Long-Term Detection of Propofol Glucuronide in Urine Following Anesthetic Induction and Maintenance with Propofol

doi:10.4236/pp.2013.47076

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Pharmacology & Pharmacy, 2013, 4, 528-534

http://dx.doi.org/10.4236/pp.2013.47076 Published Online October 2013 (http://www.scirp.org/journal/pp)

Long-Term Detection of Propofol Glucuronide in Urine

Following Anesthetic Induction and Maintenance with

Propofol

Joseph Salerno*, Joseph Jones, Mary Jones, Charles Plate, Douglas Lewis

United States Drug Testing Laboratories, Inc. (USDTL), Des Plaines, USA.

Email: *[email protected]

Received August 7th, 2013; revised September 9th, 2013; accepted September 21st, 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Propofol is the most commonly used compound for the intravenous induction and maintenance of anesthesia. Propofol

addiction and abuse have become causes for concern in the healthcare community, especially among anesthesia and

surgical professionals. The US Drug Enforcement Administration does not list propofol on any Schedules and most

hospitals do not have inventory controls in place to prevent its misuse. Propofol is detectable in blood plasma as the

parent compound for as much as 15 hours post-anesthesia. The metabolite propofol glucuronide (PPFG) has been de-

tected in blood and urine as far out as 60 hours. Here we report the long-term renal excretion of PPFG in specimens

from A) four participants following a 14-day course of orally ingested propofol dosing, and B) a female patient follow-

ing anesthetic induction and 15 minutes’ maintenance with propofol. Urinary PPFG was measurable well above limits

of quantitation up to 6 days following oral ingestion and 28 days post-anesthesia. We also present a third set of data

evaluating the likelihood of passive exposure to aerosolized propofol in the surgical environment by analyzing the lev-

els of urinary PPFG of healthcare workers following operating room work shifts. The results presented here demon-

strate that quantitation of PPFG in urinary samples is an efficient method of long-term screening for propofol misuse

and abuse.

Keywords: Anesthetics; Drug Testing; Metabolism; Pharmacokinetics; Propofol; Propofol Glucuronide; Urine

1. Introduction

Propofol (2,6-diisopropylphenol; Diprivan®, AstraZeneca

Pharmaceuticals) is a fast-acting, short-duration, hypnotic

agent that is administered intravenously for the induction

and maintenance of general anesthesia [1]. With a quick

recovery time following induction and minimal side ef-

fects [2], propofol has become the most widely used com-

pound for intravenously administered general anesthesia

[3]. Propofol rapidly enters the Central Nervous System,

very smoothly induces unconsciousness, and undergoes

swift metabolic clearance [4]. The highly lipophilic na-

ture of propofol results in storage and slow release from

deep tissue depots such as fat deposits and muscle tissues

[5].

Although not traditionally seen as a drug of abuse,

non-procedural misuse of propofol by anesthesiology and

surgical healthcare professionals with direct access to the

compound has become a cause for concern [6]. Propofol

abuse among healthcare professionals increased five-fold

from 1997 to 2011, and despite a low incidence of abuse

among anesthesia-based providers (0.10%), the rate of

fatality due to abuse is high (28%) [6]. The fatality ha-

zard of propofol abuse owes in great part to the com-

pound’s extremely narrow window of safety resulting

from the rapid onset of unconsciousness during adminis-

tration. The small difference between a therapeutic dose

and a potentially hazardous dose that can cause acute

respiratory depression creates a very real risk of fatal

overdose if the drug is self-administered [7]. Propofol is

not scheduled with the US Drug Enforcement Admini-

stration and 71% of surveyed anesthesia programs have

no control system in place to secure and account for pro-

pofol supplies [6].

Propofol is metabolized in the liver where it is

*Corresponding author.

