Summary
Although the liver plays the major role in drug metabolism [e.g. by oxidative cytochrome P450 (CYP)-dependent phase I and conjugation or phase II reactions], drug metabolising enzymes are also present at other sites. Depending on the particular drug and enzymes involved, these extrahepatic organs and/or tissues can contribute to the elimination of drugs and, thus, should be considered in any discussion of drug disposition.
By the use of relatively new techniques in molecular biology, e.g. immunoblotting with antibodies directed to various CYP isoenzymes, the tissue and organ distribution of these drug metabolising enzymes can be determined. In addition, microsomal and cytosolic enzyme activity and capacity can be directly assessed in vitro by incubation of the enzymes with the drugs of interest. Both approaches have demonstrated the presence of 3 CYP families at different extrahepatic sites, such as the mucosa of the gastrointestinal tract, kidney, lung, brain or skin. Enzymes including epoxide hydrolases, hydrolysing enzymes, glutathione S-transferases, UDP-glucuronosyltransferases, sulphotransferases, N-acetyltransferases, and methyltransferases are discussed.
Indirect evidence of extrahepatic drug metabolism can be generated from pharmacokinetic studies whenever total body clearance exceeds liver blood flow, or when severe liver dysfunction or anhepatic conditions do not affect metabolic clearance. Indeed, extrahepatic metabolism has been demonstrated for numerous drugs. Therefore, the metabolic profile and sites of enzymatic reactions for each drug should be determined.
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References
Achari R, Hulse JD, Drissel D, Matier WL. Pharmacokinetics of flestolol in man: preliminary data. British Journal of Clinical Pharmacology 20: 691–694, 1985
Allgayer H, Ahnfelt NO, Kruis W, Klotz U, Frank-Holmberg K, et al. Colonic N-acetylation of 5-aminosalicylic acid in inflammatory bowel disease. Gastroenterology 97: 38–41, 1989
Anderson LM, Ward JM, Park SS, Rice JM. Immunohistochemical localization of cytochromes P450 with polyclonal and monoclonal antibodies. Pathology and Immunopathology Research 8: 61–94, 1989
Andersson M, Billstrom A, Domellof L, Gustavsson B. Cardiopulmonary elimination of 5-fluorouracil after bolus injection in the hepatic artery. European Journal of Surgical Oncology 13: 35–39, 1987
Ansher SS, Jakoby WB. N-Methyltransferases. In Mulder (Ed.) Conjugation reactions in drug metabolism, pp. 233–250, Taylor & Francis Ltd, London, 1990
Back DJ, Bates M, Breckenridge AM, Ellis A, Hall JM, et al. The in vitro metabolism of ethinyloestradiol, mestranol and levonorgestrel by human jejunal mucosa. British Journal of Clinical Pharmacology 11: 275–278, 1981
Back DJ, Rogers SM. Review: first-pass metabolism by the gastrointestinal mucosa. Alimentary Pharmacology and Therapeutics 1: 339–357, 1987
Barnes TS, Shaw PM, Burke MD, Melvin WT. Monoclonal antibodies against human cytochrome P450. Biochemical Society Transactions 14: 621, 1986
Beaune P, Flinois JP, Kiffel L, Kremers P, Leroux JP. Purification of a new cytochrome P450 from human liver microsomes. Biochimica Biophysica Acta 860: 364–370, 1985
Behrendt H, Korting HCh, Braun-Falco O. Zum Metabolismus von Pharmaka in der Haut. Hautarzt 40: 8–13, 1989
Bhamre V, Shankar ASK, Ravindranath V. Microsomal cytochrome P450 in human brain regions. Biochemical Pharmacology 44: 1223–1225, 1992
