内源性氢化可的松代谢与环孢霉素血药浓度剂量比的相关性研究
摘要
目的研究尿中氢化可的松(F)及可的松(E)6β-羟基化代谢率与环孢霉素(CsA)血药浓度剂量比的相关性。
方法尿中F和E采用高效液相色谱紫外吸收法(HPLC-UV)测定。采用Diamonsil C18色谱柱(200x4.6mm,5μm),流动相为甲醇-0.1%甲酸水溶液进行梯度洗脱,流速为1.0mL·min~(-1),检测波长为254nm。样品提取剂为二氯甲烷。尿中6β-羟基化氢化可的松(6β-OHF)和6β-羟基化可的松(6β-OHE)的浓度也采用HPLC-UV法测定。采用Diamonsil C18色谱柱(200×4.6 mm,5μm),流动相为乙腈-0.1%甲酸水溶液进行梯度洗脱,流速为1.0mL·min~(-1),检测波长为244 nm。样品处理包括以下步骤:尿样上Oasis HLB固相萃取柱后被乙酸乙酯-乙醚的混合溶剂洗脱,有机相再用硫酸钠饱和的碱液和酸液洗杂质。在肾移植患者尿中F及E的6β羟基化代谢率与CsA血药浓度剂量比的相关性研究中,共有105名肾移植病人(80名男性,25名女性)参加了该试验。在试验当天清晨受试者服用CsA前,收集血样和尿样各约5 mL。尿中6β-OHF、6β-OHE、F和E的浓度用HPLC-UV法测定。全血中CsA稳态谷浓度用荧光偏振免疫分析法(FPIA)测定。采用Spearman秩相关检验比较尿中6β-OHF+6β-OHE/F+E和CsA血药浓度剂量比(C/D)、6β-OHF+6β-OHE/F+E和体重校正的CsA血药浓度剂量比(C/D/W)之间的相关性,同时采用Wilcoxon秩和检验比较各项指标之间的差异。
结果F、E和内标峰在该色谱条件下得到较好分离。尿中F和E的定量下限均为5.0 ng·ml~(-1),3种不同浓度下测得的准确度在89.74%和107.64%之间,日内和日间精密度均小于12.21%。尿中F和E在5.0-320.0和5.0-400.0 ng·ml~(-1)浓度范围内线性关系良好。尿中6β-OHF、6β-OHE和内标峰在该色谱条件下也得到较好分离。6β-OHF和6β-OHE的定量下限均为5.0 ng·ml~(-1),3种不同浓度下测得的准确度在92.16%和109.77%之间,日内和日间精密度均小于7.4%。6β-OHF和6β-OHE在5.0-500.0和5.0-400.0 ng·ml~(-1)浓度范围内线性关系良好。在肾移植患者尿中F及E的6β羟基化代谢率与CsA血药浓度剂量比的相关性研究中,无论考虑全部受试者以及男性或女性受试者的数据,6β-OHF+6β-OHE/F+E与C/D、C/D/W均存在一定相关性。各项指标在术后不同时间同样存在相关性。钙通道阻滞剂合用组较不合用组则表现出相对较弱的负相关。6β-OHF+6β-OHE/F+E在术后不同时间段没有明显差异,而C/D、C/D/W则存在显著性差异。6β-OHF+6β-OHE/F+E和C/D存在性别间差异,而C/D/W则没有表现出明显的性别间差异。合用钙通道阻滞剂使6β-OHF+6β-OHE/F+E显著降低,而C/D和C/D/W则没有明显变化。
结论本研究提供了两种简便、灵敏、准确的高效液相紫外检测法,适用于同时测定尿中F和E以及6β-OHF和6β-OHE的浓度。6β-OHF+6β-OHE/F+E和CsA血药浓度剂量比之间存在一定的负相关性,可能可以用于评价同为生物药剂学分类Ⅱ类的CYP3A和P-gp重叠底物药动学,但是更加准确的指标还有待于进一步的研究。
Objective The present study was undertaken to demonstrate if a correlation can be seen between cortisol (F) and cortisone (E) 6β-hydroxylation metabolism and the ratio of cyclosporine (CsA) blood concentrations to dose.
