Cytochrome P450-mediated metabolism in the human gut wall

Journal of Pharmacy and Pharmacology

Volumn 61, Issue 5, 2009, Pages 541-558

  Thelen, Kirstin ^a   Dressman, Jennifer B ^a  

^a GOETHE UNIVERSITY   (Germany)

Author keywords

CYP; Cytochrome P450; First pass metabolism; Gut wall metabolism; Intestinal metabolism

Indexed keywords

CLARITHROMYCIN; CYCLOSPORIN A; CYTOCHROME P450; CYTOCHROME P450 1A; CYTOCHROME P450 1A1; CYTOCHROME P450 2C; CYTOCHROME P450 2D6; CYTOCHROME P450 2E1; CYTOCHROME P450 2J2; CYTOCHROME P450 3A; CYTOCHROME P450 3A43; CYTOCHROME P450 3A5; CYTOCHROME P450 3A7; DEXAMETHASONE; EBASTINE; ERYTHROMYCIN; ETHINYLESTRADIOL; EXCIPIENT; FELODIPINE; HYPERICUM PERFORATUM EXTRACT; KETOCONAZOLE; LOPINAVIR PLUS RITONAVIR; MIDAZOLAM; NIFEDIPINE; RAPAMYCIN; RIFAMPICIN; SAQUINAVIR; TACROLIMUS; TERFENADINE; UNCLASSIFIED DRUG; VERAPAMIL; DRUG; ISOENZYME;

ACTIVE TRANSPORT; DRUG BIOAVAILABILITY; DRUG CROSS REACTIVITY; DRUG DIFFUSION; DRUG METABOLISM; DRUG PROTEIN BINDING; DRUG TRANSFORMATION; ENDOCYTOSIS; ENZYME INDUCTION; ENZYME INHIBITION; FIRST PASS EFFECT; FOOD DRUG INTERACTION; GRAPEFRUIT JUICE; HUMAN; INTESTINE BLOOD FLOW; REVIEW; SMALL INTESTINE; VOLUNTEER; ANIMAL; BIOAVAILABILITY; DRUG ANTAGONISM; DRUG INTERACTION; ENZYMOLOGY; INTESTINE MUCOSA; LIVER; METABOLISM; ORAL DRUG ADMINISTRATION;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; CYTOCHROME P-450 ENZYME SYSTEM; DRUG INTERACTIONS; HUMANS; INTESTINAL MUCOSA; INTESTINE, SMALL; ISOENZYMES; LIVER; PHARMACEUTICAL PREPARATIONS;

EID: 68949103975     PISSN: 00223573     EISSN: None     Source Type: Journal    
DOI: 10.1211/jpp/61.05.0002     Document Type: Review

References (245)

1. Rowland M, Tozer TN. Clinical Pharmacokinetics - Concepts and Applications, 3rd edn. Baltimore: Lippincott Williams & Wilkins, 1995.
2. Benet LZ et al. Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery. J Control Release 1999; 62: 25-31.
3. de Waziers I et al. Cytochrome P 450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues. J Pharmacol Exp Ther 1990; 253: 387-394.
4. Paine MF et al. The human intestinal cytochrome P450 'pie'. Drug Metab Dispos 2006; 34: 880-886.
5. Watkins PB et al. Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. J Clin Invest 1987; 80: 1029-1036.
6. Czernik PJ et al. Glucuronidation of estrogens and retinoic acid and expression of UDP-glucuronosyltransferase 2B7 in human intestinal mucosa. Drug Metab Dispos 2000; 28: 1210-1216.
7. Radominska-Pandya A et al. UDP-glucuronosyltransferases in human intestinal mucosa. Biochim Biophys Acta 1998; 1394: 199-208.
8. Strassburg CP et al. Polymorphic gene regulation and interindividual variation of UDP-glucuronosyltransferase activity in human small intestine. J Biol Chem 2000; 275: 36164-36171.
9. Chen G et al. Human gastrointestinal sulfotransferases: identification and distribution. Toxicol Appl Pharmacol 2003; 187: 186-197.
10. Pacifici GM et al. Tissue distribution of drug-metabolizing enzymes in humans. Xenobiotica 1988; 18: 849-856.
11. Windmill KF et al. Localization of N-acetyltransferases NAT1 and NAT2 in human tissues. Toxicol Sci 2000; 54: 19-29.
12. Gibbs JP et al. Comparison of human liver and small intestinal glutathione S-transferase-catalyzed busulfan conjugation in vitro. Drug Metab Dispos 1998; 26: 52-55.
13. Prueksaritanont T et al. Comparative studies of drug-metabolizing enzymes in dog, monkey, and human small intestines, and in Caco-2 cells. Drug Metab Dispos 1996; 24: 634-642.
14. Engeland K, Maret W. Extrahepatic, differential expression of four classes of human alcohol dehydrogenase. Biochem Biophys Res Commun 1993; 193: 47-53.
15. Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999; 286: 487-491.
16. Wienkers LC, Heath TG. Predicting in vivo drug interactions from in vitro drug discovery data. Nat Rev Drug Discov 2005; 4: 825-833.
