臺灣博碩士論文加值系統

Nifedipine (1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicarboxylic acid dimethyl ester, NF)為dihydropyridine類鈣離子通道阻斷劑，藥理作用為擴張心肌、冠狀動脈及週邊血管平滑肌，臨床上廣泛應用於高血壓、心絞痛、以及週邊血管疾病如Raynoud’s Phenomenon。NF的藥物動態學特性曾被廣泛的研究與討論，其中Ahsan、Renwick等人的研究結果發現，不同族群間NF之藥品動態具有顯著之差異。但有關於臺灣族群之NF藥品動態學研究則尚未見，由於NF的廣泛用途，也基於臺灣族群人民之福祉，因而衍生了本研究之進行。
本研究採用於台灣進行之藥品生體相等性試驗的數據，集合199位健康男性自願受試者，單次口服投與德國Bayer藥廠生產之NF (Adalat®)10 mg後，根據24小時內藥物血中濃度變化情形，運用non-compartment pharmacokinetics方法以及利用WinNonlin套裝軟體計算NF之藥物動態學參數，Cmax、Tmax、AUC及T1/2，並比較台灣居民與其他族群間之藥動學差異。以Student’s t test進行統計學上之雙尾檢定，訂定p<0.05為具有統計學上之意義。
本研究中，NF於台灣健康男性自願受試者吸收十分迅速，平均Cmax為143.24±53.37 ng/ml，Tmax中位數為0.50 (Q1,0.33~Q3,0.67)小時，平均AUC為297.12±124.62 ng ml-1 h，平均T1/2為3.3±1.8小時。其中不論是AUC、Cmax、T1/2皆比白種人高，且具有統計學上之意義 (p<0.001)。台灣人NF的 AUC及Cmax與日本人相似，顯示國人日本人具有相似的藥物動態學特性。而與白種人比較起來，NF於台灣族群之藥動學在AUC方面與白種人有顯著不同，顯示台灣族群對於NF之代謝有比白種人低的可能性。

Nifedipine (1,4-Dihydro-2,6-dimethyl-4-(2-nitro-phenyl)-3,5- pyridine dicarboxylic acid dimethyl ester, NF) is a dihydropyridine calcium channel blocker. NF has been shown to be an effective and relative well-tolerated treatment for stable, variant and unstable angina, mild to severe hypertension and Raynoud’s phenomenon.
Studies on NF pharmacokinetics have been published. It is well known that after oral administration there is great interindividual variability in disposition of NF. According to the published literature of NF, Ahsan and Renwick have found the ethnic differences among several populations.
The ethnic differences of NF metabolism have been reported in many studies,however the pharmacokinetics of NF in Taiwan residents has not been studied.
We conduted a retrospective review of NF bioequivalence studies which completed in the past five years in Taiwan. One hundred and ninty-nine healthy male volunteers who attend the bioequivalence studies were all within the range of ideal body weight. After an overnight fasting, each subject was given a single capsule containing 10 mg of Adalat® manufactured by Bayer, German, as a reference drug. Pharmacokinetic parameters (Cmax, Tmax, AUC and T1/2) which derived from Adalat® administered were calculated by non-compartmental analysis with WinNonlin® program. The difference of pharmacokinetic between Taiwan residents and other population were evaluated as well.
After administration of Adalat®, NF is absorbed very fast, the average Cmax of NF in healthy volunteers in Taiwan residents is 143.2±53.4 ng/ml, AUC is 297.1±124.6 ngml-1h and T1/2 is 3.3±1.8 hr, median of Tmax is 0.5 hr (Q1, 0.33~ Q3, 0.67). Compared to the published literature of NF in other population, the AUC, Cmax, and T1/2 of NF were significantly (p<0.001) higher in Taiwan residents than in Caucasians, however, the AUC and Cmax were similar between Taiwan residents and Japanese. According to the published antimode of AUC distribution, 22.5 ng«h/ml/mg, which proposed by Kleinbloesem, there are 69.3% subjects belong to slow metabolizer in Taiwan residents.