Bodenham A, Quinn K, Park GR. Extrahepatic morphine metabolism in man during the anhepatic phase of orthotopic liver transplantation. British Journal of Anaesthesiology 63: 380–384, 1989
Bosron WF, Li TK. Genetic polymorphism of human liver alcohol and aldehyde dehydrogenases, and their relationship to alcohol metabolism and alcoholism. Hepatology 6: 502–510, 1986
Bowen J, Spino M, Tesoro A, Pop R, Patterson A. Theophylline (theo) biotransformation by human lung microsomes. Clinical Pharmacology and Therapeutics 51: 178, 1992
Bredberg U, Eyjolfsdottir GS, Paalzow L, Tfelt-Hansen P, Tfelt-Hansen V. Pharmacokinetics of methysergide and its metabolite methylergometrine in man. European Journal of Clinical Pharmacology 30: 75–77, 1986
Burke MD, Orrenius S. Isolation and comparison of endoplasmic reticulum membranes and their mixed function oxidase activities from mammalian extrahepatic tissues. Pharmacology and Therapeutics 7: 549–599, 1979
Burman LA, Nilsson-Eble I, Hutchison M, Hawroth SJ, Norrby SR. Pharmacokinetics of meropenem and its metabolite ICI 213,689 in healthy subjects with known renal metabolism of imipenem. Journal of Antimicrobial Chemotherapy 27: 219–224, 1991
Caballeria J, Frezza M, Hernández-Muñoz, Di Padova C, Korsten Ma, et al. Gastric origin of the first-pass metabolism of ethanol in humans: effect of gastrectomy. Gastroenterology 97: 1205–1209, 1989
Cappiello M, Franchi M, Giuliani L, Pacifici GM. Distribution of 2-naphthol sulphotransferase and its endogenous substrate adenosine 3′-phosphate 5′-phosphosulphate in human tissues. European Journal of Clinical Pharmacology 37: 317–320, 1989
Cappiello M, Giuliani L, Pacifici GM. Distribution of UDP-glucuronosyltransferase and its endogenous substrate uridine 5′-diphosphoglucuronic acid in human tissues. European Journal of Clinical Pharmacology 41: 345–350, 1991
Cheng YF, Lundberg T, Bondesson U, Lindstrom L, Gabrielsson J. Clinical pharmacokinetics of clozapine in chronic schizophrenic patients. European Journal of Clinical Pharmacology 34: 445–449, 1988
Cheung YW, Liwan PoA, Irwin WJ. Cutaneous biotransformation as parameter in the modulation of the activity of topical corticosteroids. International Journal of Pharmaceutics 26: 175–189, 1985
Cohen GM, Flockhart IR. The partial purification and properties of a human erythrocyte 4-nitroacetophenone reductase. Xenobiotica 5: 213–222, 1975
Collins JM, Dedrick RL, King FG, Speyer JL, Myers CE. Nonlinear pharmacokinetic models for 5-fluorouracil in man: intravenous and intraperitoneal routes. Clinical Pharmacology and Therapeutics 28: 235–246, 1980
Conolly ME, Davies DS, Dollery CT, Morgan CD, Paterson JW, et al. Metabolism of isoprenaline in dog and man. British Journal of Pharmacology 46: 458–472, 1972
Dahl-Puustinen M-L, Dumont E, Bertilsson L. Glucuronidation of E-10-hydroxynortriptyline in human liver, kidney, and intestine. Drug Metabolism and Disposition 17: 433–436, 1989
Dahm K, Breuer H. Characterisierung und Kinetik einer mikrosomalen UDP-Glukuronat-Testeron-Glukuronyltransferase beim Menschen. Hoppe-Seyler’s Physiological Chemistry 345: 139–149, 1966
Dawson I, Pryse-Davies J. The distribution of certain enzymes in the normal human gastrointestinal tract. Gastroenterology 44: 745–760, 1963
De Waziers I, Cugnenc PH, Yang CS, Leroux JP, Beaune PH. Cytochrome P450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues. Journal of Pharmacology and Experimental Therapeutics 253: 387–394, 1990
