Research progress of <em>in vivo</em> biomarkers for CYP3A enzyme

ZHU Sang; ZHANG Feng; GAO Shouhong; WANG Zhipeng; CHEN Wangsheng; TAO Xia

doi:10.3969/j.issn.1006-0111.2016.05.001

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Article Navigation > Journal of Pharmaceutical Practice and Service > 2016 > 34(5): 385-388,402

ZHU Sang, ZHANG Feng, GAO Shouhong, WANG Zhipeng, CHEN Wangsheng, TAO Xia. Research progress of in vivo biomarkers for CYP3A enzyme[J]. Journal of Pharmaceutical Practice and Service, 2016, 34(5): 385-388,402. doi: 10.3969/j.issn.1006-0111.2016.05.001

Citation:

ZHU Sang, ZHANG Feng, GAO Shouhong, WANG Zhipeng, CHEN Wangsheng, TAO Xia. Research progress of in vivo biomarkers for CYP3A enzyme[J]. Journal of Pharmaceutical Practice and Service, 2016, 34(5): 385-388,402. doi: 10.3969/j.issn.1006-0111.2016.05.001

Research progress of in vivo biomarkers for CYP3A enzyme

doi: 10.3969/j.issn.1006-0111.2016.05.001

Department of Pharmacy, Changzheng Hospital, Shanghai 200003, China

Received Date: 2015-12-30
Rev Recd Date: 2016-03-15

Abstract

Human cytochrome P450 (CYP) 3A, which is widely involved in the various drug metabolism, is most abundant in liver and intestine. The activity of CYP3A enzyme may be induced or inhibited in the process of drug metabolisms, and affect the metabolism of other CYP3A substrates and modulators vice versa. At present, in vitro probe drugs and in vivo biomarkers are both available to evaluate the activity of CYP3A enzyme. The former requires oral probe drugs, the latter does not need for those drugs and just allows laboratory technicians to detect endogenous substrates, such as 4β-hydroxycholesterol and 6β-hydroxycortisol. As reported, studies on CYP3A help to explain the inter-individually variability in drug metabolism, to indicate dose adjustments in combination regimens when drug interactions exist, to predict drug efficacy and toxicity reaction for providing theoretical guidance for individualized medication, and to reduce market risk of new drugs for the potential drug interactions. We summarized these two kinds of endogenous biomarkers and their clinical application in this review.
- In vivo biomarkers,
- 4β-hydroxycholesterol,
- 6β-hydroxycortisol