From the result above, there may be slower metabolism of NF in Taiwan residents than in Caucasians.

中文摘要I
英文摘要III
第一章 緒論1
第一節 藥物與族群差異3
(一) 族群間差異 (Ethnic differences)3
(二) 族群差異對藥物表現的影響因素 (Ethnic factors)4
(三) Nifedipine族群間藥動學差異6
第二節 化學特性及藥品安定性 10
第三節 臨床藥理學13
(一) 作用機轉13
(二) 臨床效果18
(三) 臨床用途19
(四) 使用劑量21
(五) 副作用及不良反應22
(六) 藥物交互作用22
(七) 禁忌症26
(八) 注意事項：26
第四節 藥物動態學27
(一) 吸收 (Absorption)30
(二) 分佈 (Distribution)32
(三) 代謝 (Metabolism)33
(四) 排除 (Elimination)37
(五) 年齡對nifedipine藥動學的影響38
(六) 疾病對nifedipine藥動學的影響39
第五節 研究目的41
第二章 研究方法42
第一節 研究對象42
第二節 資料統整42
第三節 數據分析43
(一) 電腦設備43
(二) 藥物動態學參數之計算43
(三) Nifedipine在台灣居民與其他族群之藥動學差異比較45
(四) 統計方法45
第三章 研究結果46
第一節 Nifedipine藥物動態學46
第二節 Nifedipine在台灣健康成年人與其他族群之藥動學差異比較 54
第四章 研究討論61
第一節 研究限制61
(一) NF藥物動態學參數計算61
(二) 族群間藥物動態學差異比較61
第二節 台灣居民之Nifedipine藥物動態學62
第三節 台灣居民與其他族群之nifedipine藥物動態學差異比較65
第四節 未來展望72
第五章 結論73
參考文獻74

Ahsan CH, Renwick AG, Macklin B, Challenor VF, Waller DG and George CF. Ethnic difference in the pharmacokinetics of oral nifedipine. British Journal of Clinical Pharmacology. 31: 399~403, 1991.
Ahsan CH, Renwick AG, Waller DG, Challenor VF, George CF and Amanullah M. The influences of dose and ethnic origins on the phatmacokinetics of nifedipine. Clinical Pharmacology and Therapeutics. 54: 329~338, 1993.
Anon. The sixth report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Archives of Internal Medicine. 157: 2413-2446, 1997.
Ball SE, Scatina J, Kao J, Ferron GM, Fruncillo R, Mayer P, Weinryb I, Guida M, Hopkins PJ, Warner N, and Hall J. Population distribution and effects on drug metabolism of a genetic variant in the 5’ promotor region of CYP3A4. Clinical Pharmacology and Therapeutics. 66: 288~294, 1999.
Banzet O, Colin JN, Thibonnier M, Singlas E, Alexandre JM and Corvol P. Acute antihypertensive effect and pharmacokinetics of a tablet preparation of nifedipine. European Journal of Clinical Pharmacology. 4: 145~150, 1983.
Beaune PH, Umbenhauer DR, Bork RW, Lloyd RS, and Guengerich FP. Isolation and sequence determination of a cDNA clone related to human cytochrome P-450 nifedipine oxidase. Proceedings of the National Academy of Sciences of the United States of America. 83: 8064~8068, 1986.
Belch JJF & Ho M: Pharmacotherapy of Raynaud's phenomenon. Drugs. 52: 682-695, 1996.
Bogaert MG, Rosseel MT Joos R, and Boelaert J. Plasma concentrations of nifedipine in patients with renal failure. Arzneimittelforschung. 34: 307-308, 1984.
van Bortel L, Bohm R, Mooij J, Schiffers P, and Rahn KH. Total and free steady-state plasma levels and pharmacokinetics of nifedipine in patients with terminal renal failure. European Journal of Clinical Pharmacology. 37: 185-189, 1989.
