointestinal Tract (Johnson LR, Christense J, Jackson MJ, Jacobson ED and Walsh JH eds) vol 2, pp 631-663, Raven Press, New York.
149. Wilkinson GR (1987) Clearance approaches in pharmacology. Pharmacol Rev 39:1-47.
150. Wilson CG and Washington N (1989) Small intestine: Transit and absorption of drugs, in Physiological Pharmaceutics: Biological Barriers to Drug Absorption (Wilson CG and Washington N eds) pp 71-90, Ellis Horwood, Ltd., Chichester.
151. Wu CY, Benet LZ, Hebert MF, Gupta SK, Rowland M, Gomez DY and Wacher VJ (1995) Differentiation of absorption and first-pass gut and hepatic metabolism in humans: Studies with cyclosporine. Clin Pharmacol Ther 58:492-497.
152. Xu X, Hirayama H and Pang KS (1989) First-pass metabolism of salicylamide: Studies in the once-through vascularly perfused rat intestine-liver preparation. Drug Metab Dispos 17:556-563.
153. Zhang DY, Wikoff J, Dunbar D, Fasco M and Kaminsky L (1997) Regulation of cytochrome P450 1A1 expression in rat small intestine. Drug Metab Dispos 25: 21-26.
154. Zhao JY, Ikeguchi M. Eckersberg T and Kuo MT (1995) Modulation of multidrug resistance gene expression by dexamethasone in cultured hepatoma cells. Endocrinology 133:521-528.