17. Webber IR et al. Cyclosporin metabolism by human gastrointestinal mucosal microsomes. Br J Clin Pharmacol 1992; 33:661-664.
18. Kolars JC et al. First-pass metabolism of cyclosporin by the gut. Lancet 1991; 338: 1488-1490.
19. Hebert MF et al. Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther 1992; 52: 453-457.
20. Gorski JC et al. The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin. Clin Pharmacol Ther 1998; 64: 133-143.
21. Paine MF et al. First-pass metabolism of midazolam by the human intestine. Clin Pharmacol Ther 1996; 60: 14-24.
22. Thummel KE et al. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther 1996; 59: 491-502.
23. Floren LC et al. Tacrolimus oral bioavailability doubles with coadministration of ketoconazole. Clin Pharmacol Ther 1997; 62: 41-49.
24. Holtbecker N et al. The nifedipine-rifampin interaction - evidence for induction of gut wall metabolism. Drug Metab Dispos 1996; 24: 1121-1123.
25. Rashid TJ et al. Factors affecting the absolute bioavailability of nifedipine. Br J Clin Pharmacol 1995; 40: 51-58.
26. Lown KS et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest 1997; 99: 2545-2553.
27. Lundahl J et al. Effects of grapefruit juice ingestion - pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men. Eur J Clin Pharmacol 1997; 52: 139-145.
28. Regardh CG et al. Pharmacokinetics of felodipine in patients with liver disease. Eur J Clin Pharmacol 1989; 36: 473-479.
29. Fromm MF et al. Differential induction of prehepatic and hepatic metabolism of verapamil by rifampin. Hepatology 1996; 24: 796-801.
30. von Richter O et al. Determination of in vivo absorption, metabolism, and transport of drugs by the human intestinal wall and liver with a novel perfusion technique. Clin Pharmacol Ther 2001; 70: 217-227.
31. Valentin J. Basic anatomical and physiological data for use in radiological protection: reference values. Oxford: Pergamon, 2002.
32. Lin JH et al. Is the role of the small intestine in first-pass metabolism overemphasized? Pharmacol Rev 1999; 51: 135-157.
33. Hansen JT, Koeppen BM. Netter's Atlas of Human Physiology, 1st edn. Teterboro, NJ: Icon Learning Systems, 2002.
34. Doherty MM, Charman WN. The mucosa of the small intestine: how clinically relevant as an organ of drug metabolism? Clin Pharmacokinet 2002; 41: 235-253.
35. Tortora GJ, Grabowski SR. The digestive system. In: Tortora GJ, Grabowski SR, eds. Principles of Anatomy and Physiology, 10th edn. New York: Wiley, 2003: 851-905.
36. Versantvoort CHM et al. Methodologies to Study Human Intestinal Absorption. National Institute of Public Health and the Environment, RIVM report 630030001, 2000.
37. Dharmsathaphorn K. Intestinal water and electrolyte secretion and absorption. In: West JB, ed. Best and Taylor's Physiological Basis of Medical Practice, 12th edn. Baltimore: Williams & Wilkins, 1993: 707-726.
38. Lipski PS et al. Ageing and duodenal morphometry. J Clin Pathol 1992; 45: 450-452.
39. Mayersohn M. Principles of drug absorption. In: Banker GS, Rhodes CT, eds. Modern Pharmaceutics, 4th edn. New York: Dekker, 2002: 29-93.
40. Riecken EO et al. Quantitative study of mucosal structure, enzyme activities and phenylalanine accumulation in jejunal biopsies of patients with early and late onset diabetes. Gut 1979; 20: 1001-1007.
41. Swanson VL, Thomassen RW. Pathology of the jejunal mucosa in tropical sprue. Am J Pathol 1965; 46: 511-551.
42. Wigley C. Microstructure of the small intestine. In: Standring S, ed. Gray's Anatomy, 39th edn. Edinburgh: Elsevier, 2005: 1157-1161.
43. Snyder WS et al. Digestive system. In: International Commission on Radiological Protection, ed. Report of the Task Group on Reference Man, Oxford: Pergamon, 1975: 122-151.
44. Chou CC. Intestinal blood flow regulation. In: Dulbecco, R, ed. Encyclopedia of Human Biology, 4th edn. San Diego: Academic Press, 1991: 547-556.
45. Jacobson LF,Noer RJ. The vascular pattern of the intestinal villi in various laboratory animals and man. Anat Rec 1952; 114: 85-101.
46. Reynolds DG et al. The vascular architecture of the small intestinal mucosa of the monkey (Macaca mulatta); Anat Rec 1967; 159: 211-218.
47. Testa B, Krämer SD. The biochemistry of drug metabolism - an introduction: part 1. Principles and overview. Chem Biodivers 2006; 3: 1053-1101.
48. Zanger UM et al. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 2004; 369: 23-37.
49. Alison MR et al. Hepatic stem cells: from inside and outside the liver? Cell Prolif 2004; 37: 1-21.
50. Bullen TF et al. Characterization of epithelial cell shedding from human small intestine. Lab Invest 2006; 86: 1052-1063.
