Original Article J. St. Marianna Univ.Vol. 6, pp. 183–193, 2015

1 Department of Anesthesiology, St. Marianna University School of Medicine2 Department of Pharmacogenomics, St. Marianna University Graduate School of Medicine3 Institute of Experimental Animals, St. Marianna University School of Medicine

Effects of Genetic Polymorphism of CYP2B6 and UGT1A9 and

Sex Differences on Pharmacokinetics of Propofol

Yuki Kobayashi1, Makito Yokozuka1, Hidetoshi Miyakawa1, Minoru Watanabe3, Toshio Kumai2, and Takeshi Tateda1

(Received for Publication: August 19, 2015)

AbstractBackground: Genetic polymorphisms of metabolic enzymes, as well as a patient’s sex, age, and individual

susceptibility, affect the pharmacokinetics of propofol. Several reports show that polymorphisms of metabolicenzymes of propofol affect loss of consciousness during propofol anesthesia. We investigated whether geneticpolymorphisms of the liver cytochrome P450 2B6 (CYP2B6), the main metabolic enzyme for propofol, andUDP-glucuronosyltransferase 1A9 (UGT1A9), as well as sex differences, affect the pharmacokinetics of propo‐fol.

Methods: Between June 2009 and May 2011, 94 patients (51 males, 43 females) who underwent respira‐tory surgery with total intravenous anesthesia were examined. Arterial blood samples were collected immedi‐ately or 5, 10, 20, 30 and 60 min after the termination of propofol infusion for the determination of the propofolblood concentrations and genetic polymorphisms of CYP2B6 and UGT1A9. We analyzed blood pharmacokinet‐ics of propofol and assessed the association between genetic polymorphisms, sex differences, and blood phar‐macokinetics. Stepwise multiple linear regression analysis was used to detect important factors of pharmacoki‐netics of propofol.

Results: Although C0 (the blood concentrations of propofol immediately after the termination of propofolinfusion) rose for the T/T mutation in CYP2B6, there were no significant differences in changes of blood propo‐fol concentrations after the termination of drug infusion and in waking times for both genetic polymorphisms.C0 was significantly higher in females than in males (1.7: 1.4 μg/mL, female: male, P=0.015) and the rate ofdecline in the blood propofol concentration from C0 to C5 was faster in females than in males (67: 60%,P=0.015). Stepwise multiple regression analysis revealed that sex (B = 0.32, P = 0.01) was a contributor to C0

(R = 0.27, P = 0.01).Conclusions: We suggest that differences between females and males for C0 and the rate of decline in the

blood propofol concentration may cause individual differences in both sensitivity and recovery of consciousnessfrom propofol anesthesia. We conclude that polymorphisms of CYP2B6, but not UGT1A, and sex differencesaffect the pharmacokinetics of propofol.

Key wordsgenetic polymorphism, blood pharmacokinetics, sex differences, propofol

Introduction

Propofol is widely used as an intravenous anes‐

thetic. Propofol has several advantages, such as easycontrol of the depth of anesthesia, a rapid recovery ofconsciousness, and less postoperative nausea and

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vomiting after anesthesia1). However, it is well knownthat individual differences exist in propofol’s anes‐thetic effects. For example, anesthetic effect site con‐centrations can vary between 2.78–4.34 μg/mL2).Iwakiri et al. and Ueta et al. demonstrated that effectsite concentrations of propofol for the loss of con‐sciousness differed according to age and between in‐dividuals3)4). Furthermore, a few reports also existshowing that emergence from anesthesia is signifi‐cantly delayed after propofol with fentanyl infu‐sion5)6). Major factors in waking times for intravenousanesthetics include liver metabolism and renal excre‐tion of anesthetics. Propofol is mainly metabolized inthe liver and is inactivated by hepatic clearance andmetabolic enzymes. The main metabolic enzymes in‐volved in propofol breakdown are the oxidation-re‐duction enzyme, human liver cytochrome P450 2B6(CYP2B6), and the drug conjugation enzyme, UDP-glucuronosyltransferase1A9 (UGT1A9). Propofol ismetabolized by its hydroxylation by CYP2B6 and byits glucuronidation by UGT1A9, resulting in propofolchanging into a conjugated compound that has no an‐esthetic activity and is excreted in urine, as with othermetabolites7).

