Evidence from in vitro and in vivo studies has indicated that the constituents of herbal preparations interact with various CYP enzymes extensively, either as substrates, inhibitors and/or inducers, and it is apparent that the modulation of CYPs by herbs is complex, depending on the type of source of herb, their administration dose, regimen and route, the target organ and the species. These interactions will not be confined to the liver, but may also occur in other tissues where the CYPs are considerably expressed, in particular in the gastrointestinal site, as medicinal herbs are most often given orally. In addition, the multiple ingredients in herbs may modify the intestinal pH and motility, and inhibit and/or induce intestinal drug transporters such as P-gp, and thus change the rate and extent of concomitant drug absorption.
High throughput screening assays may represent a useful strategy for the study of herb-CYP interactions. They are capable of handling the great number of herbal constituents (e.g. a single herb usually contains dozens of constituents), and have the ability to provide in vitro inhibition data as a criterion for monitoring herb-drug metabolic interactions involving human drug metabolizing enzymes (in particular the CYPs).
In silico approaches represent a useful tool for the study of herb-CYP interactions as
demonstrated by our studies and studies by other researchers. Our established pharmacophore model could readily distinguish the most potent inhibitor if CYP1A2. Thus, this model could be used as a high throughput-screening tool to identify natural constituents of herbal preparations that inhibit CYP1A2, before undertaking in vitro determinations. This will help avoid coadministration of drugs that are extensively metabolized by CYP1A2 with herbal products that showed potent inhibitory effects on this enzyme.
Herb-CYP interactions may have important clinical and toxicological implications, and rigorous testing for possible drug interactions with widely used herbs is needed. It is perhaps time to consider herbs not as alternative medicine based on tradition and experience, but as phytotherapy, and an integrated part of modern medical treatment. Regulations on medicinal herbs would be desirable, but this would be a matter of considerable debate. However, safety (e.g. herb-drug interactions), quality and efficacy should be proved, based on an objective and appropriate standard as for modern medicines.
However, herb-drug interactions are difficult to characterize and resolve, because of the lack of comprehensive federal regulations regarding safety, efficacy, and manufacturing standards for herbal medicines. It has been proposed that herbs are appropriately labelled to alert consumers to possible interactions with other concomitantly used drugs and to recommend a consultation with their general practitioners, pharmacists, and/or other medical carers. It is time to consider herbs not as alternative medicine based on tradition and experience, but as phytotherapy, an integrated part of medical treatment (Qiu, 2007). Regulations with regard to safety (e.g. herb-drug interactions), quality and efficacy of herbs would be highly desirable. Thus, monitoring of adverse events when herbal medicines are coadministered with drugs can be systematically carried out and potential herb-drug interactions be identified. This would enable more accurate product labelling and a body of useful information on potential herb-drug interactions to medical professionals.
References
Aarnoutse RE, Kleinnijenhuis J, Koopmans PP, Touw DJ, Wieling J, Hekster YA and Burger DM (2005) Effect of low-dose ritonavir (100 mg twice daily) on the activity of cytochrome P450 2D6 in healthy volunteers. Clin Pharmacol Ther 78:664-674. Abass K, Reponen P, Turpeinen M, Jalonen J and Pelkonen O (2007) Characterization of
diuron N-demethylation by mammalian hepatic microsomes and cDNA-expressed human cytochrome P450 enzymes. Drug Metab Dispos 35:1634-1641.
Abdel-Rahman SM, Marcucci K, Boge T, Gotschall RR, Kearns GL and Leeder JS (1999) Potent inhibition of cytochrome P-450 2D6-mediated dextromethorphan
O-demethylation by terbinafine. Drug Metab Dispos 27:770-775.
Abernethy DR and Todd EL (1985) Impairment of caffeine clearance by chronic use of low-dose oestrogen-containing oral contraceptives. Eur J Clin Pharmacol
28:425-428.