Method Simultaneous determination of F and E in human urine was performed by high-performance liquid chromatography with ultraviolet absorbance detection (HPLC-UV). The separation was achieved on a Diamonsil C18 column (200×4.6mm,5μm), monitored by UV absorption at 254nm and operated at 1.0 mL·min~(-1) using the gradient elution of methanol and water containing 0.1% formic acid. The extraction solvent was dichlormethane. Simultaneous determination of 6β-hydroxycorisol (6β-OHF) and 6β-hydroxycortisone (6β-OHE) in human urine was also performed by HPLC-UV. The separation was achieved on a Diamonsil C18 column (200×4.6mm,5μm), monitored by UV absorption at 244nm and operated at 1.0 mL·min~(-1) using the gradient elution of acetonitrile and water containing 0.1% formic acid. The procedure consisted of steps as followed: elution of the urine sample with ethyl acetate-diethyl ether on an Oasis HLB extraction cartridge and subsequent wash of the organic extracts with alkaline and acidic solutions saturated with sodium sulfate. In the study on correlation between F and E 6β-hydroxylation metabolism and the C/D ratio of CsA in renal transplant recipients, 105 renal transplant recipients (80 males and 25 females) participate in this study. Blood and urine samples were collected before CsA administration on the study day. 6β-OHF、6β-OHE、F and E in urine were determined by HPLC-UV. Trough concentrations of CsA in whole blood were assayed by FPIA. Correlations between 6β-OHF+6β-OHE/F+E and the C/D ratio of CsA, 6β-OHF+6β-OHE/F+E and weight-normalized C/D ratio of CsA were examined by Spearman's rank correlation analysis. Parameter values obtained under different conditions were compared using Wilcoxon's rank sum test.
Result A good separation of F、E and internal standard was obtained. The lower limits of quantitation were 5.0 ng/ml for F and E in urine. Accuracy determined at three concentrations ranged between 89.74% and 107.64%. The intra-day and inter-day relative standard deviations were less than 12.21%. Good linear correlations in urine were found between 5.0 and 320.0 ng-ml~(-1) for F, 5.0 and 400.0 ng-ml~(-1) for E, respectively. A good separation of 6β-OHF、6β-OHE and internal standard was also obtained. The lower limits of quantitation were 5.0 ng/ml for F and E. Accuracy determined at three concentrations ranged between 92.16% and 109.77%. The intra-day and inter-day relative standard deviations were less than 7.4%. Good linear correlations were found between 5.0 and 500.0 ng-ml~(-1) for 6β-OHF, 5.0 and 400.0 ng-ml~(-1) for 6β-OHE, respectively. In the study on correlation between F and E 6β-hydroxylation metabolism and the C/D ratio of CsA in renal transplant recipients, there were inverse correlations between 6β-OHF+6β-OHE/F+E and the C/D ratio of CsA, 6β-OHF+6β-OHE/F+E and weight-normalized C/D ratio of CsA in all, male and female subjects. Correlations were also found during different postoperative periods. An inverse correlation between them was weaker with calcium channel blockers co-administration. Significant differences were seen in the C/D ratio of CsA and weight-normalized C/D ratio of CsA during different postoperative periods, but not in 6β-OHF+6β-OHE/F+E. 6β-OHF+6β-OHE/F+E and the C/D ratio of CsA showed sexual dimorphism while weight-normalized C/D ratio of CsA didn't. A decrease was also seen in 6β-OHF+6β-OHE/F+E with calcium channel blockers co-administration. But no significant differences were found in the C/D ratio of CsA and weight-normalized C/D ratio of CsA.
Conclusion The present study provides two simple, sensitive and accurate techniques for simultaneous determination of 6β-OHF and 6β-OHE or F and E in human urine. An inverse correlation has been found between 6β-OHF+6β-OHE/F+E and the C/D ratio of CsA. It may be used as a predictor of pharmacokinetics of CYP3A and P-gp substrates belonged to the biopharmaceutical classification system (BCS)Ⅱ, but the more precise indexes will be studied in our further researches.