Castañeda-Hernández G, Hoyo-Vadillo C, Palma-Aguirre A, and Flores- Murrieta FJ. Pharmacokinetics of oral nifedipine in different populations. Journal of Clinical Pharmacology. 32: 140~145, 1992.
Challenor V, Waller DG, Gruchy BS, Renwick Ag and George CF. The effects of food and posture on the pharmacokinetics of a biphasic release preparation of nifedipine. British Journal of Clinical Pharmacolgy. 22: 565~570, 1986.
Clary C & Schweizer E: Treatment of MAOI hypertensive crisis with sublingual nifedipine. Journal of Clinical Psychiatry. 48: 249-250, 1987.
Corbalan R, Gozalez R and Chamorro G, Munoz M, Rodriguez JA, and Casanegra P. Effect of calcium inhibitor, nifedipine, on exercise tolerance in patients with angina pectoris: a double-blind study. Chest. 79: 302-305, 1981.
De Morais SMF, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, and Goldstein JA. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Molecular Pharmacology 46: 594~8, 1994.
Duhm B, Maul W, Medenwald H, Patzschke K and Wegner LA. Tierexperimentalle Untersuchungen zur Pharmakokinetik und Biotransformation von radioactive markiertem 4-(2'nitrophenyl)-2, 6-dimethyl-1, 4-dihydropyridin-3, 5-dicarbonsäuredimethyl ester. Arzneimittel-Forschung 22: 42~52, 1972.
Edeki T. Clinical importance of genetic polymorphism of drug oxidation. Mount Sinai Journal of Medicine 63: 291~300, 1996.
Ene MD and Roberts CJ. Pharmacokinetics of nifedipine after oral administration in chronic liver disease. Journal of Clinical Pharmacology. 27: 1001-1004, 1987.
Felix CA, Walker AH, Lange BJ, William TM, Winick NJ, Cheung NK, Lovett BD, Nowell PC, and Blair IA.. Association of CYP3A4 genotype with treatment related leukemia. Proceedings of the National Academy of Sciences of the United States of America. 95: 13176~13181, 1998.
Foster TS, Hamann SR and Richards VR, Bryant PJ. Graves DA, and McAllister RG. Nifedipine kinetics and bioavailability after single intravenous and oral doses in normal subjects. Journal of Clinical Pharmacology. 23: 161-170, 1983.
Furberg CD, Psaty BM, and Meyer JV. Nifedipine dose-related increase in mortality in patients with coronary heart disease. Circulation. 92: 1326-1331, 1995.
Ginsburg R, Lamb IH, Schroeder JS, Hu M, and Harrison DC. Randomized double-blind comparison of nifedipine and isosorbide dinitrate therapy in variant angina pectoris due to coronary artery spasm. The American Heart Journal 103: 44-48, 1982.
Grossman E, Messerli Fh, Grodzicki T, and Kowey P. Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies? JAMA. 276: 1328-1331, 1996.
Guengerich FP, Martin MV, Beaune PH, Kremers P, Wolff T and Waxman DJ. Characterization of rat and human liver microsomal cytochrome P450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidation drug metabolism. The Journal of Biological Chemistry. 261: 5051~5060, 1986.
Hamann SR and McAllister Jr RG. Measurement of nifedipine in plasma by gas-liquid chromatography and electrone-capture detection. Clinical Chemistry. 29: 158~160, 1983.
Hill JA, Feldman RL, Pepine CJ, and Conti CR. Randomized double- blind comparison of nifedipine and isosorbide dinitrate in patients with coronary artery spasm. American Journal of Cardiology. 49: 431-438, 1982.
Hirasawa K, Shen WF, Kelly DT, Roubin G, Tateda K and Shibata J. Effect of food ingestion on nifedipine absorbtion and hemodynamic response. European Journal of Clinical Pharmacology. 28: 105~107, 1985.
