Effect of CYP3A4 *1G polymorphism on fentanyl in patients undergoing laparoscopic radical resection of colorectal cancer

doi:10.3969/j.issn.1673-8640.2023.05.003

Abstract

Abstract:

Objective To assess the effect of CYP3A4 *1G polymorphism on the dose of fentanyl in patients undergoing laparoscopic radical resection of colorectal cancer. Methods Totally，101 patients receiving fentanyl anesthesia laparoscopic radical resection of colon tumors at Zhongshan Hospital of Fudan University between July 2018 and April 2020 were enrolled. CYP3A4 *1G genotype was determined，and the relation between CYP3A4 *1G polymorphism and the dose of fentanyl was evaluated by multiple linear regression analysis. Results The results of multiple linear regression analysis showed that age，intraoperative fentanyl dose and the polymorphisms of CYP3A4 *1G，CYP3A5 *3 and OPRM1 A118G were risk factors for the dose of fentanyl in post-anesthesia care unit （PACU）（P<0.05）. After adjusting for age，sex，weight，height，intraoperative fentanyl dose，operation time and the polymorphisms of OPRM1 A118G，CYP3A5 *3 and COMT V158M，CYP3A4*1G wild type（*1*1） was found to be a risk factor for increased fentanyl dose in PACU [β=-13.99，95% confidence interval（CI） -26.78--1.20，P=0.035]. Compared to fentanyl dose in patients with CYP3A4 *1G mutant genotypes [*1*1G（heterozygous） and *1G*1G（homozygous）]，the wild type ones were 13.99 μg higher. There was no correlation between CYP3A4 *1G polymorphism and fentanyl dose in 24 h patient-controlled intravenous analgesia (PCIA) after operation（β=-7.79，95% CI -33.70--18.11，P=0.557），as well as that in 48 h PCIA after operation（β=-10.28，95% CI -22.70-2.15，P=0.108）. Compared with CYP3A4*1G wild type （*1*1） patients，the PACU and fentanyl dose in 24 h PCIA after operation of patients with CYP3A4*1G mutant genotypes [*1*1G （heterozygous） and *1G*1G （homozygous）] were decreased （P<0.05）. Conclusions CYP3A4 *1G polymorphism is an independent factor for fentanyl dose. Compared with mutated type，the anesthetic effect may be similar to wild type subjects by consuming less fentanyl.

Key words: CYP3A4 *1G, Fentanyl, Dose, Post-anesthesia care unit, Patient-controlled intravenous analgesia, Risk factor

CLC Number:

R446.1

SU Xi, ZHOU Yan, HUANG Jian, GAO Yaoyi, LI Yihao, WANG Beili, PAN Baishen, GUO Wei. Effect of CYP3A4 *1G polymorphism on fentanyl in patients undergoing laparoscopic radical resection of colorectal cancer[J]. Laboratory Medicine, 2023, 38(5): 419-423.

Figures/Tables 4

References 17

[1]	LUO J, MIN S. Postoperative pain management in the postanesthesia care unit:an update[J]. J Pain Res, 2017, 10:2687-2698. DOI URL
[2]	LV J, LIU F, FENG N, et al. CYP3A4 gene polymorphism is correlated with individual consumption of sufentanil[J]. Acta Anaesthesiol Scand, 2018, 62(10):1367-1373. DOI PMID
[3]	VIDERMAN D, TAPINOVA K, NABIDOLLAYEVA F, et al. Intravenous versus epidural routes of patient-controlled analgesia in abdominal surgery:systematic review with meta-analysis[J]. J Clin Med, 2022, 11(9):2579. DOI URL
[4]	MCNICOL E D, FERGUSON M C, HUDCOVA J. Patient controlled opioid analgesia versus non-patient controlled opioid analgesia for postoperative pain[J]. Cochrane Database Syst Rev, 2015, 2015(6):CD003348.
[5]	彭盛亮, 黄丹, 肖凡, 等. 右美托咪啶复合芬太尼对清醒经鼻气管插管的镇静效果[J]. 实用医学杂志, 2018, 34(12):2061-2064.
[6]	CHACCOUR C J, HAMMANN F, ALUSTIZA M, et al. Cytochrome P450/ABC transporter inhibition simultaneously enhances ivermectin pharmacokinetics in the mammal host and pharmacodynamics in Anopheles gambiae[J]. Sci Rep, 2017, 7(1):8535. DOI
[7]	DONG Z L, LI H, CHEN Q X, et al. Effect of CYP3A4*1G on the fentanyl consumption for intravenous patient-controlled analgesia after total abdominal hysterectomy in Chinese Han population[J]. J Clin Pharm Ther, 2012, 37(2):153-156. DOI PMID
[8]	MUNRO A W, MCLEAN K J, GRANT J L, et al. Structure and function of the cytochrome P450 peroxygenase enzymes[J]. Biochem Soc Trans, 2018, 46(1):183-196. DOI URL
[9]	LI J, PENG P, MEI Q, et al. The impact of UGT2B7 C802T and CYP3A4*1G polymorphisms on pain relief in cancer patients receiving oxycontin[J]. Support Care Cancer, 2018, 26(8):2763-2767. DOI PMID
[10]	TAKAHASHI K, NISHIZAWA D, KASAI S, et al. Genome-wide association study identifies polymorphisms associated with the analgesic effect of fentanyl in the preoperative cold pressor-induced pain test[J]. J Pharmacol Sci, 2018, 136(3):107-113. DOI URL
[11]	张卫, 张豪勇, 阚全程, 等. CYP3A4*1G基因多态性对女性健康志愿者芬太尼药效学的影响[J]. 中华麻醉学杂志, 2012, 32(1):67-69.
[12]	YUAN R, ZHANG X, DENG Q, et al. Impact of CYP3A4*1G polymorphism on metabolism of fentanyl in Chinese patients undergoing lower abdominal surgery[J]. Clin Chim Acta, 2011, 412(9-10):755-760. DOI PMID
[13]	ZHANG W, YUAN J J, KAN Q C, et al. Influence of CYP3A53 polymorphism and interaction between CYP3A53 and CYP3A4*1G polymorphisms on post-operative fentanyl analgesia in Chinese patients undergoing gynaecological surgery[J]. Eur J Anaesthesiol, 2011, 28(4):245-250. PMID
[14]	GONZALEZ E, JAIN S, SHAH P, et al. Development of robust quantitative structure-activity relationship models for CYP2C9,CYP2D6,and CYP3A4 catalysis and inhibition[J]. Drug Metab Dispos, 2021, 49(9):822-832. DOI URL
[15]	PU J, WANG N, HUANG Z K, et al. Correlation between gene polymorphism and opioid efficacy in patients with gastric or intestinal cancer[J]. Eur Rev Med Pharmacol Sci, 2019, 23(21):9393-9410.
[16]	KHARASCH E D, WHITTINGTON D, HOFFER C. Influence of hepatic and intestinal cytochrome P4503A activity on the acute disposition and effects of oral transmucosal fentanyl citrate[J]. Anesthesiology, 2004, 101(3):729-737. DOI PMID
[17]	GENVIGIR F D, SALGADO P C, FELIPE C R, et al. Influence of the CYP3A4/5 genetic score and ABCB1 polymorphisms on tacrolimus exposure and renal function in Brazilian kidney transplant patients[J]. Pharmacogenet Genomics, 2016, 26(10):462-472. DOI URL