References

[1]	Thummel KE, Shen DD, Podoll TD, et al. Use of midazolam as a human cytochrome P450 3A probe: I. In vitro-in vivo correlations in liver transplant patients[J]. J Pharmacol Exp Ther, 1994, 271(1): 549-556.
[2]	韩现芹, 李健, 王群. 用药动学方法研究甘草和连翘对牙鲆CYP3A活性的影响[C]. 第十二届中国科协年会论文集. 福州,2010: 1-7.
[3]	De wildt SN, Berns MJ, Van den anker JN. 13C-erythromycin breath test as a noninvasive measure of CYP3A activity in newborn infants: a pilot study[J]. Ther Drug Monit, 2007, 29(2): 225-230.
[4]	Mirghani RA, Sayi J, Aklillu E, et al. CYP3A5 genotype has significant effect on quinine 3-hydroxylation in Tanzanians, who have lower total CYP3A activity than a Swedish population[J]. Pharmacogenet Genomics, 2006, 16(9): 637-645.
[5]	Shoun H, Fushinobu S. Physiological function, reaction mechanism, and structure of cytochrone P450nor[J]. Seikagaku, 2008, 80(6): 560-568.
[6]	Burk O, Wojnowski L. Cytochrome P450 3A and their regulation[J]. Naunyn Schmiedebergs Arch Pharmacol, 2004, 369(1): 105-124.
[7]	Paine MF, Hart HL, Ludington SS, et al. The human intestinal cytochrome P450 "pie"[J]. Drug Metab Dispos, 2006, 34(5): 880-886.
[8]	Akiyoshi T, Saito T, Murase S, et al. Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants[J]. Drug Metab Dispos, 2011, 39(4): 724-728.
[9]	Hustert E, Haberl M, Burk O, et al. The genetic determinants of the CYP3A5 polymorphism[J]. Pharmacogenetics, 2001, 11(9): 773-779.
[10]	Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression[J]. Nat Genet, 2001, 27(4): 383-391.
[11]	Lin YS, Dowling AL, Quigley SD, et al. Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism[J]. Mol Pharmacol, 2002, 62(1): 162-172.
[12]	Bodin K, Andersson U, Rystedt E, et al. Metabolism of 4 beta -hydroxycholesterol in humans[J]. J Biol Chem, 2002, 277(35): 31534-31540.
[13]	Hukkanen J, Puurunen J, Hyotylainen T, et al. The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity[J]. Br J Clin Pharmacol, 2015, 80(3): 473-479.
[14]	Yang Z, Rodrigues AD. Does the long plasma half-life of 4beta-hydroxycholesterol impact its utility as a cytochrome P450 3A (CYP3A) metric?[J]. J Clin Pharmacol, 2010, 50(11): 1330-1338.
[15]	Diczfalusy U, Nylen H, Elander P, et al. 4beta-Hydroxycholesterol, an endogenous marker of CYP3A4/5 activity in humans[J]. Br J Clin Pharmacol, 2011, 71(2): 183-189.
[16]	Goodenough AK, Onorato JM, Ouyang Z, et al. Quantification of 4-beta-hydroxycholesterol in human plasma using automated sample preparation and LC-ESI-MS/MS analysis[J]. Chem Res Toxicol, 2011, 24(9): 1575-1585.
[17]	Dutreix C, Lorenzo S, Wang Y. Comparison of two endogenous biomarkers of CYP3A4 activity in a drug-drug interaction study between midostaurin and rifampicin[J]. Eur J Clin Pharmacol, 2014, 70(8): 915-920.
[18]	Bjorkhem-bergman L, Backstrom T, Nylen H, et al. Comparison of endogenous 4beta-hydroxycholesterol with midazolam as markers for CYP3A4 induction by rifampicin[J]. Drug Metab Dispos, 2013, 41(8): 1488-1493.
[19]	Leil TA, Kasichayanula S, Boulton DW, et al. Evaluation of 4beta-Hydroxycholesterol as a Clinical Biomarker of CYP3A4 Drug Interactions Using a Bayesian Mechanism-Based Pharmacometric Model[J]. CPT Pharmacometrics Syst Pharmacol, 2014, 25(3):e120.
[20]	Kasichayanula S, Boulton DW, Luo WL, et al. Validation of 4beta-hydroxycholesterol and evaluation of other endogenous biomarkers for the assessment of CYP3A activity in healthy subjects[J]. Br J Clin Pharmacol, 2014, 78(5): 1122-1134.
[21]	Diczfalusy U, Kanebratt KP, Bredberg E, et al. 4beta-hydroxycholesterol as an endogenous marker for CYP3A4/5 activity. Stability and half-life of elimination after induction with rifampicin[J]. Br J Clin Pharmacol, 2009, 67(1): 38-43.
[22]	Furuta T, Suzuki A, Mori C, et al. Evidence for the validity of cortisol 6 beta-hydroxylation clearance as a new index for in vivo cytochrome P450 3A phenotyping in humans[J]. Drug Metab Dispos, 2003, 31(11): 1283-1287.