Horster FA, Duhm B Maul W, Medenwald H, Patzschke K, and Wegner LA. Clinical investigations of the pharmacikinetics of radioactively marked 1,4-Dihydro-2,6-dimethyl- 4-(2-nitrophenyl)-3,5- pyridine dicarboxylic acid dimethyl ester. Arzneimittel-Forsch. 22: 330~334, 1972.
Hoyo-Vadillo C, Castañeda-Hernández G, Herrera JE, Vidal-Gárate J, Salazar LA, Moremo-Ramos A, Chávez F, Tena I and Hong E. Pharmacokinetics of oral nifedipine: relevance of the distribution phase. Journal of Clinical Pharmacology 29: 251~256, 1989a.
Hoyo-Vadillo C, Castañeda-Hernández G, Herrera JE, Vidal-Gárate J, Salazar LA, Moremo-Ramos A, Chávez F and Hong E. Pharmacokinetics of nifedipine slow release tablet in Mexican subjects: further evidence for an oxidation polymorphism. Journal of Clinical Pharmacology. 29: 816~820, 1989b.
Huysmans FT, Sluiter HE, Thien TA et al: Acute treatment of hypertensive crisis with nifedipine. British Journal of Clinical Pharmacology. 16: 725-727, 1983.
Johnson JA. Influence of race or ethinicity on pharmacokinetics of drugs. Journal of Pharmaceutical Sciences. 86: 1328~1333, 1997.
Kinirons MT, Lang CC, He HB, Chebreselasie K, Shay S, Robin DW and Wood AJJ. Triazolam pharmacokinetics and pharmacodynamics in Caucasians andSouthern Asian. Ethnicity and CYP3A activity. British Journal of Clinical Pharmacology. 41: 69~72, 1996.
Kleinbloesem CH, van Brummelen P, Faber H, Danhof M, Vermeulen NPE and Breimer DD. Variability in nifedipine pharmacokinetics and dynamics: a new oxidation polymorphism in man. Biochemical Pharmacology. 33 :3721~3724, 1984d.
Kleinbloesem CH, van Brummelen P, van de Linde, JA, Voogd PJ and Breimer DD. Nifedipine: kinetics and dynamics in healthy subjects. Clinical Pharmacology and Therapeutics. 35: 742~749, 1984a.
Kleinbloesem CH, van Harten J, van de Linde JA, Voogd PJ and Breimer DD. Liquid chromatographic determination of nifedipine in plasma and of its main metabolite in urine. Journal of Chromatography. 308 : 209~216, 1984b.
Kloner RA. Nifedipine in ischemic heart disease. Circulation. 92: 1074-1078, 1995.
Kondo S, Kuchiki A, Yamamoto K, Akimoto K and Takahashi K. Identification of nifedipine metabolites and their determination by gas chromatography. Chemical and Pharmaceutical Bulletin. 28: 1~7, 1980.
Kozjek F, Primozic S, Mrhar A, Karba R and Rämsch KD. The bioavailability of oral nifedipine formulations: a statistical and simulation approach. Biopharmaceutics and Drug Disposition. 8:23~35, 1987.
Lacche A & Basaglia P: Hypertensive emergencies: effects of therapy by nifedipine administered sublingually. Current Therapeutic Research. 34: 879-887, 1983.
Lesko LJ, Hunter R, Burgess RC and Rodgers GP. Accumulation of nifedipine after multiple doses. Journal of Pharmacy and Pharmacology. 38: 486~488, 1986.
Leucuta SE. The kinetics of nifedipine release from porous hydrophilic matrices and the pharmacokinetics in man. Pharmazie. 43: 845~848, 1988.
Lewis JG. Adverse reactions to calcium antagonists. Drugs 25:196-222, 1983
Lin KM, Lau JK, Smith R, Phillips P, Antal W and Poland RE. Comparison of alprazolam plasma levels in normal Asian and Caucasian male volunteers. Psychopharmacology. 96: 365~369, 1988.