方法尿中F和E采用高效液相色谱紫外吸收法(HPLC-UV)测定。采用Diamonsil C18色谱柱(200x4.6mm,5μm),流动相为甲醇-0.1%甲酸水溶液进行梯度洗脱,流速为1.0mL·min~(-1),检测波长为254nm。样品提取剂为二氯甲烷。尿中6β-羟基化氢化可的松(6β-OHF)和6β-羟基化可的松(6β-OHE)的浓度也采用HPLC-UV法测定。采用Diamonsil C18色谱柱(200×4.6 mm,5μm),流动相为乙腈-0.1%甲酸水溶液进行梯度洗脱,流速为1.0mL·min~(-1),检测波长为244 nm。样品处理包括以下步骤:尿样上Oasis HLB固相萃取柱后被乙酸乙酯-乙醚的混合溶剂洗脱,有机相再用硫酸钠饱和的碱液和酸液洗杂质。在肾移植患者尿中F及E的6β羟基化代谢率与CsA血药浓度剂量比的相关性研究中,共有105名肾移植病人(80名男性,25名女性)参加了该试验。在试验当天清晨受试者服用CsA前,收集血样和尿样各约5 mL。尿中6β-OHF、6β-OHE、F和E的浓度用HPLC-UV法测定。全血中CsA稳态谷浓度用荧光偏振免疫分析法(FPIA)测定。采用Spearman秩相关检验比较尿中6β-OHF+6β-OHE/F+E和CsA血药浓度剂量比(C/D)、6β-OHF+6β-OHE/F+E和体重校正的CsA血药浓度剂量比(C/D/W)之间的相关性,同时采用Wilcoxon秩和检验比较各项指标之间的差异。
结果F、E和内标峰在该色谱条件下得到较好分离。尿中F和E的定量下限均为5.0 ng·ml~(-1),3种不同浓度下测得的准确度在89.74%和107.64%之间,日内和日间精密度均小于12.21%。尿中F和E在5.0-320.0和5.0-400.0 ng·ml~(-1)浓度范围内线性关系良好。尿中6β-OHF、6β-OHE和内标峰在该色谱条件下也得到较好分离。6β-OHF和6β-OHE的定量下限均为5.0 ng·ml~(-1),3种不同浓度下测得的准确度在92.16%和109.77%之间,日内和日间精密度均小于7.4%。6β-OHF和6β-OHE在5.0-500.0和5.0-400.0 ng·ml~(-1)浓度范围内线性关系良好。在肾移植患者尿中F及E的6β羟基化代谢率与CsA血药浓度剂量比的相关性研究中,无论考虑全部受试者以及男性或女性受试者的数据,6β-OHF+6β-OHE/F+E与C/D、C/D/W均存在一定相关性。各项指标在术后不同时间同样存在相关性。钙通道阻滞剂合用组较不合用组则表现出相对较弱的负相关。6β-OHF+6β-OHE/F+E在术后不同时间段没有明显差异,而C/D、C/D/W则存在显著性差异。6β-OHF+6β-OHE/F+E和C/D存在性别间差异,而C/D/W则没有表现出明显的性别间差异。合用钙通道阻滞剂使6β-OHF+6β-OHE/F+E显著降低,而C/D和C/D/W则没有明显变化。
结论本研究提供了两种简便、灵敏、准确的高效液相紫外检测法,适用于同时测定尿中F和E以及6β-OHF和6β-OHE的浓度。6β-OHF+6β-OHE/F+E和CsA血药浓度剂量比之间存在一定的负相关性,可能可以用于评价同为生物药剂学分类Ⅱ类的CYP3A和P-gp重叠底物药动学,但是更加准确的指标还有待于进一步的研究。
Objective The present study was undertaken to demonstrate if a correlation can be seen between cortisol (F) and cortisone (E) 6β-hydroxylation metabolism and the ratio of cyclosporine (CsA) blood concentrations to dose.
