研究背景：
由於藥物和食物常被人們同時服用，因此研究藥物與食品間之交互作用是一個很重要的課題。近幾年來有許多研究明確指出葡萄柚汁會抑制cytochrome P450 3A (CYP450 3A)的活性，而增加經由CYP3A代謝之藥物的生體可用率。其它文獻也證明了果汁和藥品間存在的交互作用，蔓越莓汁和CYP2C9的受質warfarin間的交互作用就是一個例子。蔓越莓目前在台灣市場上已非常普遍，很多臨床研究也證實對人類健康有所助益，最主要的功能就是預防泌尿系統感染。

研究目的：
由於tadalafil為一具選擇性的磷酸雙水解酶第五型(phosphodiesterase type 5, PDE5)抑制劑，用來治療男性性功能勃起障礙，其主要經由CYP3A代謝而排出體外，因此，本研究主要是探討蔓越莓汁在tadalafil代謝上的影響，進一步了解蔓越莓汁對於CYP3A活性的抑制作用。

研究方法：
利用高效液相層析定量方法，視分析樣品來源不同而調整移動相之梯度比例，將tadalafil及其代謝物達到良好的分離；以體外大白鼠肝臟微粒體研究蔓越莓汁對於tadalafil代謝上抑制CYP3A的作用；也藉由大白鼠活體來研究蔓越莓汁與tadalafil在藥物動力學上的交互作用。

研究結果：
結果顯示蔓越莓汁對於CYP3A酵素活性呈現不可逆性的抑制作用，而且隨著蔓越莓汁劑量的增加及預培養時間的延長，抑制CYP3A活性程度也隨之增加，表示蔓越莓汁中含有不可逆性的抑制成分。除此之外，當口服2mL蔓越莓汁30分鐘後，再口服10mg/kg tadalafil會增加血中濃度曲線下面積(area under the concentration-time curve, AUC)，為控制組的1.6倍。然而，蔓越莓汁對靜脈注射投予tadalafil在排除半衰期（elimination half-life, T1/2）及血中濃度曲線下面積並沒有影響。

研究結論：
體外試驗證實蔓越莓汁的確會抑制大白鼠肝臟中CYP3A的活性，此外，在大白鼠體內抑制腸道代謝功能卻不影響tadalafil在肝臟中的代謝，因而增加了tadalafil藥品的暴露。

Introduction. Since food and drugs are taken together frequently, it is important to investigate the food-drug interactions. Recent studies revealed that grapefruit juice inhibited the catalytic activity of CYP3A and resulted in an increase in the oral bioavailability of the drugs that are metabolized by CYP3A. Other fruit juice-drug interactions have also been documented, for example the interaction of cranberries with the CYP2C9 substrate warfarin. Cranberry is popular in markets in Taiwan, and it has been used in for a wide variety of therapeutic purposes, including the reduction of the recurrence of urinary tract infection.

Purpose. In this study, the effect of cranberry juice on the metabolism of tadalafil, an oral selective phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction and a CYP3A substrate, was investigated to explore the inhibitory effect of cranberry juice on CYP3A activity.

Methods. The concentrations of tadalafil and its metabolites in biological matrices were measured by reverse-phase HPLC methods using gradient or isocratic elution mode. The inhibitory effect of cranberry juice on the in vitro CYP3A-mediated metabolism of tadalafil was investigated using rat liver microsomes. The in vivo pharmacokinetic interaction of cranberry juice with tadalafil was examined in rats.

Results. Cranberry juice displayed non-competitive type of inhibition on in vitro CYP3A activity. The extent of inhibition depended on the amount of juice added, and it increased as the pre-incubation time increased, indicating that cranberry juice contains a mechanism-based inhibitor. In comparison with water, the area under the concentration-time curve（AUC）of tadalafil was approximately 1.6-fold higher when cranberry juice（2ml）was taken orally 30 min before the oral administration of tadalafil（10mg/kg）in rats. In contrast, the elimination half-life and AUC of tadalafil administered intravenously were not altered by the administration of cranberry juice.

Conclusions. Cranberry juice demonstrates significant inhibition of rat CYP3A activity in vitro. Furthermore, cranberry juice impairs the function of enteric but not hepatic metabolism of tadalafil in rats, thereby enhancing the systemic exposure of tadalafil.

Allison RD and Purich DL. Practical considerations in the design of initial velocity enzyme rate assays. Methods Enzymol 63:3-22, 1979.

Aoyama T, Yamano S, Waxman DJ et al. Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine. J Biol Chem 264:10388-95, 1989.

Bailey DG, Dresser GK. Interactions between grapefruit juice and cardiovascular drugs. Am J Cardiovasc Drugs 4:281-97, 2004.

Cheng CL, Chou CH. Determination of tadalafil in small volumes of plasma by high-performance liquid chromatography with UV detection. J Chromatogr B 822:278-84, 2005.