Lindholm A; Welsh M, Alton C and Kahan BD. Demographic factors influencing cyclosporine pharmacokinetic parameters in patients with uremia: Racial differences in bioavailability. Clininical Pharmacology and Therapeutics. 52；359~71, 1992.
Lip PL & Lip GYH: Untitled (letter). Eye. 13: 391, 1999.
Lobo J, Jack DB and Kendall MJ. The intra- and inter-subject variability of nifedipine pharmacokinetics in young volunteers. European Journal of Clinical Pharmacology. 30: 57~60, 1986.
Low RI, Takeda P and Mason DT, and DeMaria AN. Effects of calcium channel blocking agents on cardiovascular function. The American Journal of Cardiology 49: 547, 1982.
Lown KS, Mayo RR, Leichtman AB, Hsiao HL, Turgeon DK, Schmiedlin-Ren P, Brown MB, Guo W, Rossi SJ, Benet LZ and Watkins PB. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clininical Pharmacology and Therapeutics. 62: 248~260,1997.
Martsevich SY, Metelitsa VI and Rumiantsev DO, Piotrovskii VK, Slastnikova ID, Egorov LV, and Vygodin VA. Development of tolerance to nifedipine in patients with stable angina pectoris. British Journal of Clinical Pharmacology. 29: 339-346, 1990.
McAllister Jr RG. Clinical pharmacokinetics of calcium channel antagonists. Journal of Cardiovascular Pharmacology. 4: 5340~5345, 1982.
Meyer UA. Molecular mechanisms of genetic polymorphism of drug metabolism. Annual Review of Pharmacology and Toxicology 37: 269~96, 1997.
Mooss AN, Mohiuddin SM and Hilleman DE, and Sketch MH Sr. A comparison of sublingual nifedipine versus nitroglycerin in the treatment of acute angina pectoris. DICP : the Annals of Pharmacotherapy 23: 562-564, 1989.
Mueller HS and Chahine RA. Interim report of multicenter double-blind, placebo-controlled studies of nifedipine in chronic stable angina. American Journal of Medicine. 71: 645-657, 1981.
Myers MG and Rämsch KD. Comparative pharmacokinetics and antihypertensive effects of the nifedipine tablet and capsule. Journal of Cardiovascular Pharmacology. 10 (suppl. 10): 76~78, 1987.
Nakashima T, Inoki M and Nakanishi Y. Nifedipine serum concentration; effects upon blood pressure and heart rate in normotensive volunteers. European Journal of Drug Metabolism and Pharmacokinetics. 9: 73~78, 1984.
Nelson DR, Koymans L and Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, Waterman MR, Gotoh O, Coon MJ, Estabrook RW, Gunsalus IC, and Nebert DW. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics. 6:1~42, 1996.
Ochs HR, Rämsch KD, Verburbur-Ochs B, Greenblatt DJ and Gerloff J. Nifedipine: Kinetics and dynamics after single oral doses. Klinische Wochenschrift. 62: 427~429, 1984.
Opie LH and White DA. Adverse interaction between nifedipine and beta-blockade. British Medical Journal. 281: 1462, 1980.
Opie LH and Messerli FH. Nifedipine and mortality: grave defects in the dossier. Circulation. 92: 1068-1073, 1995.
Opie LH. Calcium channel blokers for hypertension: dissecting the evidence for adverse effects. American Journal of Hypertension. 10: 565-77, 1997.
Otto J and Lesko LJ. Protein binding of nifedipine. Journal of Pharmacy and Pharmacology. 38: 399~40, 1986.
Pabst G, Lutz D, Molz KH, Dahmen W and Jaeger H. Pharmacokinetics and bioavailability of three different galenic nifedipine preparations. Arzneimittel-Forschung- Drug Research. 36; 256~260, 1986.
Palma-Aguirre JA, Rosas-Alcazar G, Rodriguez JM, Leon-Urrea F and Montoya-Cabrera MA. Bioavailability and pharmacokinetics of nifedipine administered by different routes in healthy volunteers. Archivos de Investigacion Medica. 20: 129~135, 1989.