Long-Term Detection of Propofol Glucuronide in Urine Following

Anesthetic Induction and Maintenance with Propofol

529

oxidized to 1,4-di-isopropyl quinol, and both propofol

and quinol are subsequently conjugated to glucuronic

acid and excreted in urine [8]. Total body clearance rates

for propofol have generally been seen to exceed hepatic

blood flow indicating other potential routes of clearance

outside the liver [4,8]. Less than 0.3% of the parent

compound is excreted unchangeably [9]. Whether this

disappearance of native propofol in the excreted samples

is indicative of complete metabolic destruction of or

rapid sequestration in deep tissues has not been entirely

characterized. Propofol glucuronide (PPFG) is the pri-

mary metabolite among at least seven major and minor

metabolites, accounting for as much as 62% of recove-

rable conjugated propofol in urine specimens [9].

Post-mortem forensic protocols detect the use of pro-

pofol test for the parent compound in blood samples

[10-14]. However, the brief serum half-life of propofol

(21 - 56 minutes) [15] makes this approach unreliable for

routine substance abuse testing. To our knowledge, the

15-hour profile of propofol in plasma seen by Bleeker et

al. (2008) is the longest window of recovery of the parent

compound reported for blood samples [8]. In the same

report, Bleeker et al. detected urinary PPFG concen-

trations as far out as 60 hours post-anesthesia, suggesting

that testing for propofol use in living subjects is more

easily carried out by measuring PPFG concentrations in

urinary specimens.

Here we report the long-term disappearance profile for

urinary PPFG in specimens collected from a female

patient over a 28-day period following routine procedural

anesthetic induction and maintenance using propofol.

Specimens were assayed for PPFG (ng/mL) by liquid

chromatography tandem mass spectrometry (LC-MS/

MS), and PPFG levels were normalized to 100 mg/dL

creatinine to account for changes in urinary output [16].

In addition, we discuss the findings from two of our

unpublished pilot studies on urinary PPFG clearance, and

the implications of all three datasets on the practice of

routine screening for propofol misuse and abuse.

2. Experimental

2.1. Ethics Statement

The patient who provided specimens for this study is one

of the authors and an employee of United States Drug

Testing Laboratories (USDTL). Specimens provided for

one of our pilot studies were submitted voluntarily by

employees of USDTL. Specimens from the second pilot

study were de-identified aliquots remaining from speci-

mens referred to our lab for routine analysis and con-

sidered waste at the time of assay. Samples from USDTL

employees were voluntarily given, and neither these nor

the waste specimens required an ethics review.

2.2. Subject History and Specimen

Collection-Urinary PPFG Profile Following

Propofol Anesthesia

This study quantified the disappearance of PPFG in the

urine of a female patient following anesthetic induction

and maintenance with propofol during a routine colo-

noscopy examination. The patient was five feet and three

inches tall (1.6 m), 150 lbs. (68 kg), and age 45 - 50 years

old. Propofol was administered intravenously in a total of

250 mL of fluid. A total of 300 mg of propofol was

administered, beginning with a 30 mg induction. Anes-

thesia was maintained for 15 minutes following induction,

and sedation lasted for 25 minutes. Propofol was tolerat-

ed well by the patient.

Thirteen urine specimens ≥10 mL in volume were

collected from the subject periodically over a period of

28 days. The interval between specimen collections

varied from 1 - 5 days. Urine was collected in 100 mL

polypropylene specimen cups and stored at 2˚C - 8˚C

until tested. The patient’s daily medications, taken orally

prior to specimen collection, included 80 mg acetyl-

salicylic acid (aspirin), 10 mg pravastatin, 1000 mg fish

oil, 10 mg cetirizine hydrochloride, 1500 mg glucosa-

mine, 1250 mg chondroitin-sulfate, and a non-prescrip-

tion multivitamin.

2.3. Subject History and Specimen

Collection-Pilot Study #1: Urinary PPFG

Profile Following Oral Ingestion of Propofol

Pilot study #1 measured the concentration of PPFG in

urine samples taken from four USDTL employees who

had ingested 50 mg of propofol in gel-caps daily for 14

days. Following the 14 day ingestion, ≥10 mL samples

were collected at irregular intervals as the subjects

needed to void over a six day period, and tested for PPFG.

Urine was collected in 100 mL polypropylene specimen

cups and stored at 2˚C - 8˚C until tested. The participants

consisted of two males and two females between the ages

of 45 - 65 years and ranging in weight from 150 - 300

lbs.