Adedoyin A, Frye RF, Mauro K and Branch RA (1998) Chloroquine modulation of specific metabolizing enzymes activities - investigation with selective five drug cocktail. Br
J Clin Pharmacol 46:215-219.
Adithan C, Gerard N, Vasu S, Balakrishnan R, Shashindran CH and Krishnamoorthy R (2003) Allele and genotype frequency of CYP2C9 in Tamilnadu population. Eur J
Clin Pharmacol 59:707-709.
Agudo A, Sala N, Pera G, Capella G, Berenguer A, Garcia N, Palli D, Boeing H, Del Giudice G, Saieva C, Carneiro F, Berrino F, Sacerdote C, Tumino R, Panico S, Berglund G, Siman H, Stenling R, Hallmans G, Martinez C, Bilbao R, Barricarte A, Navarro C, Quiros JR, Allen N, Key T, Bingham S, Khaw KT, Linseisen J, Nagel G, Overvad K, Tjonneland A, Olsen A, Bueno-de-Mesquita HB, Boshuizen HC,
Peeters PH, Numans ME, Clavel-Chapelon F, Boutron-Ruault MC, Trichopoulou A, Lund E, Offerhaus J, Jenab M, Ferrari P, Norat T, Riboli E and Gonzalez CA (2006) Polymorphisms in metabolic genes related to tobacco smoke and the risk of gastric cancer in the European prospective investigation into cancer and nutrition. Cancer
Epidemiol Biomarkers Prev 15:2427-2434.
Agundez JA, Ramirez R, Hernandez M, Llerena A and Benitez J (1997) Molecular heterogeneity at the CYP2D gene locus in Nicaraguans: impact of gene-flow from Europe. Pharmacogenetics 7:337-340.
Ahmed SM, Banner NR and Dubrey SW (2001) Low cyclosporin-A level due to Saint-John's-wort in heart transplant patients. J Heart Lung Transplant 20:795. Aklillu E, Carrillo JA, Makonnen E, Hellman K, Pitarque M, Bertilsson L and
Ingelman-Sundberg M (2003) Genetic polymorphism of CYP1A2 in Ethiopians affecting induction and expression: characterization of novel haplotypes with single-nucleotide polymorphisms in intron 1. Mol Pharmacol 64:659-669.
Aklillu E, Persson I, Bertilsson L, Johansson I, Rodrigues F and Ingelman-Sundberg M (1996) Frequent distribution of ultrarapid metabolizers of debrisoquine in an ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 278:441-446.
Akutsu T, Kobayashi K, Sakurada K, Ikegaya H, Furihata T and Chiba K (2007)
Identification of human cytochrome p450 isozymes involved in diphenhydramine N-demethylation. Drug Metab Dispos 35:72-78.
Alderman J, Preskorn SH, Greenblatt DJ, Harrison W, Penenberg D, Allison J and Chung M (1997) Desipramine pharmacokinetics when coadministered with paroxetine or sertraline in extensive metabolizers. J Clin Psychopharmacol 17:284-291.
Alexanderson B, Evans DA and Sjoqvist F (1969) Steady-state plasma levels of nortriptyline in twins: influence of genetic factors and drug therapy. Br Med J
4:764-768.
Allabi AC, Gala JL, Desager JP, Heusterspreute M and Horsmans Y (2003) Genetic
polymorphisms of CYP2C9 and CYP2C19 in the Beninese and Belgian populations.
Br J Clin Pharmacol 56:653-657.
Allabi AC, Gala JL and Horsmans Y (2005) CYP2C9, CYP2C19, ABCB1 (MDR1) genetic polymorphisms and phenytoin metabolism in a Black Beninese population.
Pharmacogenet Genomics 15:779-786.