Genetic polymorphisms in CYP2B6 andUGT1A9 have been reported, along with their allelefrequency in the Japanese population8–10). Severalstudies have shown that the allele frequency of theG516T mutation of CYP2B6 was approximately20%, and the variation among genetic polymor‐phisms decreased the enzyme activity ofCYP2B68)10–12). In contrast, Saito Y et al. and GirardH et al. have reported that the allele frequency of theI399C>T mutation of UGT1A9 was approximately64% and that the variant increased the conjugationactivity of propofol9)13).

Because of enzyme activity changes induced bythese mutations, the anesthetic effect of propofol isaffected and can result in individual differences intimes of emergence from anesthesia. To date, fewstudies have examined times of emergence in relationto genetic polymorphisms and propofol. Previouslywe reported differences in waking times from propo‐fol anesthesia and examined genetic polymorphismsof CYP2B6 and UGT1A9 and age, and their relation‐ship with the propofol dose upon waking14)15).

In the present study, we investigated the bloodpropofol pharmacokinetics of patients who were an‐esthetized by total intravenous anesthesia for respira‐tory surgery. The aim of our study was to examinethe effect of genetic polymorphisms of CYP2B6 and

UGT1A9 and sex differences on propofol pharmaco‐kinetics.

Materials and Methods

Ethical considerationsThe study was approved by the Ethics Commit‐

tee of St. Marianna University School of Medicine(No.1529) and registered with the UMIN ClinicalTrials Registry (ID 002009). Written informed con‐sent was obtained from each patient before the study.

PatientsPatients who were scheduled for respiratory sur‐

gery, and treated by total intravenous anesthesia us‐ing propofol were enrolled in this study. Exclusioncriteria included patients who were scheduled for anintraoperative blood transfusion, and those with sig‐nificant liver, renal, or respiratory dysfunction, dis‐turbance of consciousness, or dementia.

Anesthetic methodPremedication was not administered to all pa‐

tients. All patients received epidural anesthesia be‐fore the induction of anesthesia. An epidural catheterwas inserted into vertebral interspaces Th9/10 orTh10/11. General anesthesia was induced with pro‐pofol and 0.5 μg/kg/min remifentanil. Tracheal intu‐bation was facilitated with 0.9 mg/kg rocuronium.Anesthesia was maintained by total intravenous anes‐thesia with propofol, remifentanil, and an oxygen-airmixture. Although local anesthetics and fentanylwere not administered intraoperatively, 0.125% or0.25% levobupivacaine and fentanyl were adminis‐tered via epidural catheter for postoperative analgesiaafter anesthesia. The dose of propofol was deter‐mined based on weight (mg/kg/h). An infusion pump(Terufusion TCI pump TE-371, Terumo Co., Tokyo,Japan) without a target-controlled infusion (TCI) sys‐tem was used with a manually-controlled infusion(MCI) system16). Before the induction of anesthesia, abispectral index of EEG (BIS) monitoring (Med‐tronic, Doblin, Ireland; ver. 2.11) was established, aswell as routine monitoring, including automatic non‐invasive blood pressure, electrocardiogram and pulseoximeter. An arterial line was placed in either the leftor right radial artery for blood sampling after the in‐duction of general anesthesia. Propofol was titrated toBIS values of 40–60. If the BIS value decreased toless than 40, the dose of propofol was decreased. Ifthe BIS value increased to more than 60, the dose ofpropofol was increased. After surgery, the adminis‐

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tration of propofol and remifentanil was discontinuedand the time taken to wake up (return of conscious‐ness: ROC) was measured. The time from the termi‐nation of propofol infusion until ROC, defined aseyes opening and a handgrip on verbal command, aswell as the return of spontaneous respiration, definedas a respiratory rate of 8 breaths/min and lower than50 mmHg of PETCO2, were documented. We askedpatients to open their eyes every 30s after BIS levelsexceeded 70 following the termination of propofoladministration, and measured the time with a stop‐watch before meeting the above-mentioned wakingcriteria.