51. Creamer B. The turnover of the epithelium of the small intestine. Br Med Bull 1967; 23: 226-230.
52. Crosby WH. A concept of the pathogenesis of anemia applied to disorders of the intestinal mucosa. Am J Dig Dis 1961; 6: 492-498.
53. Gassler N et al. Molecular characterisation of non-absorptive and absorptive enterocytes in human small intestine. Gut 2006; 55: 1084-1089.
54. Potten CS et al. The intestinal epithelial stem cell: the mucosal governor. Int J Exp Pathol 1997; 78: 219-243.
55. Potten CS et al. Regulation and significance of apoptosis in the stem cells of the gastrointestinal epithelium. Stem Cells 1997; 15: 82-93.
56. Hillgren KM et al. In vitro systems for studying intestinal drug absorption. Med Res Rev 1995; 15: 83-109.
57. Hunter J, Hirst BH. Intestinal secretion of drugs. The role of P-glycoprotein and related drug efflux systems in limiting oral drug absorption. Adv Drug Deliv Rev 1997; 25: 129-157.
58. Lennernäs H. Intestinal permeability and its relevance for absorption and elimination. Xenobiotica 2007; 37: 1015-1051.
59. Pade V, Stachansky S. 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. Pharm Res 1997; 14: 1210-1215.
60. Hu M, Borchardt RT. Mechanism of L-alpha-methyldopa transport through a monolayer of polarized human intestinal epithelial cells (Caco-2). Pharm Res 1990; 7: 1313-1319.
61. Inui K et al. Transepithelial transport of oral cephalosporins by monolayers of intestinal epithelial cell line Caco-2: specific transport systems in apical and basolateral membranes. J Pharmacol Exp Ther 1992; 261: 195-201.
62. Barthe L et al. Gastrointestinal absorption of drugs: methods and studies. Fundam Clin Pharmacol 1999; 13: 154-168.
63. Artursson P, Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem Biophys Res Commun 1991; 175: 880-885.
64. Goldberg M, Gomez-Orellana I. Challenges for the oral delivery of macromolecules. Nat Rev Drug Discov 2003; 2: 289-295.
65. Meunier V et al. The human intestinal epithelial cell line Caco-2; pharmacological and pharmacokinetic applications. Cell Biol Toxicol 1995; 11: 187-194.
66. Lennernäs H. Does fluid flow across the intestinal mucosa affect quantitative oral drug absorption? Is it time for a reevaluation? Pharm Res 1995; 12: 1573-1582.
67. Thummel KE et al. Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. Adv Drug Deliv Rev 1997; 27: 99-127.
68. Chiba M et al. Hepatic and intestinal metabolism of indinavir, an HIV protease inhibitor, in rat and human microsomes. Major role of CYP3A. Biochem Pharmacol 1997; 53: 1187-1195.
69. Fagerholm U. Prediction of human pharmacokinetics - gut-wall metabolism. J Pharm Pharmacol 2007; 59: 1335-1343.
70. Klippert P et al. 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 1982; 31: 2545-2548.
71. Chalasani N et al. Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: effects of transjugular intrahepatic portosystemic shunts. Hepatology 2001; 34: 1103-1108.
72. Yang J et al. Prediction of intestinal first-pass metabolism. Curr Drug Metab 2007; 8: 676-684.
73. Matheson PJ et al. Regulation of intestinal blood flow. J Surg Res 2000; 93: 182-196.
74. Lundgren O. Microcirculation of the gastrointestinal tract and pancreas. In: Renkin E, Michel CC, eds. Handbook of Physiology, Vol. IV, Section 2: The Cardiovascular System. Washington DC: American Physiological Society, 1984: 799-864.
75. Hultén L et al. Sympathetic nervous control of intramural blood flow in the feline and human intestines. Gastroenterology 1977; 72: 41-48.
76. Fisher JM et al. Midazolam metabolism by modified Caco-2 monolayers: effects of extracellular protein binding. J Pharmacol Exp Ther 1999; 289: 1143-1150.
77. Fisher MB, Labissiere G. The role of the intestine in drug metabolism and pharmacokinetics: an industry perspective. Curr Drug Metab 2007; 8: 694-699.
78. Hall SD et al. Molecular and physical mechanisms of first-pass extraction. Drug Metab Dispos 1999; 27: 161-166.
79. Mouly SJ et al. Contributions of CYP3A4, P-glycoprotein, and serum protein binding to the intestinal first-pass extraction of saquinavir. J Pharmacol Exp Ther 2004; 308: 941-948.
80. Paine MF et al. Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. J Pharmacol Exp Ther 1997; 283: 1552-1562.
81. Centeno F, Gutiérrez-Merino C. Location of functional centers in the microsomal cytochrome P450 system. Biochemistry 1992; 31: 8473-8481.
82. Nebert DW, Gonzales FJ. P450 genes: structure, evolution, and regulation. Annu Rev Biochem 1987; 56: 945-949.
83. Nelson DR et al. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics 2004; 14: 1-18.
84. Pavek P, Dvorak Z. Xenobiotic-induced transcriptional regulation of xenobiotic metabolizing enzymes of the cytochrome P450 superfamily in human extrahepatic tissues. Curr Drug Metab 2008; 9: 129-143.