Method Simultaneous determination of F and E in human urine was performed by high-performance liquid chromatography with ultraviolet absorbance detection (HPLC-UV). The separation was achieved on a Diamonsil C18 column (200×4.6mm,5μm), monitored by UV absorption at 254nm and operated at 1.0 mL·min~(-1) using the gradient elution of methanol and water containing 0.1% formic acid. The extraction solvent was dichlormethane. Simultaneous determination of 6β-hydroxycorisol (6β-OHF) and 6β-hydroxycortisone (6β-OHE) in human urine was also performed by HPLC-UV. The separation was achieved on a Diamonsil C18 column (200×4.6mm,5μm), monitored by UV absorption at 244nm and operated at 1.0 mL·min~(-1) using the gradient elution of acetonitrile and water containing 0.1% formic acid. The procedure consisted of steps as followed: elution of the urine sample with ethyl acetate-diethyl ether on an Oasis HLB extraction cartridge and subsequent wash of the organic extracts with alkaline and acidic solutions saturated with sodium sulfate. In the study on correlation between F and E 6β-hydroxylation metabolism and the C/D ratio of CsA in renal transplant recipients, 105 renal transplant recipients (80 males and 25 females) participate in this study. Blood and urine samples were collected before CsA administration on the study day. 6β-OHF、6β-OHE、F and E in urine were determined by HPLC-UV. Trough concentrations of CsA in whole blood were assayed by FPIA. Correlations between 6β-OHF+6β-OHE/F+E and the C/D ratio of CsA, 6β-OHF+6β-OHE/F+E and weight-normalized C/D ratio of CsA were examined by Spearman's rank correlation analysis. Parameter values obtained under different conditions were compared using Wilcoxon's rank sum test.
Result A good separation of F、E and internal standard was obtained. The lower limits of quantitation were 5.0 ng/ml for F and E in urine. Accuracy determined at three concentrations ranged between 89.74% and 107.64%. The intra-day and inter-day relative standard deviations were less than 12.21%. Good linear correlations in urine were found between 5.0 and 320.0 ng-ml~(-1) for F, 5.0 and 400.0 ng-ml~(-1) for E, respectively. A good separation of 6β-OHF、6β-OHE and internal standard was also obtained. The lower limits of quantitation were 5.0 ng/ml for F and E. Accuracy determined at three concentrations ranged between 92.16% and 109.77%. The intra-day and inter-day relative standard deviations were less than 7.4%. Good linear correlations were found between 5.0 and 500.0 ng-ml~(-1) for 6β-OHF, 5.0 and 400.0 ng-ml~(-1) for 6β-OHE, respectively. In the study on correlation between F and E 6β-hydroxylation metabolism and the C/D ratio of CsA in renal transplant recipients, there were inverse correlations between 6β-OHF+6β-OHE/F+E and the C/D ratio of CsA, 6β-OHF+6β-OHE/F+E and weight-normalized C/D ratio of CsA in all, male and female subjects. Correlations were also found during different postoperative periods. An inverse correlation between them was weaker with calcium channel blockers co-administration. Significant differences were seen in the C/D ratio of CsA and weight-normalized C/D ratio of CsA during different postoperative periods, but not in 6β-OHF+6β-OHE/F+E. 6β-OHF+6β-OHE/F+E and the C/D ratio of CsA showed sexual dimorphism while weight-normalized C/D ratio of CsA didn't. A decrease was also seen in 6β-OHF+6β-OHE/F+E with calcium channel blockers co-administration. But no significant differences were found in the C/D ratio of CsA and weight-normalized C/D ratio of CsA.
Conclusion The present study provides two simple, sensitive and accurate techniques for simultaneous determination of 6β-OHF and 6β-OHE or F and E in human urine. An inverse correlation has been found between 6β-OHF+6β-OHE/F+E and the C/D ratio of CsA. It may be used as a predictor of pharmacokinetics of CYP3A and P-gp substrates belonged to the biopharmaceutical classification system (BCS)Ⅱ, but the more precise indexes will be studied in our further researches.
引文
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[10] Streetman DS, Bertino JS, Nafziger AN. Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics, 2000, 10:187-216.