We collected blood samples at 0, 5, 10, 20, 30and 60 min after the termination of propofol infusionfor the determination of pharmacokinetics and geno‐typing.

DNA analysisWe analyzed genetic polymorphisms of

CYP2B6 and UGT1A9 from collected blood sam‐ples. Genomic DNA was extracted by the Departmentof Pharmacologenomics St. Marianna UniversityGraduate School of Medicine, and genetic polymor‐phisms of CYP2B6 and UGT1A9 were analyzed bythe Department of Drug Metabolism and Pharmaco‐kinetics, Showa Pharmaceutical University.

Genetic polymorphisms of CYP2B6 were deter‐mined by polymerase chain reaction-restriction frag‐ment length polymorphism (PCR-RFLP) analysis,while genetic polymorphisms of UGT1A9 were de‐termined by the direct sequence method using se‐quencing primers, an ABI BigDye terminator cyclesequencing kit (Applied Biosystems, Foster City, CA,USA), and an ABI PRISM 3730x1 DNA analyzer(Applied Biosystems). Genomic DNA prepared fromblood cells of the study participants was analyzed. Ithas been shown that the CYP2B6*6 allele is a usefulbiomarker for drug disposition17), and the intronic sin‐gle nucleotide polymorphism (SNP) UGT1A9I399C>T is associated with increased UGT1A9 pro‐tein levels and increased glucuronidation activities to‐ward propofol15)18).

Pharmacokinetic analysisWe also determined blood propofol levels by

high performance liquid chromatography (HPLC).Propofol (>99%) was obtained from Sigma-Aldrich(St. Louis, MO, USA) as an analytical standard19).Plasma samples (100μL) were treated by adding400μL of CH3OH. After vortex mixing, the tubes

were centrifuged at 10,000g for 10 min. An aliquot ofthe supernatant after filter treatment (Millex-LG,0.20μm, Millipore, Tokyo, Japan) was injected ontoan analytical C18 reversed-phase column (150 mm ×4.6 mm, Capcell Pak C18 UG120 S5, Shiseido, Tokyo,Japan) maintained at 30°C. The mobile phase was55% (v/v) acetonitrile at a flow rate of 0.6 mL/ min20).The elution profiles of propofol were monitored fluo‐rometrically at an excitation wavelength of 270nmand an emission wavelength of 310 nm. Plasma con‐centrations of propofol were kinetically analyzed byPhoenix WinNonlin software version 6 (Pharsight,Mountain View, CA, USA) using a two-compartmentanalysis15). We then calculated the half-life of distri‐bution (t1/2α) and elimination (t1/2β) and the area underthe blood concentration-time curve for 60 min(AUC0–60). The AUC was calculated using the trape‐zoid method by blood level measurements at eachpoint, from the termination of propofol infusion to 60min thereafter.

Statistical analysisResults are presented as the median (interquar‐

tile range, IQR). Chi square, Mann-Whitney andKruskal-Wallis tests were used for statistical analysis(SPSS ver.21; IBM, Tokyo, Japan). Furthermore,stepwise multiple linear regression was used to exam‐ine the factors to pharmacokinetics of propofol. Weanalyzed age, sex, height, body weight, body massindex (BMI), dose of propofol, CYP2B6, andUGT1A9 as factors to pharmacokinetics of propofol.

A P-value less than 0.05 was considered statisti‐cally significant.

Results

Ninety-four patients (51 males, 43 females) whounderwent respiratory surgery and total intravenousanesthesia using propofol were enrolled in St. Ma‐rianna University School of Medicine Hospital be‐tween June 2009 and May 2011.

1. Genotyping resultsAll 94 patients were genotyped for polymor‐

phisms in the CYP2B6 and UGT1A9 genes. A wild-type homozygote (G/G) of CYP2B6 G516T wasfound in 55 cases (59%), a variant heterozygote(G/T) was found in 35 cases (37%), and a variant ho‐mozygote (T/T) was found in 4 cases (4%). The wild-type homozygote (C/C) of UGT1A9 I399 C>T waspresent in 14 cases (15%), the variant heterozygote(C/T) was present in 43 cases (46%), and the variant

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Table 1A. Patient Demographics for CYP2B6

Table 1B. Patient Demographics for UGT1A9

homozygote (T/T) was present in 37 cases (39%)(Table 1A, 1B). There were no significant differencesin the patients’ backgrounds according to the geneticpolymorphisms of CYP2B6 and UGT1A9 (Table 1A,1B).