85. Seliskar M, Rozman D. Mammalian cytochromes P450 - importance of tissue specificity. Biochim Biophys Acta 2007; 1770: 458-466.
86. Testa B, Krämer SD. The biochemistry of drug metabolism - an introduction: Part 2. Redox reactions and their enzymes. Chem Biodivers 2007; 4: 257-405.
87. Nelson DR et al. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 1996; 6: 1-42.
88. Ingelman-Sundberg M et al. 2008; The home page of the Human Cytochrome P450 (CYP) Allele Nomenclature Committee, www.cypalleles.ki.se (accessed 1 October 2008).
89. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005; 352: 2211-2221.
90. Nelson D 2008; Cytochrome P450 home page, http://drnelson. utmem.edu/CytochromeP450.html (accessed 1 October 2008).
91. Rendic S, Di Carlo FJ. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev 1997; 29: 413-580.
92. Gillette JR. The use of theoretical pharmacokinetic concepts in studies of the mechanisms of formation of chemically reactive metabolites in vitro and in vivo. Drug Metab Dispos 1983; 14: 9-33.
93. Monks TJ, Lau SS. Reactive intermediates and their toxicological significance. Toxicology 1988; 52: 1-53.
94. Chang GWM, Kam PCA. The physiological and pharmacological roles of cytochrome P450 isoenzymes. Anaesthesia 1999; 54: 42-50.
95. Lin JH, Lu AYH. Interindividual variability in inhibition and induction of cytochrome P450 enzymes. Annu Rev Pharmacol Toxicol 2001; 41: 535-567.
96. Peters WHM, Kremers PG. Cytochromes P-450 in the intestinal mucosa of man. Biochem Pharmacol 1989; 38: 1535-1538.
97. ShimadaT et al. Interindividual variations in human liver cytochrome P-450 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 1994; 270: 414-423.
98. Zhang Q et al. Characterization of human small intestinal cytochromes P-450. Drug Metab Dispos 1999; 27: 804-809.
99. Kolars JC et al. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest 1992; 90: 1871-1878.
100. Kolars JC et al. CYP3A gene expression in human gut epithelium. Pharmacogenetics 1994; 4: 247-259.
101. McKinnon RA et al. Characterization of CYP3A gene subfamily expression in human gastrointestinal tissues. Gut 1995; 36: 259-267.
102. Murray GI et al. The immunocytochemical localisation and distribution of cytochrome P-450 in normal human hepatic and extrahepatic tissues with a monoclonal antibody to human cytochrome P-450. Br J Clin Pharmacol 1988; 25: 465-475.
103. Watkins PB. The barrier function of CYP3A4 and P-glycoprotein in the small bowel. Adv Drug Deliv Rev 1997; 27:161-170.
104. Lown KS et al. Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Drug Metab Dispos 1994; 22: 947-955.
105. Galetin A, Houston JB. Intestinal and hepatic metabolic activity of five cytochrome P450 enzymes: impact on prediction of first-pass metabolism. J Pharmacol Exp Ther 2006; 318: 1220-1229.
106. Galetin A et al. Maximal inhibition of intestinal first-pass metabolism as a pragmatic indicator of intestinal contribution to the drug-drug interactions for CYP3A4 cleared drugs. Curr Drug Metab 2007; 8: 685-693.
107. Glaeser H et al. Shed human enterocytes as a tool for the study of expression and function of intestinal drug-metabolizing enzymes and transporters. Clin Pharmacol Ther 2002; 71: 131-140.
108. Watkins PB. Noninvasive tests of CYP3A enzymes. Pharmacogenetics 1994; 4: 171-184.
109. Van de Kerkhof EG et al. In vitro methods to study intestinal drug metabolism. Curr Drug Metab 2007; 8: 658-675.
110. Gibson GG et al. Receptor-dependent transcriptional activation of cytochrome P4503A genes: induction mechanisms, species differences and interindividual variation in man. Xenobiotica 2002; 32: 165-206.
111. Lamba JK et al. Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 2002; 54: 1271-1294.
112. Bièche I et al. Reverse transcriptase-PCR quantification of mRNA levels from cytochrome (CYP)1, CYP2 and CYP3 families in 22 different human tissues. Pharmacogenet Genomics 2007; 17: 731-742.
113. Lin YS et al. Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. Mol Pharmacol 2002; 62: 162-172.
114. Schmiedlin-Ren P et al. Expression of enzymatically active CYP3A4 by Caco-2 cells grown on extracellular matrix-coated permeable supports in the presence of 1alpha, 25-dihydroxyvitamin D3. Mol Pharmacol 1997; 51: 741-754.
115. Gorski JC et al. Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily. Biochem Pharmacol 1994; 47: 1643-1653.
116. Yang J et al. Cytochrome P450 3A expression and activity in the human small intestine. Clin Pharmacol Ther 2004; 76: 391.
117. Bork RW et al. Characterization of mRNA species related to human liver cytochrome P-450 nifedipine oxidase and the regulation of catalytic activity. J Biol Chem 1989; 264: 910-919.