[23]	Shibata S, Takahashi H, Ono N, et al. Longitudinal monitoring of CYP3A activity in patients receiving 3 cycles of itraconazole pulse therapy for onychomycosis[J]. J Clin Pharm Ther, 2014, 39(2): 181-185.
[24]	Hu ZY, Zhao YS, Wu D, et al. Endogenous cortisol 6 beta-hydroxylation clearance is not an accurate probe for overall cytochrome P450 3A phenotyping in humans[J]. Clin Chim Acta, 2009, 408(1-2): 92-97.[25] Peng CC, Templeton I, Thummel KE, et al. Evaluation of 6beta-hydroxycortisol, 6beta-hydroxycortisone, and a combination of the two as endogenous probes for inhibition of CYP3A4 in vivo[J]. Clin Pharmacol Ther, 2011, 89(6): 888-895.
[25]	Marde Arrhen Y, Nylen H, Lovgren-sandblom A, et al. A comparison of 4beta-hydroxycholesterol : cholesterol and 6beta-hydroxycortisol : cortisol as markers of CYP3A4 induction[J]. Br J Clin Pharmacol, 2013, 75(6): 1536-1540.
[26]	Ohno M, Yamaguchi I, Ito T, et al. Circadian variation of the urinary 6beta-hydroxycortisol to cortisol ratio that would reflect hepatic CYP3A activity[J]. Eur J Clin Pharmacol, 2000, 55(11-12): 861-865.
[27]	Fleishaker JC, Pearson PG, Wienkers LC, et al. Biotransformation of tirilazad in human: 2. Effect of ketoconazole on tirilazad clearance and oral bioavailability[J]. J Pharmacol Exp Ther, 1996, 277(2): 991-998.
[28]	Shibasaki H, Hosoda K, Goto M, et al. Intraindividual and interindividual variabilities in endogenous cortisol 6beta-hydroxylation clearance as an index for in vivo CYP3A phenotyping in humans[J]. Drug Metab Dispos, 2013, 41(2): 475-479.
[29]	Luo X, Zheng L, Cai N, et al. Evaluation of 6beta-hydroxycortisol and 6beta-hydroxycortisone as biomarkers for cytochrome P450 3A activity: insight into their predictive value for estimating oral immunosuppressant metabolism[J]. J Pharm Sci, 2015, 104(10): 3578-3586.
[30]	Diczfalusy U, Miura J, Roh HK, et al. 4Beta-hydroxycholesterol is a new endogenous CYP3A marker: relationship to CYP3A5 genotype, quinine 3-hydroxylation and sex in Koreans, Swedes and Tanzanians[J]. Pharmacogenet Genomics, 2008, 18(3): 201-208.
[31]	Tremblay-franco M, Zerbinati C, Pacelli A, et al. Effect of obesity and metabolic syndrome on plasma oxysterols and fatty acids in human[J]. Steroids, 2015, 99(Pt B): 287-292.
[32]	Mannheimer B, Wagner H, Ostenson CG, et al. No impact of vitamin D on the CYP3A biomarker 4beta-hydroxycholesterol in patients with abnormal glucose regulation[J]. PLoS One, 2015, 10(4): e0121984.
[33]	Woolsey SJ, Beaton MD, Choi YH, et al. Relationships between endogenous plasma biomarkers of constitutive CYP3A activity with single time-point oral midazolam microdose phenotype in healthy subjects[J]. Basic Clin Pharmacol Toxicol, 2016,118(4):284-291.
[34]	Woolsey SJ, Mansell SE, Kim RB, et al. CYP3A activity and expression in nonalcoholic fatty liver disease[J]. Drug Metab Dispos, 2015, 43(10): 1484-1490.
[35]	Suzuki Y, Itoh H, Sato F, et al. Significant increase in plasma 4beta-hydroxycholesterol concentration in patients after kidney transplantation[J]. J Lipid Res, 2013, 54(9): 2568-2572.
[36]	Suzuki Y, Itoh H, Fujioka T, et al. Association of plasma concentration of 4beta-hydroxycholesterol with CYP3A5 polymorphism and plasma concentration of indoxyl sulfate in stable kidney transplant recipients[J]. Drug Metab Dispos, 2014, 42(1): 105-110.
[37]	Muro EP, Fillekes Q, Kisanga ER, et al. Intrapartum single-dose carbamazepine reduces nevirapine levels faster and may decrease resistance after a single dose of nevirapine for perinatal HIV prevention[J]. J Acquir Immune Defic Syndr (1999), 2012, 59(3): 266-273.
[38]	Baranyai D, Muro E, Godtel-armbrust U, et al. Reduction of nevirapine-driven HIV mutations by carbamazepine is modulated by CYP3A activity[J]. J Antimicrob Chemother, 2014, 69(7): 1933-1937.
[39]	卜书红, 张健, 陆晓彤, 等. 儿童癫痫患者CYP酶活性与血清卡马西平浓度和临床疗效的相关性分析[J]. 医药导报, 2010, 29(4): 430-432.
[40]	张健, 唐跃年, 刘海涛, 等. 急性淋巴细胞性白血病患儿化疗前后CYP3A酶活性研究[J]. 中国药师, 2007, 10(2): 110-112.
[41]	Rouits E, Charasson V, Petain A, et al. Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients[J]. Br J Cancer, 2008, 99(8): 1239-1245.