[11] Stein CM, Kinirons MT, Pinkus T, et al. Comparison of the dapsone recovery ratio and the erythromycin breath test as in vivo probes of CYP3A activity in patients with the rheumatoid arthritis receiving cyclosporine. Clin Pharmacol Ther, 1996, 59: 47-51.
[12] Hirth J, Watkins PB, Strawderman M, et al. The effect of an individual' s cytochrome CYP3A4 activity on docetaxel clearance. Clin Cancer Res, 2000, 6: 1255-1258.
[13] Krivoruk Y, Kinirons MT, Wood AJJ, et al. Metabolism of cytochrome P4503A substrates in vivo administered by the same route: lack of correlation between alfentanil clearance and erythromycin breath test. Clin Pharmacol Ther, 1994, 56: 608-614.
[14] Krecic-Shepard ME, Barnas CR, Slimko J, et al. In vivo cpmparison of putative probes of CYO3A4/5 activity: erythromycin, dextromethorphan, and verapamil. Clin Pharmacol Ther, 1999, 66: 40-50.
[15] Kinirons MT, O' Shea D, Kim RB, et al. Failure of erythromycin breath test to correlate with midazolam clearance as a probe of cytochrome P4503A. Clin Pharmacol Ther, 1999, 66: 224-231.
[16] Lan LB, DaltonJT, Schuetz EG. MDR1 limits CYP3A metabolism in vivo. Mol Pharmacol, 2000, 58: 863-869.
[17] Thummel KE, Wilkinson GR. In vitro and in vivo interactions involving human CYP3A. Annu Rev Pharmacol Toxicol, 1998, 38: 389-430.
[18] Streetman DS, Bertino JS, Nafziger AN. Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics (2000), 10:187-216.
[19] Zhu B, 0u-Yang DS, Cheng ZN, et al. Sing plasma sampling to predict oral clearance of CYP3A probe midazolam. Acta Pharmacol Sin, 2001, 22: 634- 638.
[20] Carrillo JA, Ramos SI, Agundez JAG, et al. Analysis of midazolam and metabolites in plasma by high-performance liquid chromatography: probe of CYP3A. Ther Drug Monit, 1998, 20: 319-324.
[21] Lee LS, Bertino JS Jr, Nafziger AN. Limited sampling models for oral midazolam: midazolam plasma concentrations, not the ratio of 1-hydroxyl- midazolam to midazolam plasma concentrations, accurately predicts AUC as a biomarker of CYP3A activity. J Clin Pharmacol, 2006, 46:229-234.
[22] Kim JS, Nafziger AN, Tsunoda SM, et al. Limited sampling strategy to predict AUC of the CYP3A phenotyping probe midazolam in adults: application to various assay techniques. J Clin Pharmacol, 2002, 42: 376-382.
[23] Lin YS, Lockwood GF, Graham MA, et al. In-vivo phenotyping for CYP3A by a single-point determination of midazolam plasma concentration. Pharmacogenetics, 2001, 11:781-791.
[24] Galteau MM, Shamsa F. Urinary 6β -hydroxycortisol: a validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals. Eur J Clin Pharmacol, 2003, 59: 713-733.
[25] Chen YC, Gotzkowsky SK, Nafziger AN, et al. Poor correlation between 6-hydroxycortisol:cortisol molar ratios and midazolam clearance as measure of hepatic CYP3A activity. Br J Clin Pharmacol, 2006, 62: 187-195.
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[28] Furuta T, Suzuki A, Mori C, et al. Evidence for the validity of cortisol 6β-hydroxylation clearance as a new index for in vivo cytochrome P450 3A phenotyping in humans. Drug Metab Dispos, 2003, 31: 1283-1287.
[29] Hu Z, Gong Q, Hu X, et al. Simultaneous determination of 6β-hydroxycortisol and cortisol in human urine and plasma by liquid chromatography with ultraviolet absorbance detection for phenotyping the CYP3A activity. J Chromatogr B, 2005, 826:238-243.
[30] Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol, 1992, 44: 275-283.