118. Canaparo R et al. Expression of CYP3A isoforms and P-glycoprotein in human stomach, jejunum and ileum. Clin Exp Pharmacol Physiol 2007; 34: 1138-1144.
119. Kivistö KT et al. Expression of CYP3A4, CYP3A5 and CYP3A7 in human duodenal tissue. Br J Clin Pharmacol 1996; 42: 387-389.
120. Koch I et al. Interindividual variability and tissue-specificity in the expression of cytochrome P450 3A mRNA. Drug Metab Dispos 2002; 30: 1108-1114.
121. von Richter O et al. Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther 2004; 75: 172-183.
122. Berggren S et al. Gene and protein expression of P-glycoprotein, MRP1, MRP2, and CYP3A4 in the small and large human intestine. Mol Pharm 2007; 4: 252-257.
123. Thörn M et al. Cytochromes P450 and MDR1 mRNA expression along the human gastrointestinal tract. Br J Clin Pharmacol 2005; 60: 54-60.
124. Soars MG et al. In vitro analysis of human drug glucuronidation and prediction of in vivo metabolic clearance. J Pharmacol Exp Ther 2002; 301: 382-390.
125. Hirota N et al. In vitro/in vivo scaling of alprazolam metabolism by CYP3A4 and CYP3A5 in humans. Biopharm Drug Dispos 2001; 22: 53-71.
126. Labroo RB et al. Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy, and drug interactions. Drug Metab Dispos 1997; 25: 1072-1080.
127. Obach RS et al. Metabolic characterization of the major human small intestinal cytochrome P450s. Drug Metab Dispos 2001; 29: 347-352.
128. Jounaïdi Y et al. Detection of CYP3A5 allelic variant: a candidate for the polymorphic expression of the protein? Biochem Biophys Res Commun 1996; 221: 466-470.
129. Kuehl P et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001; 27: 383-391.
130. Yu K et al. Effect of the CYP3A5 genotype on the pharmacokinetics of intravenous midazolam during inhibited and induced metabolic states. Clin Pharmacol Ther 2004; 76: 104-112.
131. Gibbs MA et al. Inhibition of cytochrome P-450 3A (CYP3A) in human intestinal and liver microsomes: Comparison of KI values and impact of CYP3A5 expression. Drug Metab Dispos 1999; 27: 180-187.
132. Kaminsky LS, Zhang Q. The small intestine as a xenobioticmetabolizing organ. Drug Metab Dispos 2003; 31: 1520-1525.
133. Gervot L et al. CYP3A5 is the major cytochrome P450 3A expressed in human colon and colonic cell lines. Environ Toxicol Pharmacol 1996; 2: 381-388.
134. Niwa T et al. Comparison of kinetic parameters for drug oxidation rates and substrate inhibition potential mediated by cytochrome P450 3A4 and 3A5. Curr Drug Metab 2008; 9: 20-33.
135. Uesugi M et al. Effect of intestinal CYP3A5 on postoperative tacrolimus trough levels in living-donor liver transplant recipients. Pharmacogenet Genomics 2006; 16: 119-127.
136. Kitada M et al. Significance of cytochrome P-450 (P-450 HFLa) of human fetal livers in the steroid and drug oxidations. Biochem Pharmacol 1987; 36: 453-456.
137. Komori M et al. Fetus-specific expression of a form of cytochrome P-450 in human livers. Biochemistry 1990; 29: 4430-4433.
138. Raucy JL, Carpenter SJ. The expression of xenobioticmetabolizing cytochromes P450 in fetal tissues. J Pharmacol Toxicol Methods 1993; 29: 121-128.
139. Yaffe SJ et al. The presence of a monooxygenase system in human fetal liver microsomes. Life Sci II 1970; 9: 1189-1200.
140. Fakhoury M et al. Localization and mRNA expression of CYP3A and P-glycoprotein in human duodenum as a function of age. Drug Metab Dispos 2005; 33: 1603-1607.
141. Burk O et al. Molecular mechanisms of polymorphic CYP3A7 expression in adult human liver and intestine. J Biol Chem 2002; 277: 24280-24288.
142. Westlind A et al. Cloning and tissue distribution of a novel human cytochrome P450 of the CYP3A subfamily, CYP3A43. Biochem Biophys Res Commun 2001; 281: 1349-1355.
143. Ingelman-Sundberg M. Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms. Naunyn Schmiedebergs Arch Pharmacol 2004; 369: 89-104.
144. Goldstein JA. Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol 2001; 52: 349-355.
145. Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998; 45: 525-538.
146. Klose TS et al. Gene structure of CYP2C8 and extrahepatic distribution of the human CYP2Cs. J Biochem Mol Toxicol 1999; 13: 289-295.
147. Lasker JM et al. Characterization of CYP2C19 and CYP2C9 from human liver: respective roles in microsomal tolbutamide, S-mephenytoin, and omeprazole hydroxylations. Arch Biochem Biophys 1998; 353: 16-28.
148. Läpple F et al. Differential expression and function of CYP2C isoforms in human intestine and liver. Pharmacogenetics 2003; 13: 565-575.
149. Lindell M et al. Variable expression of CYP and Pgp genes in the human small intestine. Eur J Clin Invest 2003; 33: 493-499.