Diasio RB, Harris BE. Clinical pharmacology of 5-fluorouracil. Clinical Pharmacokinetics 16: 215–237, 1989
Di Padova C, Worner TM, Julkunen R, Lieber CS. Effects of fasting and chronic alcohol consumption on the first-pass metabolism of ethanol. Gastroenterology 92: 1169–1173, 1987
Dodgson K, Spencer B, Wynn CH. Studies on sulfatases: 12. The arylsulfatases of human tissues. Biochemical Journal 62: 500–507, 1956
Dogra S, Isaac PA, Cockshott IDV, Foy JM. Pulmonary extraction of propofol in post-cardiopulmonary by-pass patients. Journal of Drug Development 2 (Suppl. 2): 133, 1989
Eyles DW, Pond SM. Stereospecific reduction of haloperidol in human tissues. Biochemical Pharmacology 44: 867–871, 1992
Flinois J-P, Chabin M, Egros F, Dufour A, de Waziers I, et al. Metabolism rate of oxodipine in rats and humans: comparison of in vivo and in vitro data. Journal of Pharmacology and Experimental Therapeutics 261: 381–386, 1992
Floch MH, van Noorden S, Spiro HM. Histochemical localisation of gastric and small bowel mucosal enzymes of man, monkey and chimpanzee. Gastroenterology 52: 230–238, 1967
Geddes DM, Nesbitt K, Trail T, Blackburn JP. First-pass uptake of 14C propranolol by the lung. Thorax 34: 810–813, 1979
George CF. Drug metabolism by the gastrointestinal mucosa. Clinical Pharmacokinetics 6: 259–274, 1981
Gibby EM, Cohen GM. Conjugation of 1-naphthol by human bronchus and bronchoscopy samples 33: 739–743, 1984
Gonzalez FJ. Human cytochromes P450: problems and prospects. Trends in Pharmacological Sciences 13: 346–352, 1992
Gram TE, Okine LK, Gram RA. The metabolism of xenobiotics by certain extrahepatic organs and its relation to toxicity. Annals of Reviews in Pharmacology and Toxicology 26: 259–292, 1986
Gray PA, Park GR, Cockshott ID, Douglas EJ, Shuker B, et al. Propofol metabolism in man during the anhepatic and reperfusion phases of liver transplantation. Xenobiotica 22: 105–114, 1992
Guengerich FP. Human cytochrome P450 enzymes. Life Sciences: 50, 1471–1478, 1992
Guengerich FP, Dannan GA, Wright ST, Martin MV, Kaminsky LS. Purification and characterisation of liver microsomal cytochromes P450: electrophoretic, spectral, catalytic and immunochemical properties and inducibility of eight isoenzymes isolated from rats treated with phenobarbital or β-naphthol flavone. Biochemistry 21: 6019–6030, 1982
Guenthner TM. Epoxide hydrolases. In Mulder (Ed.) Conjugation reactions in drug metabolism, pp. 365–404, Taylor & Francis Ltd, London, 1990
Hartiala K. Metabolism of hormones, drugs and other substances by the gut. Physiology Reviews 53: 496–534, 1973
Haustein KO, Pachaly C, Megges R, Franke P. Investigation into the species specific deacylation of pentaacetyl-gitoxin. European Journal of Clinical Pharmacology 14: 425–430, 1978
Herman RJ, Van-Pham JD, Szakacs CB. Disposition of lorazepam in human beings: enterohepatic recirculation and first-pass effect. 46: 18–25, 1989
Hoensch HP, Schwenck M. Intestinal absorption and metabolism of xenobiotics in humans. In Schiller (Ed.) Intestinal toxicology, pp. 169–192, Raven Press, New York, 1984
Hoensch HP, Steinhardt HJ, Weiss G, Hang D, Maeir A, et al. Effects of semisynthetic diets on xenobiotic metabolising enzyme activity and morphology of small intestinal mucosa in humans. Gastroenterology 86: 1519–1530, 1984