2. Correlations between genotype and propofolpharmacokinetics

No significant difference was found in changesof blood propofol levels after the termination of pro‐pofol infusion, between genetic polymorphisms ofCYP2B6 and UGT1A9 (Figure 1A, 1B). No correla‐tion was established between CYP2B6 and UGT1A9genotypes and pharmacokinetics such as t1/2α, t1/2β,AUC0–60, waking time, and propofol infusion dose(Table 2A, 2B). However, we observed that the C0

(plasma concentration of propofol just after termina‐tion of propofol infusion) significantly increased inhomozygotes (T/T) compared with that of heterozy‐gotes (G/T) and homozygotes (G/G) in genetic poly‐morphisms of CYP2B6 (P=0.025) (Figure 1A, Table2A).

3. Propofol pharmacokinetics and sex differencesC0 was significantly higher in female than in

male patients (Figure 2, Table 3). Also, the propofoldisappearance rate at 10 min after the termination ofinfusion was 60% (IQR: 54–70) in males and 67%(IQR 62–71) in females. The disappearance rate ofpropofol was significantly higher in females than inmales (P = 0.024) (Figure 2).

There was a significant difference between sexand each of the following factors: age, height, bodyweight, BMI, and C0 (Table 3). Stepwise multiple re‐gression analysis revealed that sex (B = 0.32, P =0.01) was a contributor to C0 (R = 0.27, P = 0.01).

Discussion

Several reports have shown that genetic poly‐morphisms of enzymes involved in propofol metabo‐lism affect the length of unconsciousness during pro‐pofol anesthesia14)21). We hypothesized that geneticpolymorphisms of CYP2B6, the main metabolic en‐zyme for propofol and UGT1A9, as well as sex dif‐ferences, could affect the pharmacokinetics of propo‐

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Fig. 1A. Change in blood propofol levels over time after the termination of propofol

infusion for CYP2B6. Wild-type homozygotes (G/G), variant heterozygotes

(G/T) and variant homozygotes (T/T) in genetic polymorphisms of CYP2B6.

Fig. 1B. Change in blood propofol levels over time after the termination of propofol

infusion for UGT1A9. Wild-type homozygotes (C/C), variant heterozygotes

(C/T) and variant homozygotes (T/T) in genetic polymorphisms of UGT1A9.

fol during propofol anesthesia.The allele frequencies of CYP2B6 G516T and

UGT1A9 I399C>T mutations identified in our study

were 23% and 62%, respectively. These frequenciesare similar to past reports of approximately 20% and64% of the allele frequencies of Japanese past reports

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Table 2A. Pharmacokinetic Analysis of Polymorphisms of CYP2B6

Table 2B. Pharmacokinetic Analysis of Polymorphisms of UGT1A9

in CYP2B6 G516T8)10) and UGT1A9 I399C>T muta‐tions9), respectively. In our study, no significant dif‐ferences were found between genetic polymorphismsand waking times after propofol anesthesia.

Approximately 70% of propofol is metabolizedvia glucuronic acid conjugation by UGT1A9, whilethe remaining 30% is metabolized by CYP2B6,CYP2C9, sulphotransferase (SULT) 1A, and NAD(P) quinone oxidoreductase (NQO1). UGT1A9 playsa large role in propofol metabolism, thereby suggest‐ing that any polymorphisms in this gene have a majorimpact on the metabolism of propofol. Several stud‐ies have demonstrated that genetic polymorphismsaffect propofol’s induction dose of unconsciousness,in addition to affecting its blood levels and clearanceafter the termination of propofol infusion15)22)23). Inour study, the CYP2B6 G516T mutation exhibited a

significant difference between G/T, G/G, and T/Tmutations for C0. However, this mutation did notshow significant differences in changes of otherblood propofol concentrations. On the other hand, theUGT1A I399C>T mutation did not show any signifi‐cant difference in changes of blood propofol levelsafter the termination of propofol infusion. We alsodid not find any significant difference between ge‐netic polymorphisms for t1/2α, t1/2β, and AUC0–60.These results suggest that, while genetic polymor‐phisms of CYP2B6 influenced the pharmacokineticsof propofol, the effects of UGT1A9 polymorphismson the pharmacokinetics of propofol were few. Ourdata thus demonstrate that genetic polymorphisms ofCYP2B6 may influence propofol pharmacokinetics.