Cholerton S, Daly AK, Idle JR et al. The role of individual human cytochrome P450 in drug metabolism and clinical response. Trends Pharmacol Sci 13:434-9, 1992.

Cotreau MM, von Moltke LL, Beinfeld MC et al. Methodologies to study the induction of rat hepatic and intestinal cytochrome P450 3A at the mRNA, protein, and catalytic activity level. J Pharmacol Toxicol Methods 43:41-54, 2000.

Curran MP, Keating GM. Tadalafil. Drugs 63:2203-12, 2003.

De Castro WV, Mertens-Talcott S, Rubner A et al. Variation of flavonoids and furanocoumarins in grapefruit juices: a potential source of variability in grapefruit juice-drug interaction studies. J Agric Food Chem 54:249-55, 2006.

Domanski TL, Finta C, Halpert JR et al. cDNA cloning and initial characterization of CYP3A43, a novel human cytochrome P450. Mol Pharmacol 59:386-92, 2001.

Dresser GK, Bailey DG, Leake BF et al. Fruit juices inhibit organic anion transporting polypeptide-mediated uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther 71:11-20, 2002.
Endres CJ, Hsiao P, Chung FS et al. The role of transporters in drug interactions. Eur J Pharm Sci 27:501-17, 2006.

Foo LT, Lu Y, Howell AB et al. The structure of cranberry proanthocyanikins which inhibit adherence of uropathogenic P-fimbriated Escherichia coli in vitro. Phytochemistry 54:173-81, 2000.

Forgue ST, Patterson BE, Bedding AW et al. Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol 63:280-8, 2005.

Fujita KI, Hidaka M, Takamura N et al. Inhibitory effects of citrus fruits on cytochrome P450 3A (CYP3A) activity in humans. Biol Pharm Bull 26:1371-3, 2003.

Gellner K, Eiselt R, Hustert E et al. Genomic organization of the human CYP3A locus: indentification of a new, inducible CYP3A gene. Pharmacogenetics 11:111-21, 2001.

Gorski JC, Huang SM, Zaheer N et al. The effect of Echinacea on CYP3A activity in vivo. Clin Pharmacol Ther 73:8, 2003.

Greenblatt DJ, von Moltke LL, Perloff ES et al. Interaction of flurbiprofen with cranberry juice, grape juice, tea, and fluconazole: In vitro and clinical studies. Clin Pharmacol Ther 79:125-33, 2006.

Grenier J, Fradette C, Morelli G et al. Pomelo juice, but not cranberry juice, affects the pharmacokinetics of cyclosporine in humans. Clin Pharmacol Ther 79:255-62, 2006.

Gupta M, Kovar A, Meibohm B et al. The clinical pharmacokinetics of phosphodiesterase-5 inhibitors for erectile dysfunction. J Clin Pharmacol 45:987-1003, 2005.

Hakkinen S, Heinonen M, Karenlampi S et al. Screening of selected flavonoids and phenolic acids in 19 berries. Food Res Intern 32:345-53, 1999.

Harkins KJ. What’s the use of cranberry juice? Age and Ageing 29:9-12, 2000.

Henig YS, Leahy MM. Cranberry juice and urinary-tract health: Science support folklore. Nutrition 16:684-7, 2000.

Hidaka M, Fujita KI, Ogikubo T et al. Short communication: Potent inhibition by star fruit of human cytochrome P450 3A (CYP3A) activity. Drug Metab Dispos 32:581-3, 2004.

Hidaka M, Okumura M, Fujita KI et al. Effects of pomegranate juice on human cytochrome P450 3A (CYP3A) and carbamazepine pharmacokinetics in rats. Drug Metab Dispos 33:644-48, 2005.

Hidaka M, Okumura M, Ogikubo T et al. Short communication: Transient inhibition of CYP3A in rats by star fruit juice. Drug Metab Dispos 34:343-45, 2006.

Howell AB, Reed JD, Krueger CG et al. A-type cranberry proanthocyanidins and uropathogenic bacterial anti-adhesion activity. Phytochemistry 66:2281-91, 2005.

Huang SM, Lesko LJ. Drug-drug, drug-dietary supplement, and drug-citrus fruit and other food interactions: what have we learned?. J Clin Pharmacol 44:559-69, 2004.

Jetter A, Kinzig-Schippers M, Walchner-Bonjean M et al. Effects of grapefruit juice on the pharmacokinetics of sildenafil. Clin Pharmacol Ther 71:21-9, 2002.

Kato R, Yamazoe Y. Sex-specific cytochrome P450 as a cause of sex- and species-related differences in drug toxicity. Toxicol Lett 64-65:661-7, 1992.

Kaufman DW, Kelly JP, Rosenberg L et al. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 287:337-344, 2002.

Kolars JC, Schmiedlin-Ren P, Schuetz JD et al. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest 90:1871-8, 1992.