Howe JL, Back DJ, Colbert J. Extrahepatic metabolism of zidovidine. British Journal of Clinical Pharmacology 33: 190–192, 1992
Hsia SL, Hao YL. Metabolic transformations of cortisol-4-14C in human skin. Biochemistry 5: 1469–1474, 1966
Hutt AJ, Caldwell J. Aminoacid conjugation In Mulder (ED.) Conjugation reactions in drug metabolism, pp. 273–305, Taylor & Francis Ltd, London, 1990
Ibraheem JJ, Paalzow L, Tfelt-Hansen P. Linear pharmacokinetics of intravenous ergotamine tartrate. European Journal of Clinical Pharmacology 29: 61–66, 1985
Ilett KF, Tee LBG, Reeves PT, Minchin RF. Metabolism of drugs and other xenobiotics in the gut lumen and wall. Pharmacology and Therapeutics 46: 67–93, 1990
Inaba T, Mahon WA, Stone RM. Phenacetin concentrations in portal and hepatic venous blood in man. International Journal of Clinical Pharmacology and Biopharmacy 17: 371–374, 1979
Ings RM, Nudemberg F, Burrows JL, Bryce TA. The pharmacokinetics of oxypentifylline in man when administered by constant intravenous infusion. European Journal of Clinical Pharmacology 23: 539–543, 1982
Inoue M, Morikawa M, Tsuboi M, Ito Y, Sugiura M. Comparative study of human intestinal and hepatic esterases as related to enzymatic properties and hydrolysing activity for ester-type drugs. Japanese Journal of Pharmacology 30: 529–535, 1980
Jansen PL, Mulder GJ, Burchell B, Bock KW. New developments in glucuronidation research: report of a workshop on ‘Glucuronidation, its role in healthy and disease’. Hepatology 15: 532–544, 1992
Jeffrey DJ, Jones KH, Langley PF. The metabolism of talampicillin in rat, dog and man. Xenobiotica 8: 419–427, 1978
Jenne JW. Isoniazid acetylation by human liver and intestinal mucosa. Abstract. Federal Proceedings 22: 540, 1963
Jorfeldt L, Lewis DH, Lofstrom JB, Post C. Lung uptake of lidocaine in healthy volunteers. Acta Anaesthesiologica Scandinavica 23: 567–584, 1979
Jorfeldt L, Lewis DH, Lofstrom JB, Post C. Lung uptake of lidocaine in man as influenced by anaesthesia, mepivacaine infusion or lung insufficiency. Acta Anaesthesiologica Scandinavica 27: 5–9, 1983
Julkuneu RJK, Dipadova C, Lieber CS. First pass metabolism of ethanol — a gastrointestinal barrier against the systemic toxicity of ethanol. Life Sciences 37: 567–573, 1985
Junod AF. Uptake, release and metabolism drugs in the lungs. Pharmacology and Therapeutics 32: 511–521, 1976
Kanto J, Gepts E. Pharmacokinetic implications for the clinical use of propofol. Clinical Pharmacokinetics 17: 308–326, 1989
Kao J, Carver MP. Cutaneous metabolism of xenobiotics. Drug Metabolism Reviews 22: 363–410, 1990
Ketterer B, Mulder GJ. Glutathione conjugation. In Mulder (Ed.) Conjugation reactions in drug metabolism, pp. 307–331, Taylor & Francis Ltd, London, 1990
Kolars JC, Awni WM, Merion RM, Watkins PB. First-pass metabolism of cyclosporin in the gut. Lancet 338: 1488–1490, 1991
Kolars JC, Schmiedlin-Ren P, Schuetz JD, Fang C, Watkins PB. Identification of rifampin-inducible P 450 III A4 (CYP 3A4) in human small bowel enterocytes. Journal of Clinical Investigations 90: 1871–1878, 1992
Kremers P, Beaune P, Cresteil T, De Grave J, Columelli S, et al. Cytochrome P450 monooxygenase activity in human and rat liver microsomes. European Journal of Biological Chemistry 118: 599–606, 1981
Kroemer H, Klotz U. Glucuronidation of drugs: a re-evaluation of the pharmacological significance of the conjugates and modulating factors. Clinical Pharmacokinetics 23: 292–310, 1992