Allabi AC, Gala JL, Horsmans Y, Babaoglu MO, Bozkurt A, Heusterspreute M and Yasar U (2004) Functional impact of CYP2C9*5, CYP2C9*6, CYP2C9*8, and
CYP2C9*11 in vivo among black Africans. Clin Pharmacol Ther 76:113-118. Allen SW, Mueller L, Williams SN, Quattrochi LC and Raucy J (2001) The use of a
high-volume screening procedure to assess the effects of dietary flavonoids on human CYP1A1 expression. Drug Metab Dispos 29:1074-1079.
Allorge D, Chevalier D, Lo-Guidice JM, Cauffiez C, Suard F, Baumann P, Eap CB and Broly F (2003) Identification of a novel splice-site mutation in the CYP1A2 gene.
Br J Clin Pharmacol 56:341-344.
Almeida JC and Grimsley EW (1996) Coma from the health food store: interaction between kava and alprazolam. Ann Intern Med 125:940-941.
Alscher DM and Klotz U (2003) Drug interaction of herbal tea containing St. John's wort with cyclosporine. Transpl Int 16:543-544.
Andersson T, Bergstrand R, Cederberg C, Eriksson S, Lagerstrom PO and Skanberg I (1991) Omeprazole treatment does not affect the metabolism of caffeine.
Gastroenterology 101:943-947.
Andersson T, Holmberg J, Rohss K and Walan A (1998) Pharmacokinetics and effect on caffeine metabolism of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole. Br J Clin Pharmacol 45:369-375.
Ansede JH and Thakker DR (2004) High-throughput screening for stability and inhibitory activity of compounds toward cytochrome P450-mediated metabolism. J Pharm Sci
93:239-255.
Awni WM, Braeckman RA, Cavanaugh JH, Locke CS, Linnen PJ, Granneman GR and Dube LM (1995a) The pharmacokinetic and pharmacodynamic interactions between the 5-lipoxygenase inhibitor zileuton and the cyclo-oxygenase inhibitor naproxen in human volunteers. Clin Pharmacokinet 29 Suppl 2:112-124.
Awni WM, Braeckman RA, Locke CS, Dube LM and Granneman GR (1995b) The
influence of multiple oral doses of zileuton on the steady-state pharmacokinetics of sulfasalazine and its metabolites, sulfapyridine and N-acetylsulfapyridine. Clin
Pharmacokinet 29 Suppl 2:98-104.
Awni WM, Cavanaugh JH, Leese P, Kasier J, Cao G, Locke CS and Dube LM (1997) The pharmacokinetic and pharmacodynamic interaction between zileuton and
terfenadine. Eur J Clin Pharmacol 52:49-54.
Awni WM, Cavanaugh JH, Tzeng TB, Witt G, Granneman GR and Dube LM (1995c) Pharmacokinetic interactions between zileuton and prednisone. Clin Pharmacokinet
29 Suppl 2:105-111.
Awni WM, Hussein Z, Cavanaugh JH, Granneman GR and Dube LM (1995d) Assessment of the pharmacokinetic interaction between zileuton and digoxin in humans. Clin
Pharmacokinet 29 Suppl 2:92-97.
Awni WM, Hussein Z, Granneman GR, Patterson KJ, Dube LM and Cavanaugh JH (1995e) Pharmacodynamic and stereoselective pharmacokinetic interactions between
zileuton and warfarin in humans. Clin Pharmacokinet 29 Suppl 2:67-76.
Aynacioglu AS, Brockmoller J, Bauer S, Sachse C, Guzelbey P, Ongen Z, Nacak M and Roots I (1999) Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. Br J Clin Pharmacol
48:409-415.
Baba T, Mimura J, Gradin K, Kuroiwa A, Watanabe T, Matsuda Y, Inazawa J, Sogawa K and Fujii-Kuriyama Y (2001) Structure and expression of the Ah receptor repressor gene. J Biol Chem 276:33101-33110.