[31] Krecic-Shepard ME, Park K, Barnas C, et al. Race and sex influence clearance of nifedipine: results of a population study. Clin Pharmacol Ther, 2000, 68: 130-142.
[32] Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs, 1995, 50: 222-239.
[33]Zhu B, Liu ZQ, Chen GL, et al. The distribution and gender different of CYP3A activity in Chinese subject. Br J Clin Pharmacol, 2003, 55: 264-269.
[34] Custodio JM, Wu CY, Benet LZ. Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption. Advanced drug delivery reviews, 2008, 60: 717-733.
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[4] Kinirons MT, O' Shea D, Downing TE, et al. Absence of correlations among three putative in vivo probes of human cytochrome P4503A activity in young healthy men. Clin Pharmacol Ther, 1993, 54: 621-629.
[5] Hunt CM, Watkins PB, Sanger P, et al. Heterogeneity of CPY3A isoforms metabolizing erythromycin and cortisol. Clin Pharmacol Ther, 1992, 51: 18-23.
[6] Furuta T, Suzuki A, Mori C, et al. Evidence for the validity of cortisol 6β-hydroxylation clearance as a new index for in vivo cytochrome P450 3A phenotyping in humans. Drug Metab Dispos, 2003, 31: 1283-1287.
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[1] Nelson DR, Koymans L, Kamataki T, et al. P450 superfamily: update on new sequences, gene mapping, accession Nos and nomenclature. Pharmacogenetics, 1996, 6: 1-42.
[2] Domanski TL, Finta C, Halpert JR, et al. cDNA cloning and initial characterization of CYP3A43, a novel human cytochrome P450. Mol Pharmacol, 2001, 59: 386-392.
[3] 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, 2001, 281: 1349-1355.
[4] Dahl ML. Cytochrome P450 phenotyping/genotyping in patients receiving antipsychotics: useful aid to prescribing? Clin Pharmacokinet, 2002, 41: 453-470.
[5] Zaigler M, Tantcheva-Poor I, Fuhr U. Problems and perspevtives of phenotyping for drug-metabolizing enzymes in man. Int J Clin Pharmacol Ther, 2000, 37: 1-9.
[6] Benet LZ. There are no useful CYP3A probes that quantitatively predict the in vivo kinetics of other CYP3A substrates and no expectation that one will be found. Molecular interventions, 2005, 5: 79-83.
[7] Yasui-Furukori N, KondoT, KubotaT, et al. No correlations between the urinary ratio of 6β-hydroxycortisol to free cortisol and pharmacokinetics of alprazolam. Eur J Clin Pharmacol, 2001, 57: 285-288.
[8] Masica AL, Mayo G, Wilkinson GR. In vivo comparisons of constitutive cytochrome P450 3A activity assessed by alprazolam, triazolam, and midazolam. Clinical pharmacology and therapeutics, 2004, 76: 341-349.
[9] Paine MF, Davis CL, Shen DD, et al. Can oral midazolam predict oral cyclosporine disposition? Eur J Pharmaceutical Sciences, 2000, 12: 51-62.
[10] Streetman DS, Bertino JS, Nafziger AN. Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics, 2000, 10:187-216.
[11] Stein CM, Kinirons MT, Pinkus T, et al. Comparison of the dapsone recovery ratio and the erythromycin breath test as in vivo probes of CYP3A activity in patients with the rheumatoid arthritis receiving cyclosporine. Clin Pharmacol Ther, 1996, 59: 47-51.
[12] Hirth J, Watkins PB, Strawderman M, et al. The effect of an individual' s cytochrome CYP3A4 activity on docetaxel clearance. Clin Cancer Res, 2000, 6: 1255-1258.
[13] Krivoruk Y, Kinirons MT, Wood AJJ, et al. Metabolism of cytochrome P4503A substrates in vivo administered by the same route: lack of correlation between alfentanil clearance and erythromycin breath test. Clin Pharmacol Ther, 1994, 56: 608-614.
[14] Krecic-Shepard ME, Barnas CR, Slimko J, et al. In vivo cpmparison of putative probes of CYO3A4/5 activity: erythromycin, dextromethorphan, and verapamil. Clin Pharmacol Ther, 1999, 66: 40-50.