Whereas, the glucuronic acid conjugation ofpropofol increased with UGT1A9 I399C>T muta‐

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Fig. 2. Change in blood propofol levels over time for each sex after the termination of

propofol infusion.

Table 3. Patient Demographics and Pharmacokinetics between Sexes

tion13). So, we had expected the AUC0–60 to be re‐duced with the mutation rather than in the absence ofthe mutation in the gene because of the fast rate ofmetabolism of propofol. However, we did not find

significant differences between UGT genetic poly‐morphisms, further demonstrating that genetic poly‐morphisms in UGT1A9 had little effect on propofolpharmacokinetics.

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We used a manually, not target-controlled, pro‐pofol infusion system. The TCI system infused targetlevel adjustment was by constant infusion and set adose of propofol (μg/mL) as effect site concentrationbased on age and body weight. In our study, we set apropofol infusion dose (mg/kg/h) based on bodyweight, with the goal of a 40–60 BIS level. There‐fore, we expected that, if a metabolic pathway be‐came inhibited due to the CYP2B6 G516T mutation,the blood level of propofol would then increase andthe level of BIS would decrease, requiring anesthesi‐ologists to decrease the dose of propofol per hour. Onthe other hand, we also expected that, if a metabolicpathway due to the UGT1A9 mutation became upre‐gulated, then the blood level of propofol would de‐crease and the level of BIS would increase, requiringanesthesiologists to increase the dose of propofol perhour. In our study, there was no significant differencebetween genetic polymorphisms for a dose perweight per time. This suggests that there was little ef‐fect of injection method on metabolic pathways influ‐enced by CYP and UGT genetic polymorphisms.

Similarly, Choong E et al. reported that therewere no significant impacts of CYP2B6 andUGT1A9 polymorphisms on propofol biotransforma‐tion after intravenous infusion using the TCI sys‐tem21). Our results showed that there was no signifi‐cant difference in pharmacokinetics between geneticpolymorphisms, consistent with the findings ofChoong E et al. Thus, our data highlight the lack ofeffect of two genetic polymorphisms in CYP2B6 andUGT1A9 on the rate of metabolism.

In our study, no significant differences were no‐ted for t1/2α, and t1/2β between genetic polymor‐phisms. The α phase is a distribution phase. Propofol,a highly lipid soluble drug, distributes to organs anddisappears rapidly from the blood after the termina‐tion of infusion. Changes in cardiac output affect αphase. In contrast, our study was carried out duringanesthesia, and patients with cardiac dysfunctionwere excluded, so that the cardiac output of patientswas kept constant24). Furthermore, metabolic enzymesdo not influence α phase, so there was little effect ont1/2α between genetic polymorphisms. The β phase isan elimination phase. After propofol redistributes tothe whole body, propofol slowly disappears from theblood and is eliminated from the body.

The main metabolic organ of propofol is theliver, and its hepatic clearance is dependent on hep‐atic blood flow25). Furthermore, the hepatic clearanceof propofol is high and is dependent on blood flow

changes but not on a decrease in metabolic activity.Total body clearance is more dependent on hepaticblood flow than metabolism25)26). Both hepatic and re‐nal blood flows were kept constant in our study. Fort1/2β to be affected more by hepatic clearance than bymetabolic activity, this would mean polymorphismsdo not affect t1/2β.

In our study, the median value of serum totalprotein was 7.1 g/dL (IQR 6.7–7.4), and the medianvalue of serum albumin was 4.3 g/dL (IQR 4.1–4.4).The serum protein-binding rate of propofol is repor‐ted as 97–98%7)27). During hypoproteinemia, the pro‐tein binding rate of propofol decreases, leading to anincrease in blood levels of unbound propofol which,in turn, may affect the pharmacokinetics and depth ofanesthesia25)28)29). In our study, patients with hypoal‐buminemia were not included. Hence, we also did notaccount for total protein levels in the analyses of thepharmacokinetics of propofol.