Patrick KS. Gas chromatographic-mass spectrometric analysis of
plasma nifedipine. Journal of Chromatography. 495: 123~130, 1989.
Rämsch KD and Sommer J. Pharmacokinetics and metabolism of nifedipine. Hypertension. 5(supp II): II-18~II-24, 1983.
Rämsch KD, Graefe KH, Scherling D, Sommer J and Ziegler R. Pharmacokinetics and metabolism of calcium-blocking agents nifedipine, nitrendipine and nimodipine. American Journal of Nephrology. 6(suppl 1): 73~80, 1986.
Rashid TJ, Martin U, Clarke H, and Waller DG. Renwick AG and George CF. Factors affecting the absolute bioavailability of nifedipine. British Journal of Clinical Pharmacology. 40: 51~58, 1995.
Rebbeck TR, Jaffe JM, Walker AH, Wein AJ and Malkowicz SB. Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. Journal of the National Cancer Institute. 90: 1225~1229, 1998.
Renwick AG, Robertson DRC, Macklin B, Challenor VF, Waller DG and George CF. The pharmacokinitics of oral nifedipine- a population study. British Journal of Clinical Pharmacology. 25: 701~708, 1988.
Renwick AG, Le Vie J, Challenor VF, Waller DG, Gruchy B and George CF. Factors affecting the pharmacokinetics of nifedipine. European Journal of clinical pharmacology. 32: 351~355, 1987.
Reitberg DP, Love SJ and Quercia GT, and Zinny MA. Effect of food on nifedipine pharmacokinetics. Clinical Pharmacology and Therapeutics. 42: 72-75, 1987.
Robertson DR, Waller DG and Renwick AG, and George CF. Age-related changes in the pharmacokinetics and pharmacodynamics of nifedipine. British Journal of Clinical Pharmacology. 25: 297-305,1988.
Robertson RM and Robertson D. Drugs used for the treatment of myocardial ischemia. In: Hardman JG, Limbird LE, ed. Goodman & Gilman’s ThePharmacological Basis of Therapeutics, 9th ed. The McGraw-Hill Companies, Inc., 1996: 768~769.
Rosenkranz JH, Schlossmann K and Scholtan W. Arzneimittel-Forsch. (Drug Research) 24: 455~466, 1974.
Satoh C, Sakai T, Kashiwagi H, Hongo K, Aizawa O, Watanabe H, Mochizuki S, Okamura T. Influence of cisapride on the pharmacokinetics and antihypertensive effect of sustained-release nifedipine. Internal Medicine. 35: 941-5, 1996.
Schellens JHM, Soons PA and Breimer DD. Lack of bimodality in nifedipine plasma kinetics in a large population of healthy volunteers. Biochemical Pharmacology. 37: 2507~2510, 1988.
Schellens JHM, van der Wart JH, Brugman M, Breimer DD. Influence of enzyme induction and inhibition on the oxidation of nifedipine, sparteine, mephenytoin and antipyrine in human as assessed by a “cocktail” study design. Journal of Pharmacology and Experimental Therapeutics. 249: 638~645, 1989.
Schumann D: Sublingual nifedipine controversy in drug delivery. Dimensions of Critical Care Nursing. 10: 314-320, 1991.
Singlas E, Martre H, Taburet AM, Jacobs C and Sari R. Effect de l’hémodialyse sur les taux plasmatiques de nifédipine. Presse Médicale. 13: 943~944, 1984.
Sorkin EM, Clissold SP and Brogden RN. Nifedipine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in ischemic heart disease, hypertension and related cardiovascular disorders. Drugs. 30: 182~274, 1985.
Sowunmi A, Radhid TJ, Akinyinka OO and Rewick AG. Ethnic difference in nifedipine kinetics: comparisons between Nigerians, Caucasians and South Asians. British Journal of Clinical Pharmacology. 40: 489~493, 1995.