Babaoglu MO, Yasar U, Sandberg M, Eliasson E, Dahl ML, Kayaalp SO and Bozkurt A (2004) CYP2C9 genetic variants and losartan oxidation in a Turkish population. Eur
J Clin Pharmacol 60:337-342.
Bachmann K, White D, Jauregui L, Schwartz JI, Agrawal NG, Mazenko R, Larson PJ and Porras AG (2003) An evaluation of the dose-dependent inhibition of CYP1A2 by rofecoxib using theophylline as a CYP1A2 probe. J Clin Pharmacol 43:1082-1090. Back DJ, Houlgrave R, Tjia JF, Ward S and Orme ML (1991) Effect of the progestogens,
gestodene, 3-keto desogestrel, levonorgestrel, norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes. J
Backlund M, Johansson I, Mkrtchian S and Ingelman-Sundberg M (1997) Signal
transduction-mediated activation of the aryl hydrocarbon receptor in rat hepatoma H4IIE cells. J Biol Chem 272:31755-31763.
Backman JT, Granfors MT and Neuvonen PJ (2006a) Rifampicin is only a weak inducer of CYP1A2-mediated presystemic and systemic metabolism: studies with tizanidine and caffeine. Eur J Clin Pharmacol 62:451-461.
Backman JT, Karjalainen MJ, Neuvonen M, Laitila J and Neuvonen PJ (2006b) Rofecoxib is a potent inhibitor of cytochrome P450 1A2: studies with tizanidine and caffeine in healthy subjects. Br J Clin Pharmacol 62:345-357.
Backman JT, Kyrklund C, Neuvonen M and Neuvonen PJ (2002) Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin Pharmacol Ther 72:685-691. Backman JT, Maenpaa J, Belle DJ, Wrighton SA, Kivisto KT and Neuvonen PJ (2000)
Lack of correlation between in vitro and in vivo studies on the effects of tangeretin and tangerine juice on midazolam hydroxylation. Clin Pharmacol Ther 67:382-390. Bae JW, Kim HK, Kim JH, Yang SI, Kim MJ, Jang CG, Park YS and Lee SY (2005) Allele
and genotype frequencies of CYP2C9 in a Korean population. Br J Clin Pharmacol
60:418-422.
Bae SK, Cao S, Seo KA, Kim H, Kim MJ, Shon JH, Liu KH, Zhou HH and Shin JG (2008) Cytochrome P450 2B6 (CYP2B6) Catalyzes the Formation of Pharmacologically Active Sibutramine Metabolites in Human Liver Microsomes. Drug Metab Dispos. Balani SK, Xu X, Pratha V, Koss MA, Amin RD, Dufresne C, Miller RR, Arison BH, Doss
GA, Chiba M, Freeman A, Holland SD, Schwartz JI, Lasseter KC, Gertz BJ, Isenberg JI, Rogers JD, Lin JH and Baillie TA (1997) Metabolic profiles of
montelukast sodium (Singulair), a potent cysteinyl leukotriene1 receptor antagonist, in human plasma and bile. Drug Metab Dispos 25:1282-1287.
Baldwin SJ, Clarke SE and Chenery RJ (1999) Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br J Clin Pharmacol
48:424-432.
Ball SE, Ahern D, Scatina J and Kao J (1997) Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2. Br
J Clin Pharmacol 43:619-626.
Ball SE, Forrester LM, Wolf CR and Back DJ (1990) Differences in the cytochrome P-450 isoenzymes involved in the 2-hydroxylation of oestradiol and 17
alpha-ethinyloestradiol. Relative activities of rat and human liver enzymes. Biochem
J 267:221-226.
Baranczewski P, Stanczak A, Sundberg K, Svensson R, Wallin A, Jansson J, Garberg P and Postlind H (2006) Introduction to in vitro estimation of metabolic stability and drug interactions of new chemical entities in drug discovery and development.
Barbenel DM, Yusufi B, O'Shea D and Bench CJ (2000) Mania in a patient receiving testosterone replacement postorchidectomy taking St John's wort and sertraline. J
Psychopharmacol 14:84-86.