Laemmli UK. Cleavage of structural properties during the assembly of the head of bacteriophage T4. Nature 227: 680–685, 1970
Leinweber F-J. Possible physiological roles of carboxylic ester hydrolases. Drug Metabolism Reviews 18: 379–439, 1987
Lockridge O. Genetic variants of human serum butyrylcholinesterase influence the metabolism of the muscle relaxant succinylcholine. In Kalow (Ed.) Pharmacogenetics in drug metabolism, pp. 15–50, Pergamon Press, New York, Oxford, 1992
Ludden TM, McNay Jr JL, Shepherd AMM, Lin MS. Clinical pharmacokinetics of hydralazine. Clinical Pharmacokinetics 7: 185–205, 1982
Lund B, Kampmann JP, Lindahl F, Molholm Hansen J. Pivampicillin and ampicillin in bile, portal and peripheral blood. Clinical Pharmacology and Therapeutics 19: 587–591, 1976
Mahon WA, Inaba T, Stone RM. Metabolism of flurazepam by the small intestine. Clinical Pharmacology and Therapeutics 22: 228–233, 1977
Mazoit JX, Sandouk P, Scherrmann JM, Roche A. Extrahepatic metabolism of morphine occurs in humans. Clinical Pharmacology and Therapeutics 48: 613–618, 1990
McDonnell WM, Scheiman JM, Traber PG. Induction of cytochrome P450 IA genes (CYP1A) by omeprazole in the human alimentary tract. Gastroenterology 103: 1509–1516, 1992
McManus ME, Boobis AR, Pacifici GM, Frempong RY, Brodie MJ, et al. Xenobiotic metabolism in the human lung. Life Sciences 26: 481–487, 1980
Moreno A, Parés X. Purification and characterization of a new alcohol dehydrogenase from human stomach. Journal of Biological Chemistry 266: 1128–1133, 1991
Morrison RA, Wiegand UW, Jähnchen E, Hohmann D, Bechtold H, et al. Isosorbide dinitrate kinetics and dynamics after intravenous, sublingual and percutaneous dosing in angina. Clinical Pharmacology and Therapeutics 33: 747–756, 1983
Mulder GJ, Coughtrie MWH, Burchell B. Glucuronidation. In Mulder (Ed.) Conjugation reactions in drug metabolism, pp. 51–105, Taylor & Francis Ltd, London, 1990
Murray GI, Barnes TS, Sewell HF, Ewen SWB, Melvin WT, et al. The immunocytochemical localisation and distribution of cytochrome P450 in normal hepatic and extrahepatic tissues with a monoclonal antibody to human cytochrome P450. British Journal of Clinical Pharmacology 25: 465–475, 1988
Murray M. P450 enzymes: inhibition mechanism, genetic regulation and effects of liver disease. Clinical Pharmacokinetics 23: 132–146, 1992
Mützel W. Pharmakokinetik und Biotransformation von Flucortinbutylester beim Menschen. Arzneimittel-Forschung 27: 2230–2233, 1977
Norrby SR, Björnegard B, Ferber F, Jones KH. Pharmacokinetics of imipenem in healthy volunteers. Journal of Antimicrobial Chemotherapy 12 (Suppl. D): 109–124, 1983
Norrby SR, Rogers JD, Ferber F, Jones KH, Zacchei AG, et al. Disposition of radiolabelled imipenem and cilastatin in normal human volunteers. Antimicrobial Chemotherapy 26: 707–714, 1984
Pacifici GM, Franchi M, Bencini C, Repetti F, Di Lascio N, et al. Tissue distribution of drug metabolising enzymes in humans. Xenobiotica 18: 849–856, 1988a
Pacifici GM, Franchi M, Gervasi PG, Longo V, Disimplicio P, et al. Profile of drug-metabolizing enzymes in human ileum and colon. Pharmacology 38: 137–145, 1989
Pacifici GM, Rane A. Metabolism of styrene oxide in different human fetal tissues. Drug Metabolism and Disposition 10: 302–305, 1982
Pacifici GM, Rane A. Profile of drug metabolising enzymes in the nuclei and microsomes of hepatic and extrahepatic tissues from monkeys. In Rystrom et al. (Eds) Extrahepatic drug metabolism & chemical carcinogenesis, pp. 33–37, Elsevier Science Publications, Amsterdam, 1983