2.4. Subject History and Specimen

Collection-Pilot Study #2: Urinary PPFG

Resulting from Incidental Exposure

Pilot study #2 utilized de-identified aliquots remaining

from specimens referred to our lab for routine analysis

and considered waste at the time of assay. Personal in-

formation for the donors of these specimens is not avai-

lable. The samples were originally collected from 27 cer-

tified registered nurse anesthetists immediately following

the completion of 8 hour or longer work shifts in

operating rooms where propofol was being administered

Long-Term Detection of Propofol Glucuronide in Urine Following

Anesthetic Induction and Maintenance with Propofol

530

to patients. The purpose of these samples was to test for

PPFG levels in the urine of anesthesia professionals

resulting from incidental exposure to aerosolized pro-

pofol during surgery.

2.5. Chemical Reagents and Materials

DRI® Creatinine-Detect reagent was purchased from

Microgenics Corporation (Fremont, CA, USA). The

internal standard, propofol glucuronide-d17 (PPFG-d17),

was purchased from Toronto Research Chemicals (To-

ronto, ON, Canada). PPFG was purchased from Cerilliant

Corporation (Round Rock, TX, USA). All solvents

(HPLC grade) were purchased from Thermo-Fisher

(Hanover Park, IL, USA). Anion exchange solid phase

extraction columns (Quaternary Amine with chloride

counter Ion, CUQAX12Z, 200 mg bed, 10 mL cartridge)

were purchased from United Chemical Technologies

(Bristol, PA, USA).

2.6. Quantification of Creatinine Concentration

of Specimens

Creatinine assays were quantified on an Olympus AU640

chemistry immunoanalyzer (Beckman Coulter, Inc., CA,

USA) using DRI® Creatinine-Detect reagent (Jaffe

method; Microgenics Corporation, Fremont, CA, USA)

[17].

2.7. Preparation of Calibration Standards and

Quality Control-PPFG

Stock solutions of PPFG and PPFG-d17 were prepared in

methanol at a concentration of 100 µg/mL. A PPFG

spiking standard working solution (0.40 µg/mL) was

prepared by further dilution with methanol. A PPFG-d17

internal standard working solution (0.40 µg/mL) was

prepared by dilution in methanol. A single-point cali-

brator (20 ng/mL) and a set of controls (0, 8, 25, and 80

ng/mL) were prepared by spiking 1 mL of certified

negative urine in a 13 × 100 glass culture tube with an

appropriate volume of PPFG spiking standard working

solution.

2.8. Specimen Preparation-PPFG

Each specimen was prepared separately by accurately

transferring 1 mL of urine to a 13 × 100 glass culture

tube. 50 µL of PPFG-d17 internal standard was added to

each specimen, calibrator or control and vortexed. The

tubes were centrifuged at 3400 × g for 5 minutes. The

samples were loaded onto the solid phase extraction

columns that had been preconditioned with 2 mL of

methanol, followed by 2 mL of deionized water. The

samples were allowed to flow through the columns at 1

mL/min. The columns were washed with 2 mL of

deionized water followed by 2 mL of methanol and then

dried under full vacuum for one minute. Drugs were

eluted from the columns into 13 × 100 glass tubes with 2

mL of methanolic formic acid (98:2) and evaporated

under nitrogen at 40˚C. The dried residues were recon-

stituted with 100 µL of deionized water by vortexing and

analyzed by LC-MS/MS.