Spital A and Scandling JD. Nifedipine in continuous ambulatory peritoneal dialysis. Archives of Internal Medicine. 143: 2025, 1983.
Stason WB, Schmid CH and Niedzwiecki D, Whiting GW, Caubet JF, Cory D, Luo D, Ross SD, and Chalmers TC. Safety of nifedipine in angina pectoris: A meta-analysis. Hypertension . 33: 24-31, 1999.
Stone PH, Antman EM, Muller JE, Braunwald E. Calcium channel blocking agents in the treatment of cardiovascular disorders: part II: hemodynamic effects and clinical applications. Annals of Internal Medicine. 97: 886-904, 1980.
Taburet AM, Singlas E, Colin JN, Benzet O, Thibonnier M and Corvol P. Pharmacokinetic studies of nifedipine tablet. Correlation with antihypertensive effects. Hypertension. 5: II-29~II-33, 1983.
Tada Y, Tsuda Y, Otsuka T, Nagasawa K, Kimura H, Kusaba T, and Sakata T. Case report: nifedipine-rifampicin interaction attenuates the effect on blood pressure in a patient with essential hypertension. American Journal of the Medical Sciences. 303: 25-7, 1992.
Tateichi T, Ohashi K, Sudo T, Sakamoto K, Toyosaki N, Hosoda S, Toyo-oka T, Kumagai Y, Sugimoto K, Fujimura A and Ebihara A. Dose dependent effect of diltiazem on the pharmacokinetics of nifedipine. The Journal of Clinical Pharmacology. 29: 994~997, 1989.
Tatro DS, ed. Drug Interaction Facts. 2001. St. Louis,Wolters Kluwer Company, 2001.
Terry RW. Nifedipine therapy in angina pectoris: Evaluation of safety and side effects. The American Heart Journal. 104: 681~689, 1982
Vetrovec GW et al. Comparative dosing and efficacy of continuous release nifedipine versus standars nifedipine for angina pectoris: clinical response., exercise performance and plasma nifedipine levels. The American Heart Journal.115: 793-8, 1988.
Waller DG, Rewick AG, Gruchy BS and George CF. The first pass metabolism of nifedipine in man. British Journal of Clinical Pharmacology. 18: 951~954, 1984.
Wedlund PJ, Aslanian WS and Jacqz E, McAllister CB, Branch RA, and Wilkinson GR. Phenotypic differences in mephenytoin pharmacokinetics in normal subjects. The Journal of Pharmacology and Experimental Therapeutics. 234: 662~669, 1985.
Xie HG, Huang SL and Zhou HH. High-performance liquid chromatography determination of urinary 4*-hydroxymephenytoin, a metabolic marker for the hepatic enzyme CYP2C19, in humans. Journal of Chromatography B. 668: 125~131, 1995.
Zhou HH, Koshakji RP and Silberstein DJ, Wilkinson GR, and Wood AJ. Altered sensitivity to and cleatance of propranolol in men of Chinese descent as compared with American whites. New England Journal of Medicine. 320: 565~570, 1989.
Zhou HH and Wood AJJ. Differences in stereoselective disposition of propranolol do not explain senditivity differences between white and Chinese subjects: Correlation between the clearance of (-)- and (+)- propranolol. Clinical Pharmacology and Therapeutics. 47: 719~723, 1990.
Zhou HH, Adedoyin A and Wilkinson GR. Differences in plasma binding of drugs between Caucasians and Chinese subjects. Clinical Pharmacology and Therapeutics. 48: 10-17, 1990.
Zhou HH and Wood AJ. Increased suppression of exercise-induced increase in rennin by propranolol in Chinese subjects. Clinical Pharmacology and Therapeutics. 50: 150~156,1991.
Zhou HH, Dheller JR, Nu H and Wood AJJ. Ethnic differences in response to morphine. Clinical Pharmacology and Therapeutics. 54: 507~513, 1993.