Komori M, Oda Y. A major glucocorticoid-inducible P450 in rat liver is not P450 3A1. J Biochem (Tokyo) 116:114-20, 1994.

Lacroix D, Sonnier M, Moncion A et al. Expression of CYP3A in the human liver--evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. Eur J Biochem 247:625-34, 1997.

Lindstrom TD, Hanssen BR, Wrighton SA et al. Cytochrome P-450 complex formation by dirithromycin and other macrolides in rat and human livers. Antimicrob Agents Chemother 37:265-9, 1993.

Lin JH, Lu AY . Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet 35:361-90, 1998.

Lin JH, Yamazaki M. Role of P-glycoprotein in pharmacokinetics : clinical implications. Clin Pharmacokinet 42:59-98, 2003.

Lin JH . Drug-drug interaction mediated by inhibition and induction of P-glycoprotein. Adv Drug Deliv Rev 55:53-81, 2003.

Lown KS, Thummel KE, Benedict PE et al. The erythromycin breath test predicts the clearance of midazolam. Clin Pharmacol Ther 57:16-24, 1995.

Nelson DR, Kamataki T, Waxman DJ et al. The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol 12:1-51, 1993.

Neuhofel AL, Wilton JH, Victory JM et al. Lack of bioequivalence of ciprofloxacin when administered with calcium-fortified orange: a new twist on an old interaction. J Clin Pharmacol 42:461-66, 2002.

Ohmori S, Ishii I, Kuriya S et al. Effects of clarithromycin and its metabolites on the mixed function oxidase system in hepatic microsomes of rats. Drug Metab Dispos 21:358-63, 1993.

packageinsert of cialis from website of FDA

Rendic S. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev 34:83-448, 2002.

Ring BJ, Patterson BE, Mitchell MI et al. Effect of tadalafil on cytochrome P450 3A4-mediated clearance: Studies in vitro and in vivo. Clin Pharmacol Ther 77:63-75, 2005.

Rodrigues AD. Drug-drug interactions. New York: M. Dekker, 2002.

Rowland M, Tozer TN. Clinical pharmacokinetics concepts and applications third edition, 2004.

Shimada T, Guengerich FP. Evidence for cytochrome P450NF, the nifedipine oxidase, being the principal enzyme involved in the bioactivation of aflatoxins in human liver. Proc Natl Acad Sci USA 86:462-5, 1989.

Suvarna R, Pirmohamed M, Henderson L et al. Possible interaction between warfarin and cranberry juice. BMJ 327:1454, 2003.

Thomas N and Tozer. Clinical pharmacokinetics. Concept and applications. Third edition

Uesawa Y, Mohri K et al. Effects of cranberry juice on nifedipin pharmacokinetics in rats. Drug Metab Rev 37:138, 2005.

Venkatakrishnan K, von Moltke LL, Obach RS et al. Drug metabolism and drug interactions: Application and clinical value of in vitro models. Curr Drug Metab 4:423-59, 2003.

Wallace AW, Victory JM, Amsden GW et al. Lack of bioequivalence when levofloxacin and calcium-fortified orange juice are coadministered to healthy volunteers. J Clin Pharmacol43:539-44, 2003.

Wallace AW, Victory JM, Amsden GW et al. Lack of bioequivalence of gatifloxacin when coadministered with calcium-fortified orange juice in healthy volunteers. J Clin Pharmacol 43:92-6, 2003.

Wang Z, Gorski JC, Hamman MA et al. The effects of St John’s wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 70:317-26, 2001.

Wang Z, Hamman MA, Huang SM et al. Effect of St John’s wort on the pharmacokinetics of fexofenadine. Clin Pharmacol Ther 71:414-20, 2002.

Watkins PB, Wrighton SA, Schuetz EG et al. Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. J Clin Invest 80:1029-36, 1987.

Weiss J, Tayler GR, Zimmermann F et al. Collection of body fluids, in The Handbook of Experimental Animals-The Laboratory Rat. (Krinke GJ ed) Academic Press, New York. p.485-510, 2000.

Westlind A, Malmebo S, Johansson I et al. Cloning and tissue distribution of a novel human cytochrome p450 of the CYP3A subfamily, CYP3A43. Biochem Biophys Res Commun 281:1349-55, 2001.

Wrighton SA, Brian WR, Sari MA et al. Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3). Mol Pharmacol 38:207-13, 1990.

Yan X, Murphy BT, Hammond GB et al. Antioxidant activities and antitumor screening of extracts from cranberry fruit (Vaccinium macrocarpon). J Agric Food Chem 50:5844-49, 2002.

Yamazaki H, Inoue K, Turvy CG et al. Effects of freezing thawing and storage of human liver samples on the microsomal contents and activities of cytochrome P450 enzymes. Drug Metab Dispos 25:168-74, 1997.
犀利士藥品仿單

楊淑珍. Cisapride and delavirdine as in vitro probes of CYP3A activity. 國立成功大學碩士論文p.38, 2005.