Pacifici GM, Temellini A, Giuliani L, Rane A, Thomas H, et al. Cytosolic epoxide hydrolase in humans: development and tissue distribution. Archives in Toxicology 62: 254–257, 1988b
Patwardhan RV, Johnson RF, Hoyumpa Jr A, Sheehan JJ, Desmond PV. Normal metabolism of morphine in cirrhosis. Gastroenterology 81: 1006–1011, 1981
Peters WHM. Purification and partial characterisation of human intestinal glutathione S-transferases. Biochemical Pharmacology 38: 1535–1538, 1988
Peters WHM, Jansen PLM. Immunocharacterisation of UDP-glucuronyltransferase isoenzymes in human liver, intestine and kidney. Biochemical Pharmacology 37: 564–567, 1988
Peters WHM, Kock L, Nagengast FM, Kremer PG. Biotransformation enzymes in human intestine: critical low levels in the colon? Gut 32: 408–412, 1991
Peters WHM, Kremers PG. Cytochromes P450 in the intestinal mucosa of man. Biochemical Pharmacology 38: 1535–1538, 1989
Piper DW, Fenton BH. β-Glucuronidase of gastric mucosal and carcinomatous origin. Clinica Chimica Acta 24: 215–219, 1969
Platzer R, Reutemann G, Galeazzi RL. Pharmacokinetics of intravenous isosorbide-dinitrate. Journal of Pharmacokinetics and Biopharmaceutics 10: 575–586, 1982
Rames A, Poirier JM, Le Coz F, Midavaine M, Lecocq B, et al. Pharmacokinetics of intravenous and oral pentoxifylline in healthy volunteers and in cirrhotic patients. Clinical Pharmacology and Therapeutics 47: 354–359, 1990
Ravindranath V, Anandathirthavarada HK, Shankar SK. Xenobiotic metabolism in human brain — presence of cytochrome P450 and associated monooxygenases. Brain Research 496: 331–335, 1989
Rivett AJ, Eddy BJ, Roth JA. Contribution of sulfate conjugation, deamination and O-methylation to metabolism of dopamine and norepinephrine in human brain. Journal of Neurochemistry 39: 1009–1016, 1982
Roerig DL, Kotrly KJ, Vucins EJ, Ahlf SB, Dawson CA, et al. First-pass uptake of fentanyl, meperidine and morphine in human lung. Anaesthesiology 67: 466–472, 1987
Rogers SM, Back DJ, Orme ML’E. Intestinal metabolism of ethinyloestradiol and paracetamol in vitro: studies using Ussing chambers. British Journal of Clinical Pharmacology 23: 727–734, 1987
Roine RP, Salmela KS, Höök-Nikanne J, Kosunen TU, Salaspuro M. Alcohol dehydrogenase mediated acetaldehyde production by Helicobacter pylori — a possible mechanism behind gastric injury. Life Sciences 51: 1333–1337, 1992
Romiti P, Giuliani L, Pacifici GM. Interindividual variability in the N-sulphation of desipramine in human liver and platelets. British Journal of Clinical Pharmacology 33: 17–23, 1992
Rowland M, Riegelman S, Harris PA, Sholkoff SD, Eyring EJ. Kinetics and acetylsalicylic acid disposition in man. Nature 215: 413–414, 1987
Schwenk M, Locher M. 1-Naphthol conjugation in isolated cells from liver, jejunum, ileum, colon and kidney of the guinea pig. Biochemical Pharmacology 34: 697–701, 1985
Speyer JL, Sugarbaker PH, Collins JM, Dedrick RL, Klecker Jr RW, et al. Portal levels and hepatic clearance of 5-fluorouracil after intraperitoneal administration in humans. Cancer Research 41: 1916–1922, 1981
Stevens JL, Bakke JE. S-Methylation. In Mulder (Ed.) Conjugation reactions in drug metabolism, pp. 251–272, Taylor & Francis Ltd, London, 1990