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通讯作者: 陈斌, bchen63@163.com

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沈阳化工大学材料科学与工程学院沈阳 110142

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Research progress of in vivo biomarkers for CYP3A enzyme

Department of Pharmacy, Changzheng Hospital, Shanghai 200003, China

Received Date: 2015-12-30

Rev Recd Date: 2016-03-15

Key words:

Abstract: Human cytochrome P450 (CYP) 3A, which is widely involved in the various drug metabolism, is most abundant in liver and intestine. The activity of CYP3A enzyme may be induced or inhibited in the process of drug metabolisms, and affect the metabolism of other CYP3A substrates and modulators vice versa. At present, in vitro probe drugs and in vivo biomarkers are both available to evaluate the activity of CYP3A enzyme. The former requires oral probe drugs, the latter does not need for those drugs and just allows laboratory technicians to detect endogenous substrates, such as 4β-hydroxycholesterol and 6β-hydroxycortisol. As reported, studies on CYP3A help to explain the inter-individually variability in drug metabolism, to indicate dose adjustments in combination regimens when drug interactions exist, to predict drug efficacy and toxicity reaction for providing theoretical guidance for individualized medication, and to reduce market risk of new drugs for the potential drug interactions. We summarized these two kinds of endogenous biomarkers and their clinical application in this review.

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Reference (41)