2.9. LC-MS/MS Conditions-PPFG

Urine specimens were analyzed using an Agilent Techno-

logies 1200 system that consisted of a G1367D auto-

sampler, a G1379B degasser, G1312B binary pump, and

a G1310 isocratic pump (Wilmington, DE, USA). Sepa-

ration was achieved using a Phenomenex Synergi RP (50

mm × 2.0 mm, 2.0 µm particle size) column held at 50˚C

in a G1316B Thermostatted Column Compartment (Wil-

mington, DE, USA). Using a flow rate of 0.25 mL/min,

the solvent system was a gradient that consisted of A

(deionized water/0.1% formic acid) and B (acetonit-

rile/0.1% formic acid). The solvent program held B at

32% from 0.0 min to 8.0 min. The detector was an

Agilent Technologies 6460 tandem mass spectrometer

using electrospray ionization (ESI) in the negative mode

(Wilmington, DE, USA). The capillary voltage was set at

4000V, the nozzle voltage set at 1000V and the deso-

lvation gas (nitrogen) was heated to 350˚C with a flow of

10 l/min. The sheath gas (nitrogen) was heated to 300˚C

and delivered at 12 l/min. The internal standard (PPFG-

d17) was monitored using the m/z 370.2 > 193.9 (quanti-

fication ion; Frag = 155; CE = 20) and m/z 370.2 > 369.7

(qualifying ion; Frag = 155; CE = 0) transitions. The m/z

353.2 > 176.5 (quantification ion; Frag = 120; CE = 28),

the m/z 353.2 > 112.6 (quantification ion; Frag = 120; CE

= 12) and m/z 353.2 > 84.7 (qualifying ion; Frag = 120;

CE = 20) transitions were used to monitor PPFG where

Frag is the Fragmentation Voltage (V) and CE is the

Collision Energy (V). All data were processed using

MassHunter B.02.01 (Wilmington, DE, USA).

2.10. Identification Criteria-PPFG

The identification criteria used for this procedure in-

cluded four components: retention time, signal to noise,

baseline resolution and relative ion intensity. The

retention time of each analyte was required to be within

0.2 min of the calibrator. A signal to noise of greater than

3:1 was required of each ion chromatogram. A minimum

of 90% return to baseline was required to consider a peak

to be adequately resolved from a co-eluting peak. The

relative ion intensity of the productions for each analyte

(mass ratio) was required to be within 20% of the

corresponding relative ion intensity of the calibrator.

Long-Term Detection of Propofol Glucuronide in Urine Following

Anesthetic Induction and Maintenance with Propofol

531

3. Results

Our limit of detection (LOD) in all three of these studies

was 4 ng/mL, and our limit of quantitation (LOQ) was 8

ng/mL. Creatinine secretion from muscles is relatively

constant in an individual, and PPFG concentrations were

normalized to 100 mg/dL creatinine levels to correct for

differences in urinary production and flow-rate by the

patient resulting from fluctuations in hydration levels

[16].

Urine samples in the oral ingestion pilot study (pilot

study #1) were collected when the subjects needed to

void, and as such occurred at irregular intervals (Table 1).

We were only able to collect samples from subject #2 for

three days, and that subject’s complete urinary PPFG

profile was not available as a result. Subjects #1, #3, and

#4 all exhibited urinary profiles well above LOD/LOQ

out to 5 - 6 days (120 - 154 hours) following the last oral

dose. The urinary PPFG profile data of these subjects

most nearly followed an exponential decay trend (Figure

1), however, this trend explains the behavior of the data

only moderately well (R2 = 0.681), likely due to the small

size of our sample population and the wide range in

physical variables of the subjects in the sample. None of

the volunteers reported any anesthetic or euphoric feel-

ings associated with ingesting propofol orally.

Of the de-identified nurse anesthetist samples from the

second pilot study, only two samples measured above the

LOD/LOQ (4.58 ng/mL and 17.34 ng/mL; normalized to

100 mg/dL creatinine; Table 2). The average of the

remaining 25 samples was 0.23 ng/mL over a range of

0.01 ng/mL to 2.20 ng/mL (normalized to 100 mg/dL

creatinine).

Thirteen urine specimens were collected periodically

from the colonoscopy patient over a period of 28 days

post-anesthesia (Table 3). The disappearance profile for

PPFG in this patient displayed an exponential decay trend

(R2 = 0.953; Figure 2). Surprisingly, PPFG was detec-

table at levels well above the LOD/LOQ for as long as 28

days post anesthesia.