Barnhart JW (1980) The urinary excretion of dextromethorphan and three metabolites in dogs and humans. Toxicol Appl Pharmacol 55:43-48.
Barone GW, Gurley BJ, Ketel BL and Abul-Ezz SR (2001) Herbal supplements: a potential for drug interactions in transplant recipients. Transplantation 71:239-241.
Barone GW, Gurley BJ, Ketel BL, Lightfoot ML and Abul-Ezz SR (2000) Drug interaction between St. John's wort and cyclosporine. Ann Pharmacother 34:1013-1016.
Barsoum NJ, Gough AW, Sturgess JM and de la Iglesia FA (1986) Parkinson-like syndrome in nonhuman primates receiving a tetrahydropyridine derivative.
Neurotoxicology 7:119-126.
Bartoli A, Xiaodong S, Gatti G, Cipolla G, Marchiselli R and Perucca E (1996) The influence of ethnic factors and gender on CYP1A2-mediated drug disposition: a comparative study in Caucasian and Chinese subjects using phenacetin as a marker substrate. Ther Drug Monit 18:586-591.
Bauer S, Stormer E, Johne A, Kruger H, Budde K, Neumayer HH, Roots I and Mai I (2003) Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients. Br J Clin Pharmacol 55:203-211. Becquemont L, Ragueneau I, Le Bot MA, Riche C, Funck-Brentano C and Jaillon P (1997)
Influence of the CYP1A2 inhibitor fluvoxamine on tacrine pharmacokinetics in humans. Clin Pharmacol Ther 61:619-627.
Beer AM and Ostermann T (2001) [St. John's wort: interaction with cyclosporine increases risk of rejection for the kidney transplant and raises daily cost of medication]. Med
Klin (Munich) 96:480-483.
Belle DJ, Ernest CS, Sauer JM, Smith BP, Thomasson HR and Witcher JW (2002) Effect of potent CYP2D6 inhibition by paroxetine on atomoxetine pharmacokinetics. J
Clin Pharmacol 42:1219-1227.
Belliard AM, Baune B, Fakhfakh M, Hocquemiller R and Farinotti R (2003) Determination of the human cytochrome P450s involved in the metabolism of 2n-propylquinoline.
Xenobiotica 33:341-355.
Benowitz NL, Swan GE, Jacob P, 3rd, Lessov-Schlaggar CN and Tyndale RF (2006) CYP2A6 genotype and the metabolism and disposition kinetics of nicotine. Clin
Pharmacol Ther 80:457-467.
Bergonzi MC, Bilia AR, Gallori S, Guerrini D and Vincieri FF (2001) Variability in the content of the constituents of Hypericum perforatum L. and some commercial extracts. Drug Dev Ind Pharm 27:491-497.
Bernauer U, Heinrich-Hirsch B, Tonnies M, Peter-Matthias W and Gundert-Remy U (2006) Characterisation of the xenobiotic-metabolizing Cytochrome P450 expression
pattern in human lung tissue by immunochemical and activity determination.
Toxicol Lett 164:278-288.
Bertelsen KM, Venkatakrishnan K, Von Moltke LL, Obach RS and Greenblatt DJ (2003) Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine. Drug Metab Dispos 31:289-293. Bertilsson L, Carrillo JA, Dahl ML, Llerena A, Alm C, Bondesson U, Lindstrom L,
Rodriguez de la Rubia I, Ramos S and Benitez J (1994) Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test. Br J Clin Pharmacol
38:471-473.
Bertilsson L, Dahl ML, Sjoqvist F, Aberg-Wistedt A, Humble M, Johansson I, Lundqvist E and Ingelman-Sundberg M (1993) Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet 341:63.
Bidstrup TB, Bjornsdottir I, Sidelmann UG, Thomsen MS and Hansen KT (2003) CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro
biotransformation of the insulin secretagogue repaglinide. Br J Clin Pharmacol
56:305-314.