[1]	Thummel KE, Shen DD, Podoll TD, et al. Use of midazolam as a human cytochrome P450 3A probe: I. In vitro-in vivo correlations in liver transplant patients[J]. J Pharmacol Exp Ther, 1994, 271(1): 549-556.
[2]	韩现芹, 李健, 王群. 用药动学方法研究甘草和连翘对牙鲆CYP3A活性的影响[C]. 第十二届中国科协年会论文集. 福州,2010: 1-7.
[3]	De wildt SN, Berns MJ, Van den anker JN. 13C-erythromycin breath test as a noninvasive measure of CYP3A activity in newborn infants: a pilot study[J]. Ther Drug Monit, 2007, 29(2): 225-230.
[4]	Mirghani RA, Sayi J, Aklillu E, et al. CYP3A5 genotype has significant effect on quinine 3-hydroxylation in Tanzanians, who have lower total CYP3A activity than a Swedish population[J]. Pharmacogenet Genomics, 2006, 16(9): 637-645.
[5]	Shoun H, Fushinobu S. Physiological function, reaction mechanism, and structure of cytochrone P450nor[J]. Seikagaku, 2008, 80(6): 560-568.
[6]	Burk O, Wojnowski L. Cytochrome P450 3A and their regulation[J]. Naunyn Schmiedebergs Arch Pharmacol, 2004, 369(1): 105-124.
[7]	Paine MF, Hart HL, Ludington SS, et al. The human intestinal cytochrome P450 "pie"[J]. Drug Metab Dispos, 2006, 34(5): 880-886.
[8]	Akiyoshi T, Saito T, Murase S, et al. Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants[J]. Drug Metab Dispos, 2011, 39(4): 724-728.
[9]	Hustert E, Haberl M, Burk O, et al. The genetic determinants of the CYP3A5 polymorphism[J]. Pharmacogenetics, 2001, 11(9): 773-779.
[10]	Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression[J]. Nat Genet, 2001, 27(4): 383-391.
[11]	Lin YS, Dowling AL, Quigley SD, et al. Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism[J]. Mol Pharmacol, 2002, 62(1): 162-172.
[12]	Bodin K, Andersson U, Rystedt E, et al. Metabolism of 4 beta -hydroxycholesterol in humans[J]. J Biol Chem, 2002, 277(35): 31534-31540.
[13]	Hukkanen J, Puurunen J, Hyotylainen T, et al. The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity[J]. Br J Clin Pharmacol, 2015, 80(3): 473-479.
[14]	Yang Z, Rodrigues AD. Does the long plasma half-life of 4beta-hydroxycholesterol impact its utility as a cytochrome P450 3A (CYP3A) metric?[J]. J Clin Pharmacol, 2010, 50(11): 1330-1338.
[15]	Diczfalusy U, Nylen H, Elander P, et al. 4beta-Hydroxycholesterol, an endogenous marker of CYP3A4/5 activity in humans[J]. Br J Clin Pharmacol, 2011, 71(2): 183-189.
[16]	Goodenough AK, Onorato JM, Ouyang Z, et al. Quantification of 4-beta-hydroxycholesterol in human plasma using automated sample preparation and LC-ESI-MS/MS analysis[J]. Chem Res Toxicol, 2011, 24(9): 1575-1585.
[17]	Dutreix C, Lorenzo S, Wang Y. Comparison of two endogenous biomarkers of CYP3A4 activity in a drug-drug interaction study between midostaurin and rifampicin[J]. Eur J Clin Pharmacol, 2014, 70(8): 915-920.
[18]	Bjorkhem-bergman L, Backstrom T, Nylen H, et al. Comparison of endogenous 4beta-hydroxycholesterol with midazolam as markers for CYP3A4 induction by rifampicin[J]. Drug Metab Dispos, 2013, 41(8): 1488-1493.
[19]	Leil TA, Kasichayanula S, Boulton DW, et al. Evaluation of 4beta-Hydroxycholesterol as a Clinical Biomarker of CYP3A4 Drug Interactions Using a Bayesian Mechanism-Based Pharmacometric Model[J]. CPT Pharmacometrics Syst Pharmacol, 2014, 25(3):e120.
[20]	Kasichayanula S, Boulton DW, Luo WL, et al. Validation of 4beta-hydroxycholesterol and evaluation of other endogenous biomarkers for the assessment of CYP3A activity in healthy subjects[J]. Br J Clin Pharmacol, 2014, 78(5): 1122-1134.
[21]	Diczfalusy U, Kanebratt KP, Bredberg E, et al. 4beta-hydroxycholesterol as an endogenous marker for CYP3A4/5 activity. Stability and half-life of elimination after induction with rifampicin[J]. Br J Clin Pharmacol, 2009, 67(1): 38-43.
[22]	Furuta T, Suzuki A, Mori C, et al. Evidence for the validity of cortisol 6 beta-hydroxylation clearance as a new index for in vivo cytochrome P450 3A phenotyping in humans[J]. Drug Metab Dispos, 2003, 31(11): 1283-1287.
[23]	Shibata S, Takahashi H, Ono N, et al. Longitudinal monitoring of CYP3A activity in patients receiving 3 cycles of itraconazole pulse therapy for onychomycosis[J]. J Clin Pharm Ther, 2014, 39(2): 181-185.
[24]	Hu ZY, Zhao YS, Wu D, et al. Endogenous cortisol 6 beta-hydroxylation clearance is not an accurate probe for overall cytochrome P450 3A phenotyping in humans[J]. Clin Chim Acta, 2009, 408(1-2): 92-97.[25] Peng CC, Templeton I, Thummel KE, et al. Evaluation of 6beta-hydroxycortisol, 6beta-hydroxycortisone, and a combination of the two as endogenous probes for inhibition of CYP3A4 in vivo[J]. Clin Pharmacol Ther, 2011, 89(6): 888-895.