150. Yeo KR et al. Abundance of cytochrome P450 in human liver: a meta-analysis. Br J Clin Pharmacol 2004; 57: 687-688.
151. Center for Molecular Design. Cytochrome P450 knowledge base, release 2006, http://cpd.ibmh.msk.su/ (accessed 7 October 2008).
152. Ingelman-Sundberg M. Polymorphism of cytochrome P450 and xenobiotic toxicity. Toxicology 2002; 181-182: 447-452.
153. Scripture CD, Pieper JA. Clinical pharmacokinetics of fluvastatin. Clin Pharmacokinet 2001; 40: 263-281.
154. Capdevila JH et al. Cytochrome P450 and arachidonic acid bioactivation. Molecular and functional properties of the arachidonate monooxygenase. J Lipid Res 2000; 41: 163-181.
155. Enayetallah AE et al. Distribution of soluble epoxide hydrolase and of cytochrome P450 2C8, 2C9, and 2J2 in human tissues. J Histochem Cytochem 2004; 52: 447-454.
156. Schaefer WRet al. Cytochrome P450 metabolites of arachidonic acid in human placenta. Prostaglandins 1997; 54: 677-687.
157. Wu S et al. Molecular cloning and expression of CYP2J2, a human cytochrome P450 arachidonic acid epoxygenase highly expressed in heart. J Biol Chem 1996; 271: 3460-3468.
158. Zeldin DC et al. CYP2J subfamily cytochrome P450s in the gastrointestinal tract: expression, localization, and potential functional significance. Mol Pharmacol 1997; 51: 931-943.
159. Elbekai RH, El-Kadi AOS. Cytochrome P450 enzymes: central players in cardiovascular health and disease. Pharmacol Ther 2006; 112: 564-587.
160. Spiecker M et al. Risk of coronary artery disease associated with polymorphism of the cytochrome P450 epoxygenase CYP2J2. Circulation 2004; 110: 2132-2136.
161. Matsumoto S et al. Involvement of CYP2J2 on the intestinal first-pass metabolism of antihistamine drug, astemizole. Drug Metab Dispos 2002; 30: 1240-1245.
162. Matsumoto S et al. In vitro inhibition of human small intestinal and liver microsomal astemizole O-demethylation: different contribution of CYP2J2 in the small intestine and liver. Xenobiotica 2003; 33: 615-623.
163. Parikh S et al. CYP2J2 and CYP4F12 are active for the metabolism of non-sedating antihistamines: terfenadine and astemizole. Drug Metab Rev 2003; 35: 190.
164. Hashizume T et al. Involvement of CYP2J2 and CYP4F12 in the metabolism of ebastine in human intestinal microsomes. J Pharmacol Exp Ther 2002; 300: 298-304.
165. Liu K et al. Characterization of ebastine, hydroxyebastine, and carebastine metabolism by human liver microsomes and expressed cytochrome P450 enzymes: major roles for CYP2J2 and CYP3A. Drug Metab Dispos 2006; 34: 1793-1797.
166. Guengerich FP. Catalytic selectivity of human cytochrome P450 enzymes: relevance to drug metabolism and toxicity. Toxicol Lett 1994; 70: 133-138.
167. Wrighton SA et al. The human drug metabolizing cytochromes P450. J Pharmacokinet Biopharm 1996; 24: 461-473.
168. Madani S et al. Comparison of CYP2D6 content and metoprolol oxidation between microsomes isolated from human livers and small intestines. Pharm Res 1999; 16: 1199-1205.
169. Prueksaritanont T et al. (+)-bufuralol 10-hydroxylation activity in human and rhesus monkey intestine and liver. Biochem Pharmacol 1995; 50: 1521-1525.
170. Zhang Q et al. Characterization of rat small intestinal cytochrome P450 composition and inducibility. Drug Metab Dispos 1996; 24: 322-328.
171. Buchthal J et al. Induction of cytochrome P4501A by smoking or omeprazole in comparison with UDP-glucuronosyltransferase in biopsies of human duodenal mucosa. Eur J Clin Pharmacol 1995; 47: 431-435.
172. Paine MF et al. Cytochrome P-450 1A1 expression in human small bowel: interindividual variation and inhibition by ketoconazole. Drug Metab Dispos 1999; 27: 360-364.
173. Windmill KF et al. The role of xenobiotic metabolizing enzymes in arylamine toxicity and carcinogenesis: functional and localization studies. Mutat Res 1997; 376: 153-160.
174. Kashfi K et al. Comparative effects of omeprazole on xenobiotic metabolizing enzymes in the rat and human. Clin Pharmacol Ther 1995; 58: 625-630.
175. McDonnell WM et al. Induction of cytochrome P450IA genes (CYP1A) by omeprazole in the human alimentary tract. Gastroenterology 1992; 103: 1509-1516.
176. Karlgren M et al. Novel extrahepatic cytochrome P450s. Toxicol Appl Pharmacol 2005; 207: 57-61.
177. Rylander T et al. Identification and tissue distribution of the novel human cytochrome P450 2S1 (CYP2S1) Biochem Biophys Res Commun 2001; 281: 529-535.