[15] Kinirons MT, O' Shea D, Kim RB, et al. Failure of erythromycin breath test to correlate with midazolam clearance as a probe of cytochrome P4503A. Clin Pharmacol Ther, 1999, 66: 224-231.
[16] Lan LB, DaltonJT, Schuetz EG. MDR1 limits CYP3A metabolism in vivo. Mol Pharmacol, 2000, 58: 863-869.
[17] Thummel KE, Wilkinson GR. In vitro and in vivo interactions involving human CYP3A. Annu Rev Pharmacol Toxicol, 1998, 38: 389-430.
[18] Streetman DS, Bertino JS, Nafziger AN. Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics (2000), 10:187-216.
[19] Zhu B, 0u-Yang DS, Cheng ZN, et al. Sing plasma sampling to predict oral clearance of CYP3A probe midazolam. Acta Pharmacol Sin, 2001, 22: 634- 638.
[20] Carrillo JA, Ramos SI, Agundez JAG, et al. Analysis of midazolam and metabolites in plasma by high-performance liquid chromatography: probe of CYP3A. Ther Drug Monit, 1998, 20: 319-324.
[21] Lee LS, Bertino JS Jr, Nafziger AN. Limited sampling models for oral midazolam: midazolam plasma concentrations, not the ratio of 1-hydroxyl- midazolam to midazolam plasma concentrations, accurately predicts AUC as a biomarker of CYP3A activity. J Clin Pharmacol, 2006, 46:229-234.
[22] Kim JS, Nafziger AN, Tsunoda SM, et al. Limited sampling strategy to predict AUC of the CYP3A phenotyping probe midazolam in adults: application to various assay techniques. J Clin Pharmacol, 2002, 42: 376-382.
[23] Lin YS, Lockwood GF, Graham MA, et al. In-vivo phenotyping for CYP3A by a single-point determination of midazolam plasma concentration. Pharmacogenetics, 2001, 11:781-791.
[24] Galteau MM, Shamsa F. Urinary 6β -hydroxycortisol: a validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals. Eur J Clin Pharmacol, 2003, 59: 713-733.
[25] Chen YC, Gotzkowsky SK, Nafziger AN, et al. Poor correlation between 6-hydroxycortisol:cortisol molar ratios and midazolam clearance as measure of hepatic CYP3A activity. Br J Clin Pharmacol, 2006, 62: 187-195.
[26] Kinirons MT, O' Shea D, Downing TE, et al. Absence of correlations among three putative in vivo probes of human cytochrome P4503A activity in young healthy men. Clin Pharmacol Ther, 1993, 54: 621-629.
[27] Hunt CM, Watkins PB, Sanger P, et al. Heterogeneity of CPY3A isoforms metabolizing erythromycin and cortisol. Clin Pharmacol Ther, 1992, 51: 18-23.
[28] Furuta T, Suzuki A, Mori C, et al. Evidence for the validity of cortisol 6β-hydroxylation clearance as a new index for in vivo cytochrome P450 3A phenotyping in humans. Drug Metab Dispos, 2003, 31: 1283-1287.
[29] Hu Z, Gong Q, Hu X, et al. Simultaneous determination of 6β-hydroxycortisol and cortisol in human urine and plasma by liquid chromatography with ultraviolet absorbance detection for phenotyping the CYP3A activity. J Chromatogr B, 2005, 826:238-243.
[30] Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol, 1992, 44: 275-283.
[31] Krecic-Shepard ME, Park K, Barnas C, et al. Race and sex influence clearance of nifedipine: results of a population study. Clin Pharmacol Ther, 2000, 68: 130-142.
[32] Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs, 1995, 50: 222-239.
[33]Zhu B, Liu ZQ, Chen GL, et al. The distribution and gender different of CYP3A activity in Chinese subject. Br J Clin Pharmacol, 2003, 55: 264-269.
[34] Custodio JM, Wu CY, Benet LZ. Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption. Advanced drug delivery reviews, 2008, 60: 717-733.