Bizub D, Wood AW and Skalka AM (1986) Mutagenesis of the Ha-ras oncogene in mouse skin tumors induced by polycyclic aromatic hydrocarbons. Proc Natl Acad Sci U S
A 83:6048-6052.
Black DJ, Kunze KL, Wienkers LC, Gidal BE, Seaton TL, McDonnell ND, Evans JS, Bauwens JE and Trager WF (1996) Warfarin-fluconazole. II. A metabolically based drug interaction: in vivo studies. Drug Metab Dispos 24:422-428.
Blaisdell J, Jorge-Nebert LF, Coulter S, Ferguson SS, Lee SJ, Chanas B, Xi T, Mohrenweiser H, Ghanayem B and Goldstein JA (2004) Discovery of new potentially defective alleles of human CYP2C9. Pharmacogenetics 14:527-537. Blumberg B, Sabbagh W, Jr., Juguilon H, Bolado J, Jr., van Meter CM, Ong ES and Evans
RM (1998) SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes
Dev 12:3195-3205.
Bock KW, Schrenk D, Forster A, Griese EU, Morike K, Brockmeier D and Eichelbaum M (1994) The influence of environmental and genetic factors on CYP2D6, CYP1A2 and UDP-glucuronosyltransferases in man using sparteine, caffeine, and
paracetamol as probes. Pharmacogenetics 4:209-218.
Boek-Dohalska L, Hodek P, Sulc M and Stiborova M (2001) alpha-Naphthoflavone acts as activator and reversible or irreversible inhibitor of rabbit microsomal CYP 3A6.
Chem Biol Interact 138:85-106.
Bon S, Hartmann K and Johanniskraut. KM (1999) Ein Enzyminduktor? Schweitzer
Apothekerzeitung 16:535-536.
Boobis AR, Sesardic D, Murray BP, Edwards RJ, Singleton AM, Rich KJ, Murray S, de la Torre R, Segura J, Pelkonen O and et al. (1990) Species variation in the response of
the cytochrome P-450-dependent monooxygenase system to inducers and inhibitors.
Xenobiotica 20:1139-1161.
Borchert P, Wislocki PG, Miller JA and Miller EC (1973) The metabolism of the naturally occurring hepatocarcinogen safrole to 1'-hydroxysafrole and the electrophilic reactivity of 1'-acetoxysafrole. Cancer Res 33:575-589.
Bort R, Gomez-Lechon MJ, Castell JV and Jover R (2004) Role of hepatocyte nuclear factor 3 gamma in the expression of human CYP2C genes. Arch Biochem Biophys
426:63-72.
Boruban MC, Yasar U, Babaoglu MO, Sencan O and Bozkurt A (2006) Tamoxifen inhibits cytochrome P450 2C9 activity in breast cancer patients. J Chemother 18:421-424. Botsch S, Gautier JC, Beaune P, Eichelbaum M and Kroemer HK (1993) Identification and
characterization of the cytochrome P450 enzymes involved in N-dealkylation of propafenone: molecular base for interaction potential and variable disposition of active metabolites. Mol Pharmacol 43:120-126.
Bourrie M, Meunier V, Berger Y and Fabre G (1996) Cytochrome p450 isoform inhibitors as a tool for the investigation of metabolic reactions catalyzed by human liver microsomes. J Pharmacol Exp Ther 277:321-332.
Brachtendorf L, Jetter A, Beckurts KT, Holscher AH and Fuhr U (2002) Cytochrome P450 enzymes contributing to demethylation of maprotiline in man. Pharmacol Toxicol
90:144-149.
Braga PC, Fossati A, Vimercati MG, Caputo R and Guffanti EE (1994) Dextrorphan and dextromethorphan: comparative antitussive effects on guinea pigs. Drugs Exp Clin
Res 20:199-203.