Sundaram RS, van Loon JA, Tucker R, Weinshilbaum RM. Sulfation pharmacogenetics: correlation of human platelet and small intestinal phenol sulfotransferases. Clinical Pharmacology and Therapeutics 46: 501–509, 1989
Takker DR, Creveling CR. O-methylation. In Mulder (Ed.) Conjugation reactions in drug metabolism, pp. 193–232, Taylor & Francis Ltd, London, 1990
Täuber V, Toda T. Biotransformation von Diflucortolonvalerianat in der Haut von Ratte, Meerschweinchen und Mensch. Arzneimittel-Forschung 26: 1484–1487, 1976
Traber PJ, Chianale JC, Florence R, Kim K, Woje KE, et al. Expression of cytochrome P450 b and P450 c genes in small intestinal mucosa of rats following treatment with phenobarbital, polyhalogenated biphenyls and organochlorine pesticides. Journal of Biological Chemistry 263: 9449–9455, 1988
Utne HE, Winkler K. Hepatic and extrahepatic elimination of ethanol in cirrhosis. With estimates of intrahepatic shunts and Km for ethanol elimination. Scandinavian Journal of Gastroenterology 15: 297–304, 1980
Vickers AEM, Fischer V, Connors S, Fisher RL, Baldeck J-P, et al. Cyclosporin A metabolism in human liver, kidney, and intestine slices. Drug Metabolism and Disposition 20: 802–809, 1992
Vincenzini MT, Favilli F, Stio M, Iantomasi T. Intestinal glutathione transport system: a possible detoxification role. Biochimica et Biophysica Acta 1073: 571–579, 1991
Vöhringer H-F, Wogenstein H-M, Rietbrock N. Die biologische Verfögbarkeit von Digitoxin. Fortschritte der Medizin 95: 2323–2331, 1977
Walle UK, Pesola GR, Walle T. Stereoselective sulphate conjugation of salbutamol in humans: comparison of hepatic, intestinal and platelet activity. British Journal of Clinical Pharmacology 35: 413–418, 1993
Watkins PB. The cytochromes P450. Gastroenterology International 3: 184–188, 1990
Watkins PB, Wrighton SA, Schuetz EG, Molowa DT, Guzelian PS. Identification of glucocorticoid cytochrome P450 in the intestinal mucosa of rats and man. Journal of Clinical Investigation 80: 1029–1036, 1987
Weinshilboum RM. Sulfate conjugation of neurotransmitters, drugs. Federal Proceedings 45: 2220–2222, 1986
Weinshilboum R. Pharmacogenetics of methylation: relationship to drug metabolism. Clinical Biochemistry 21: 201–210, 1988
Weinshilboum R. Methyltransferase pharmacogenetics. In Kalow (Ed.) Pharmacogenetics of drug metabolism, pp. 179–194, Pergamon Press, New York, 1992
Weinstein GD, Frost P, Hsia SL. In vitro interconversion of estrone and 17-ß-estradiol in human skin and vaginal mucosa. Journal of Investigative Rheumatology 51: 4–10, 1968
Yu CD, Fox JL, Ho NFH, Higuchi WI. Physical model evaluation of topical prodrug deliver. Simultaneous transport and bioconversion of vidarabine 5′-valerate IV: distribution of esterase and deaminase enzymes in hairless mouse skin. Journal of Pharmaceutical Sciences 69: 772–775, 1980
Yu PH, Rozdilsky B, Boulton AA. Sulfate conjugation of monoamines in human brain. Purification and some properties of an arylamine sulfotransferase from cerebral cortex. Journal of Neurochemistry 45: 836–843, 198
Yue Q, Odar-Cederlöf I, Svensson J-O, Säwe J. Glucuronidation of morphine in human kidney microsomes. Pharmacology and Toxicology 63: 337–341, 1988
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Krishna, D.R., Klotz, U. Extrahepatic Metabolism of Drugs in Humans. Clin. Pharmacokinet. 26, 144–160 (1994). https://doi.org/10.2165/00003088-199426020-00007
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DOI: https://doi.org/10.2165/00003088-199426020-00007