4. Discussion

4.1. Disappearance Profile of Urinary Propofol

Glucuronide

To our knowledge, only one other study has examined

the long-term profile of urinary PPFG (Bleeker et al.,

2008), which sampled blood and urine of patients out to

15 and 60 hours post-anesthesia respectively [8]. Based

on urinary clearance rates and percentage of recovered

PPFG, Bleeker et al. (2008) suggested that glucuroni-

dation of propofol would require 5 - 6 days to reach

completion and total clearance of propofol from the body,

however, the post-colonoscopy results presented here

Table 1. Urinary propofol glucuronide following sub-thera-

peutic dosing by oral ingestion: pilot study #1.1.

Subject/Hours

Post Dosing

PPFG

(ng/mL)

Creatinine

(mg/dL)

Normalized

PPFG2 (ng/mL)

#1/6 3222 15.7 20,522

#1/24 1237 50.7 2440

#1/36 183 31.2 587

#1/48 300 65.2 460

#1/72 109 102.5 106

#1/96 45 136.2 33

#1/120 30 115.0 26

#2/6 33,119 132.2 25,052

#2/24 5819 257.7 2258

#2/48 761 149.6 509

#2/72 493 193.7 255

#3/13.5 5573 57.1 9760

#3/20 451 74.9 602

#3/56.5 177 93.4 190

#3/81 326 142.5 229

#3/104 408 169.3 241

#3/129.5 358 243.3 147

#3/154 169 160.1 106

#4/22 9000 61.9 14,540

#4/37 853 68.0 1254

#4/49 226 42.7 529

#4/64.5 173 73.9 234

#4/86 103 79.2 130

#4/98 204 96.5 211

#4/99 215 111.1 194

#4/107.5 32 30.5 105

#4/118.5 91 87.9 104

#4/131.5 68 78.4 87

#4/143 89 88.4 101

#4/153 14 13.4 104

1Propofol glucuronide, creatinine and normalized propofol concentrations in

urine specimens collected from four individuals following 14 daily doses of

sub-therapeutic (50 mg), orally ingested propofol. Subjects consisted of two

males and two females between the ages of 45 - 65 years old and 150 - 300

lbs. 2Normalized PPFG concentrations are normalized to 100 mg/dL creat-

inine.

Long-Term Detection of Propofol Glucuronide in Urine Following

Anesthetic Induction and Maintenance with Propofol

532

Table 2. Urinary propofol glucuronide resulting from inci-

dental exposure: pilot study #2.1.

Subject PPFG

(ng/mL)

Creatinine

(mg/dL)

Normalized

PPFG2 (ng/mL)

#1 0.06 124.2 0.05

#2 0.03 136.3 0.02

#3 0.07 94.5 0.07

#4 0.05 159.3 0.03

#5 1.00 45.4 2.20

#6 0.01 28.6 0.04

#7 0.58 146.8 0.40

#8 0.02 68.5 0.03

#9 0.03 91.0 0.03

#10 0.01 50.6 0.02

#11 0.05 112.0 0.05

#12 0.01 188.9 0.01

#13 0.01 36.2 0.03

#14 0.32 213.6 0.15

#15 7.24 158.1 4.58

#16 0.02 65.9 0.03

#17 1.35 151.2 0.89

#18 11.2 64.6 17.34

#19 0.03 89.7 0.03

#20 0.44 126.6 0.35

#21 0.05 94.7 0.05

#22 0.01 48.6 0.02

#23 0.12 92.8 0.13

#24 0.65 194.0 0.34

#25 0.52 206.9 0.25

#26 0.50 178.2 0.28

#27 0.45 201.7 0.22

1Propofol glucuronide, creatinine and normalized propofol concentrations in

urine specimens collected from nurse anesthetists immediately following 8

hour shifts in surgical rooms during the use of propofol for patient

anesthesia. 2Normalized PPFG concentrations are normalized to 100 mg/dL

creatinine.

demonstrate easily measurable excretion of PPFG as far

out as 28 days (Table 3 and Figure 2).

The data from our oral ingestion pilot study #1 (Table

1) also showed clearly measurable levels of urinary

PPFG excretion as far as 6.4 days (154 hours) post-

dosing (Figure 1) in line with the results from Bleeker

Table 3. Propofol glucuronide, creatinine and normalized

propofol concentrations in urine specimens collected follo-

wing anesthetic induction and maintenanc e with propofol.