Recently, several reports have demonstrated sexdifferences for propofol, with the average time ofemergence after anesthesia shorter in females than inmales10)21)30)31), suggesting that males have a highersusceptibility to propofol than females32). Severalstudies have also demonstrated significantly higherlevels of the propofol metabolites propofol glucuro‐nide (PG), 4-hydroxypropofol (OHP), 4-hydroxypro‐pofol-1-O-β-D-glucuronide (Q1G), and 4-hydroxy‐propofol-4-O-β-D-glucuronide (Q4G) in females thanin males, suggesting that propofol metabolism isfaster in females compared with males10)21)33). In fe‐males, elimination and metabolic clearance are pro‐moted by a hormone balance involving estrogen andthe menstrual cycle21)30)32)34)35). The results of ourstudy suggest that the need to control perioperativeblood propofol levels to maintain a similar depth ofanesthesia is higher in females than in males. More‐over, our study showed a significant difference be‐tween males and females in C0. No significant differ‐ence was found for t1/2α and the median time ofemergence from anesthesia between the sexes.

Because males have more muscle and femaleshave more fat, this would be expected to affect thedistribution and times of emergence of a lipid solubledrug such as propofol, with shorter times of emer‐gence in females32). In our study, there were signifi‐cant differences in BMI between males and females.Although the age of patients for both sexes was high,the volume of fat and muscle were similar for bothgroups. These characteristics may lead to the lack ofsignificant differences in the distribution of propofol

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and times of emergence between the sexes. Hoymorket al. found the time of emergence was shorter in fe‐males than in males, although there were no signifi‐cant differences in propofol doses, duration of infu‐sion, and BIS levels just after the termination ofpropofol and at the return of consciousness betweenmales and females30). Although they infused propofolwith TCI system, our study differed in that we in‐fused propofol with MCI system. Additionally, theyreported a blood propofol level at waking that washigher in males than in females; the time of emer‐gence for males was also slower than for females30).Furthermore, a significant dissociation was found inthe predictive effect site level and the measurement ofblood levels of propofol of males in their study30). Itwas suggested that prediction effect site and bloodlevels do not correlate in males. Therefore, we specu‐late that only blood levels are not involved at wakingtime.

We found a significant difference between malesand females in blood levels of propofol just after thetermination of infusion (C0) and in the rate of declineof blood propofol levels for 10 min after the termina‐tion of propofol infusion.

The most important finding in our results wasthat sex was independently associated with C0 in mul‐tiple regression analysis. Hence, our pharmacokinet‐ics results agree with the theory that the metabolismof propofol is faster in females and that susceptibilityto propofol is higher in males.

LimitationsSeveral studies have found that genetic polymor‐

phism of CYP2B6 is prevalent, and it is hard to thinkonly one genetic polymorphism to influence metabo‐lism of propofol. Therefore, we need to examine theeffects of other SNPs aside from the SNP which weexamined in our present study on the metabolism ofpropofol. Additionally, because we did not analyzepropofol metabolites, we did not determine their rela‐tionship with sex differences and genetic polymor‐phisms; this also requires further study.

Conclusion

We suggest that the differences between femalesand males in the C0 and rate of decline of the propo‐fol blood concentration may cause individual differ‐ences in sensitivity and recovery of consciousnessfrom propofol anesthesia. We conclude that CYP2B6,but not UGT1A9, polymorphisms and sex differencesaffect propofol pharmacokinetics.

Further study is required to elucidate individualdifferences in the susceptibility to and pharmacoki‐netics of propofol.

Acknowledgements

We would like to thank Professor Haruhiko Na‐kamura, Department of Chest Surgery, St. MariannaUniversity School of Medicine, for his help in con‐ducting the study. We would also like to thank Pro‐fessor Hiroshi Yamazaki, Norie Murayama, NaomiShimada, and Asami Mori, Department of Drug Me‐tabolism and Pharmacokinetics, Showa Pharmaceuti‐cal University, for their help in conducting the study.

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