178. Saarikoski ST et al. CYP2S1: a short review. Toxicol Appl Pharmacol 2005; 207: 62-69.
179. Hashizume T et al. cDNA cloning and expression of a novel cytochrome P450 (CYP4F12) from human small intestine. Biochem Biophys Res Commun 2001; 280: 1135-1141.
180. Hayes CL et al. 17 beta-estradiol hydroxylation catalyzed by human cytochrome P450 1B1. Proc Natl Acad Sci USA 1996; 93: 9776-9781.
181. Shimada T et al. Activation of chemically diverse procarcinogens by human cytochrome P-450 1B1. Cancer Res 1996; 56: 2679-2984.
182. Gervot L et al. Human CYP2B6: expression, inducibility and catalytic activities. Pharmacogenetics 1999; 9: 295-306.
183. Koskela S et al. Expression of CYP2A genes in human liver and extrahepatic tissues. Biochem Pharmacol 1999; 57: 1407-1413.
184. Gomez DY et al. The effects of ketoconazole on the intestinal metabolism and bioavailability of cyclosporine. Clin Pharmacol Ther 1995; 58: 15-19.
185. Bailey DG et al. Interaction of citrus juices with felodipine and nifedipine. Lancet 1991; 337: 268-269.
186. Fuhr U et al. Effects of grapefruit juice and smoking on verapamil concentrations in steady state. Eur J Clin Pharmacol 2002; 58: 45-53.
187. Benton RE et al. Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram. Clin Pharmacol Ther 1996; 59: 383-388.
188. Weber A et al. Can grapefruit juice influence ethinylestradiol bioavailability? Contraception 1996; 53: 41-47.
189. Kupferschmidt HHT et al. Interaction between grapefruit juice and midazolam in humans. Clin Pharmacol Ther 1995; 58: 20-28.
190. Eagling VA et al. Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice components. Br J Clin Pharmacol 1999; 48: 543-552.
191. Kupferschmidt HHT et al. Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man. Br J Clin Pharmacol 1998; 45: 355-359.
192. Ducharme MP et al. Trough concentrations of cyclosporine in blood following administration with grapefruit juice. Br J Clin Pharmacol 1993; 36: 457-459.
193. Ducharme MP et al. Disposition of intravenous and oral cyclosporine after administration with grapefruit juice. Clin Pharmacol Ther 1995; 57: 485-491.
194. Bailey DG et al. Grapefruit juice - drug interactions. Br J Clin Pharmacol 1998; 46: 101-110.
195. Fuhr U. Drug interactions with grapefruit juice. Extent, probable mechanism and clinical relevance. Drug Saf 1998; 18: 251-272.
196. Kane GC, Lipsky JJ. Drug-grapefruit juice interactions. Mayo Clin Proc 2000; 75: 933-942.
197. Kiani J, Imam SZ. Medicinal importance of grapefruit juice and its interaction with various drugs. Nutr J 2007; 6: 33.
198. Saito M et al. Undesirable effects of citrus juice on the pharmacokinetics of drugs: focus on recent studies. Drug Saf 2005; 28: 677-694.
199. Guengerich FP et al. Oxidation of dihydropyridine calcium channel blockers and analogues by human liver cytochrome P-450 IIIA4. J Med Chem 1991; 34: 1838-1844.
200. Floren LC et al. Sirolimus oral bioavailability increases ten-fold with concomitant ketoconazole. Clin Pharmacol Ther 1999; 65: 159.
201. Wu C et al. Differentiation of absorption and first-pass gut and hepatic metabolism in humans: studies with cyclosporine. Clin Pharmacol Ther 1995; 58: 492-497.
202. Gupta SK et al. Erythromycin enhances the absorption of cyclosporine. Br J Clin Pharmacol 1988; 25: 401-402.
203. Olkkola KT et al. A potentially hazardous interaction between erythromycin and midazolam. Clin Pharmacol Ther 1993; 53: 298-305.
204. Yeh RF et al. Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J Acquir Immune Defic Syndr 2006; 42: 52-60.
205. Ren X et al. Pharmaceutical excipients inhibit cytochrome P450 activity in cell free systems and after systemic administration. Eur J Pharm Biopharm 2008; 70: 279-288.
206. Mountfield RJ et al. Potential inhibitory effects of formulation ingredients on intestinal cytochrome P450. Int J Pharm 2000; 211: 89-92.
207. Ren X et al. Nonionic surfactants are strong inhibitors for cytochrome P450 3A biotransformation activity in vitro and in vivo. Eur J Pharm Sci 2009; 36: 401-411.
208. Johnson BM et al. An in vitro examination of the impact of polyethylene glycol 400, Pluronic P85, and vitamin E d-alphatocopheryl polyethylene glycol 1000 succinate on P-glycoprotein efflux and enterocyte-based metabolism in excised rat intestine. AAPS Pharm Sci 2002; 4: E40.
209. Thummel KE, Wilkinson GR. In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 1998; 38: 389-430.
210. Gorski JC et al. The effect of age, sex, and rifampin administration on intestinal and hepatic cytochrome P450 3A activity. Clin Pharmacol Ther 2003; 74: 275-287.