基因位点	正向引物序列（5'~3'）	反向引物序列（5'~3'）
CYP3A4 *1G（rs2242480）	CAAGGAACACACCCATAACACT	TAGAAAGCAGATGAACCAGAGC
CYP3A5 *3（rs776746）	GTCCTTGTGAGCACTTGATG	AGCCCGATTCTGCAGCTGGA
COMT V158M（rs4680）	ACAGGCAAGATCGTGGACGC	CACCTTGGCAGTTTACCCAG
OPRM1 A118G（rs563649）	TTGGACTTTAAATATGGCAA	CATACATTGGAAATACTTAG

基因位点	正向引物序列（5'~3'）	反向引物序列（5'~3'）
CYP3A4 *1G（rs2242480）	CAAGGAACACACCCATAACACT	TAGAAAGCAGATGAACCAGAGC
CYP3A5 *3（rs776746）	GTCCTTGTGAGCACTTGATG	AGCCCGATTCTGCAGCTGGA
COMT V158M（rs4680）	ACAGGCAAGATCGTGGACGC	CACCTTGGCAGTTTACCCAG
OPRM1 A118G（rs563649）	TTGGACTTTAAATATGGCAA	CATACATTGGAAATACTTAG

CYP3A4 *1G 基因型	例数	年龄/岁	性别		体重/kg	身高/cm	芬太尼剂量
CYP3A4 *1G 基因型	例数	年龄/岁	男/例	女/例	体重/kg	身高/cm	PACU/μg	术后24 h PCIA/μg
11	50	60.74±5.95	25	25	63.42±8.91	162.86±8.12	50.40±22.15	134.90±56.55
11G+1G1G	51	58.73±5.40	33	18	64.36±8.80	166.37±6.82	37.65±26.73^*	112.55±46.70^*

CYP3A4 *1G 基因型	例数	年龄/岁	性别		体重/kg	身高/cm	芬太尼剂量
CYP3A4 *1G 基因型	例数	年龄/岁	男/例	女/例	体重/kg	身高/cm	PACU/μg	术后24 h PCIA/μg
11	50	60.74±5.95	25	25	63.42±8.91	162.86±8.12	50.40±22.15	134.90±56.55
11G+1G1G	51	58.73±5.40	33	18	64.36±8.80	166.37±6.82	37.65±26.73^*	112.55±46.70^*

项目	β值（95% CI）	P值
年龄	0.93（0.54~1.80）	0.038
性别
男	基准	0.850
女	0.99（-9.25~11.24）
体重	0.12（-0.45~0.68）	0.688
升高	-0.31（-0.97~0.36）	0.366
术中芬太尼用量	2.57（0.16~4.98）	0.039
手术时间	3.72（-5.92~13.36）	0.451
CYP3A4 *1G		0.001
11	基准
11G+1G1G	-16.75（-26.34~-7.17）
OPRM1 A118G		0.013
GG	基准
GA+AA	16.90（3.78~30.03）
COMT V158M		0.730
GG	基准
GA+AA	-1.79（-11.93~8.35）
CYP3A5 *3		0.037
GG	基准
GA+AA	10.65（0.69~20.60）