Branch RA, Adedoyin A, Frye RF, Wilson JW and Romkes M (2000) In vivo modulation of CYP enzymes by quinidine and rifampin. Clin Pharmacol Ther 68:401-411. Bravo-Villalta HV, Yamamoto K, Nakamura K, Baya A, Okada Y and Horiuchi R (2005)
Genetic polymorphism of CYP2C9 and CYP2C19 in a Bolivian population: an investigative and comparative study. Eur J Clin Pharmacol 61:179-184. Breidenbach T, Hoffmann MW, Becker T, Schlitt H and Klempnauer J (2000a) Drug
interaction of St John's wort with cyclosporin. Lancet 355:1912.
Breidenbach T, Kliem V, Burg M, Radermacher J, Hoffmann MW and Klempnauer J (2000b) Profound drop of cyclosporin A whole blood trough levels caused by St. John's wort (Hypericum perforatum). Transplantation 69:2229-2230.
Breinholt VM, Rasmussen SE, Brosen K and Friedberg TH (2003) In vitro metabolism of genistein and tangeretin by human and murine cytochrome P450s. Pharmacol
Toxicol 93:14-22.
Brockmoller J and Roots I (1994) Assessment of liver metabolic function - clinical implications. Clin Pharmacokinet 27:216-248.
Broly F, Libersa C, Lhermitte M and Dupuis B (1990) Inhibitory studies of mexiletine and dextromethorphan oxidation in human liver microsomes. Biochem Pharmacol
39:1045-1053.
Broly F, Marez D, Lo Guidice JM, Sabbagh N, Legrand M, Boone P and Meyer UA (1995) A nonsense mutation in the cytochrome P450 CYP2D6 gene identified in a
Caucasian with an enzyme deficiency. Hum Genet 96:601-603.
Broly F and Meyer UA (1993) Debrisoquine oxidation polymorphism: phenotypic consequences of a 3-base-pair deletion in exon 5 of the CYP2D6 gene.
Pharmacogenetics 3:123-130.
Brosen K (1995) Drug interactions and the cytochrome P450 system. The role of cytochrome P450 1A2. Clin Pharmacokinet 29 Suppl 1:20-25.
Brosen K, Skjelbo E, Rasmussen BB, Poulsen HE and Loft S (1993) Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 45:1211-1214. Brown CM, Reisfeld B and Mayeno AN (2008) Cytochromes P450: a structure-based
summary of biotransformations using representative substrates. Drug Metab Rev
40:1-100.
Brown PJ, Bedard LL, Reid KR, Petsikas D and Massey TE (2007) Analysis of CYP2A contributions to metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in human peripheral lung microsomes. Drug Metab Dispos 35:2086-2094.
Bryson HM, Fulton B and Benfield P (1996) Riluzole. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in amyotrophic lateral sclerosis. Drugs 52:549-563.
Burbach KM, Poland A and Bradfield CA (1992) Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proc Natl Acad Sci U S A
89:8185-8189.
Burian M, Grosch S, Tegeder I and Geisslinger G (2002) Validation of a new fluorogenic real-time PCR assay for detection of CYP2C9 allelic variants and CYP2C9 allelic distribution in a German population. Br J Clin Pharmacol 54:518-521.
Burk O and Wojnowski L (2004) Cytochrome P450 3A and their regulation. Naunyn
Schmiedebergs Arch Pharmacol 369:105-124.
Bussey HI, Wittkowsky AK, Hylek EM and Walker MB (2008) Genetic testing for warfarin dosing? Not yet ready for prime time. Pharmacotherapy 28:141-143. Buters JT, Shou M, Hardwick JP, Korzekwa KR and Gonzalez FJ (1995) cDNA-directed
expression of human cytochrome P450 CYP1A1 using baculovirus. Purification, dependency on NADPH-P450 oxidoreductase, and reconstitution of catalytic