211. Niemi M et al. Pharmacokinetic interactions with rifampicin: clinical relevance. Clin Pharmacokinet 2003; 42: 819-850.
212. Glaeser H et al. Influence of rifampicin on the expression and function of human intestinal cytochrome P450 enzymes. Br J Clin Pharmacol 2005; 59: 199-206.
213. Dürr D et al. St John's Wort induces intestinal P-glycoprotein/ MDR1 and intestinal and hepatic CYP3A4. Clin Pharmacol Ther 2000; 86: 598-604.
214. Gutmann H et al. Hypericum perforatum: which constituents may induce intestinal MDR1 and CYP3A4 mRNA expression? Planta Med 2006; 72: 685-690.
215. Floyd MD et al. Genotype-phenotype associations for common CYP3A4 and CYP3A5 variants in the basal and induced metabolism of midazolam in European- and African-American men and women. Pharmacogenetics 2003; 13: 595-606.
216. Fontana RJ et al. Effects of a chargrilled meat diet on expression of CYP3A, CYP1A, and P-glycoprotein levels in healthy volunteers. Gastroenterology 1999; 117: 89-98.
217. Flockhart DA 2007; Drug interactions - cytochrome P450 system, http://medicine.iupui.edu/flockhart/ (accessed 1 October 2008).
218. Benet LZ, Cummins CL. The drug efflux-metabolism alliance: biochemical aspects. Adv Drug Deliv Rev 2001; 50: S3-S11.
219. Christians U. Transport proteins and intestinal metabolism: P-glycoprotein and cytochrome P4503A. Ther Drug Monit 2004; 26: 104-106.
220. Ito K et al. Effects of intestinal CYP3A4 and P-glycoprotein on oral drug absorption-theoretical approach. Pharm Res 1999; 16: 225-231.
221. Kivistö KT et al. Functional interaction of intestinal CYP3A4 and P-glycoprotein. Fundam Clin Pharmacol 2004; 18: 621-626.
222. Knight B et al. Deconvoluting the effects of P-glycoprotein on intestinal CYP3A: a major challenge. Curr Opin Pharmacol 2006; 6: 528-532.
223. Suzuki H, Sugiyama Y. Role of metabolic enzymes and efflux transporters in the absorption of drugs from the small intestine. Eur J Pharm Sci 2000; 12: 3-12.
224. Zhang Y, Benet LZ. The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein. Clin Pharmacokinet 2001; 40: 159-168.
225. Cordon-Cardo C et al. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 1990; 38: 1277-1287.
226. Thiebaut F et al. Cellular localization of the multidrugresistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 1987; 84: 7735-7738.
227. Benet LZ et al. Intestinal drug metabolism and antitransport processes: a potential paradigm shift in oral drug delivery. J Control Release 1996; 39: 139-143.
228. Greiner B et al. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Invest 1999; 104: 147-153.
229. Gupta S et al. Reversal of daunorubicin resistance in P388/ADR cells by itraconazole. J Clin Invest 1991; 87: 1467-1469.
230. Hofsli E, Nissen-Meyer J. Reversal of drug resistance by erythromycin: erythromycin increases the accumulation of actinomycin D and doxorubicin in multidrug-resistant cells. Int J Cancer 1989; 44: 149-154.
231. Huang L et al. Induction of P-glycoprotein and cytochrome P450 3A by HIV protease inhibitors. Drug Metab Dispos 2001; 29: 754-760.
232. Kivistö KT et al. The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions. Br J Clin Pharmacol 1995; 40: 523-530.
233. Schuetz EG et al. P-glycoprotein: a major determinant of rifampicin-inducible expression of cytochrome P4503A in mice and humans. Proc Natl Acad Sci USA 1996; 93: 4001-4005.
234. Schuetz EG et al. Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells. Mol Pharmacol 1996; 49: 311-318.
235. Wacher VJ et al. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 1995; 13: 129-134.
236. Synold TW et al. The orphan nuclear receptor SXR coordinately regulates drugmetabolismand efflux. NatMed 2001; 7: 584-590.
237. Chan LMS et al. The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. Eur J Pharm Sci 2004; 21: 25-51.
238. Fromm MF. Importance of P-glycoprotein for drug disposition in humans. Eur J Clin Invest 2003; 33: 6-9.
239. Cummins CL et al. CYP3A4-transfected Caco-2 cells as a tool for understanding biochemical absorption barriers: studies with sirolimus and midazolam. J Pharmacol Exp Ther 2003; 308: 143-155.
240. Wu C, Benet LZ. Predicting drug disposition via application of BCS: transport/absorption/ elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res 2005; 22: 11-23.
241. Drescher S et al. P-glycoprotein-mediated intestinal and biliary digoxin transport in humans. Clin Pharmacol Ther 2003; 73: 223-231.
242. Kim RB et al. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res 1999; 16: 408-414.
243. Fojo AT et al. Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci USA 1987; 84: 265-269.
244. Mouly S, Paine MF. P-glycoprotein increases from proximal to distal regions of human small intestine. Pharm Res 2003; 20: 1595-1599.
245. Lown KS et al. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther 1997; 62: 248-260.