[25]	Marde Arrhen Y, Nylen H, Lovgren-sandblom A, et al. A comparison of 4beta-hydroxycholesterol : cholesterol and 6beta-hydroxycortisol : cortisol as markers of CYP3A4 induction[J]. Br J Clin Pharmacol, 2013, 75(6): 1536-1540.
[26]	Ohno M, Yamaguchi I, Ito T, et al. Circadian variation of the urinary 6beta-hydroxycortisol to cortisol ratio that would reflect hepatic CYP3A activity[J]. Eur J Clin Pharmacol, 2000, 55(11-12): 861-865.
[27]	Fleishaker JC, Pearson PG, Wienkers LC, et al. Biotransformation of tirilazad in human: 2. Effect of ketoconazole on tirilazad clearance and oral bioavailability[J]. J Pharmacol Exp Ther, 1996, 277(2): 991-998.
[28]	Shibasaki H, Hosoda K, Goto M, et al. Intraindividual and interindividual variabilities in endogenous cortisol 6beta-hydroxylation clearance as an index for in vivo CYP3A phenotyping in humans[J]. Drug Metab Dispos, 2013, 41(2): 475-479.
[29]	Luo X, Zheng L, Cai N, et al. Evaluation of 6beta-hydroxycortisol and 6beta-hydroxycortisone as biomarkers for cytochrome P450 3A activity: insight into their predictive value for estimating oral immunosuppressant metabolism[J]. J Pharm Sci, 2015, 104(10): 3578-3586.
[30]	Diczfalusy U, Miura J, Roh HK, et al. 4Beta-hydroxycholesterol is a new endogenous CYP3A marker: relationship to CYP3A5 genotype, quinine 3-hydroxylation and sex in Koreans, Swedes and Tanzanians[J]. Pharmacogenet Genomics, 2008, 18(3): 201-208.
[31]	Tremblay-franco M, Zerbinati C, Pacelli A, et al. Effect of obesity and metabolic syndrome on plasma oxysterols and fatty acids in human[J]. Steroids, 2015, 99(Pt B): 287-292.
[32]	Mannheimer B, Wagner H, Ostenson CG, et al. No impact of vitamin D on the CYP3A biomarker 4beta-hydroxycholesterol in patients with abnormal glucose regulation[J]. PLoS One, 2015, 10(4): e0121984.
[33]	Woolsey SJ, Beaton MD, Choi YH, et al. Relationships between endogenous plasma biomarkers of constitutive CYP3A activity with single time-point oral midazolam microdose phenotype in healthy subjects[J]. Basic Clin Pharmacol Toxicol, 2016,118(4):284-291.
[34]	Woolsey SJ, Mansell SE, Kim RB, et al. CYP3A activity and expression in nonalcoholic fatty liver disease[J]. Drug Metab Dispos, 2015, 43(10): 1484-1490.
[35]	Suzuki Y, Itoh H, Sato F, et al. Significant increase in plasma 4beta-hydroxycholesterol concentration in patients after kidney transplantation[J]. J Lipid Res, 2013, 54(9): 2568-2572.
[36]	Suzuki Y, Itoh H, Fujioka T, et al. Association of plasma concentration of 4beta-hydroxycholesterol with CYP3A5 polymorphism and plasma concentration of indoxyl sulfate in stable kidney transplant recipients[J]. Drug Metab Dispos, 2014, 42(1): 105-110.
[37]	Muro EP, Fillekes Q, Kisanga ER, et al. Intrapartum single-dose carbamazepine reduces nevirapine levels faster and may decrease resistance after a single dose of nevirapine for perinatal HIV prevention[J]. J Acquir Immune Defic Syndr (1999), 2012, 59(3): 266-273.
[38]	Baranyai D, Muro E, Godtel-armbrust U, et al. Reduction of nevirapine-driven HIV mutations by carbamazepine is modulated by CYP3A activity[J]. J Antimicrob Chemother, 2014, 69(7): 1933-1937.
[39]	卜书红, 张健, 陆晓彤, 等. 儿童癫痫患者CYP酶活性与血清卡马西平浓度和临床疗效的相关性分析[J]. 医药导报, 2010, 29(4): 430-432.
[40]	张健, 唐跃年, 刘海涛, 等. 急性淋巴细胞性白血病患儿化疗前后CYP3A酶活性研究[J]. 中国药师, 2007, 10(2): 110-112.
[41]	Rouits E, Charasson V, Petain A, et al. Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients[J]. Br J Cancer, 2008, 99(8): 1239-1245.

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Research progress of in vivo biomarkers for CYP3A enzyme

doi: 10.3969/j.issn.1006-0111.2016.05.001

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通讯作者: 陈斌, bchen63@163.com

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Research progress of in vivo biomarkers for CYP3A enzyme

doi: 10.3969/j.issn.1006-0111.2016.05.001

Department of Pharmacy, Changzheng Hospital, Shanghai 200003, China

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Research progress of in vivo biomarkers for CYP3A enzyme

doi: 10.3969/j.issn.1006-0111.2016.05.001

Abstract

References

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通讯作者: 陈斌, bchen63@163.com

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Related

Proportional views

Research progress of in vivo biomarkers for CYP3A enzyme

doi: 10.3969/j.issn.1006-0111.2016.05.001

Department of Pharmacy, Changzheng Hospital, Shanghai 200003, China

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