Subject PPFG

(ng/mL)

Creatinine

(mg/dL)

Normalized

PPFG1 (ng/mL)

1 1656 16.9 9799

4 627 13.1 4786

9 1026 34.3 2991

10 268 10.0 2680

11 282 14.3 1972

12 200 19.4 1031

14 149 21.3 700

17 141 20.0 705

18 204 30.0 680

21 679 100.0 679

22 27 10.0 270

26 49 40.0 123

28 11 10.0 110

1Normalized PPFG concentrations are normalized to 100 mg/dL creatinine.

Figure 1. Disappearance profile of urinary propofol glu-

curonide following 14 daily sub-therapeutic (50 mg) doses

by oral ingestion: pilot study #1.

et al. (2008). The oral ingestion data is interesting, in that

even at sub-therapeutic doses (50 mg daily) delivered

through the highly acidic stomach compartment, appre-

ciable recovery of urinary PPFG was observed, perhaps

suggesting that deep tissue storage (i.e. fat reserves,

muscle tissues) of propofol occurs very quickly follo-

wing dosing, and lasts much longer than previous data

have suggested.

Long-Term Detection of Propofol Glucuronide in Urine Following

Anesthetic Induction and Maintenance with Propofol

533

Figure 2. Disappearance profile of urinary propofol

glucuronide following intravenous induction and mainte-

nance of anesthesia.

Bleeker et al. (2008) hypothesized that renal reuptake,

presumably following release from sequestration in deep

tissues, and subsequent renal glucuronidation play a

major role in terminal elimination of propofol, and the

results presented here suggest their hypothesis is worth

closer pharmacokinetic investigation [8], though glucuro-

nidation may just as likely occur by the hepatic pathway

after rerelease. PPFG, like propofol, is highly lipophilic,

and the long-term excretion profile observed here may be

from slow release of both propofol and PPFG, with

subsequent conjugation of the parent compound. Further

study is necessary to completely elucidate the exact

nature and timing of storage and release.

4.2. Propofol vs. PPFG for the Detection of

Propofol Use and Abuse

Despite its narrow therapeutic window [7] propofol has a

high potential for abuse among healthcare professionals

with access to propofol stocks [18], and propofol abuse

has become a concern in the healthcare community [6].

The addictive nature of propofol has been previously

demonstrated [19,20], and several fatalities due to acute

intoxication without respiratory monitoring have occurr-

ed [10-14]. Data suggests that second-hand exposure to

propofol is high in hospital operating rooms and may

cause sensitization from chronic exposure, potentially

leading to an increased risk for use and abuse by anes-

thesia and surgical professionals [21,22]. More attention

to inventory control for propofol stocks may be war-

ranted [6], and screening to prevent non-procedural mis-

use and abuse by healthcare professionals with access

may be needed. Recent research has shown that the

course of propofol dependence can be rapid, and is often

accompanied by frequent physical injury of the user [23].

Although the population of propofol abusers is low, that

group carries the additional burden of a fatality rate (28%)

that is extremely high when compared with any tradi-

tional substance of abuse [6]. The importance of clear

identification of propofol abuse in at risk healthcare

professionals cannot be overstated.

The results shown here, along with those from Bleeker

et al. (2008), demonstrate that PPFG is a more reliable

biomarker for propofol abuse testing and monitoring than

propofol itself. Although propofol and PPFG have been

detected in several matrices including blood, urine, and

hair [24], as well as in fingernails by our laboratory group

(data not shown), a 28 day window of detection in urine,

as is shown here, would be more than sufficient as the

most cost-effective and efficient method of screening.

Patterns of addiction seen with propofol indicate abuse of

the compound involves multiple injections on frequent

occasions [10-14,20,23], and it is highly unlikely the

urinary PPFG profile for such behavior would show

faster terminal elimination from the body than is seen in

both the anesthetic and oral ingestion datasets presented

here (Figures 1 and 2).

Data from pilot study #2 involving nurse anesthetists

shows that passive exposure to aerosolized propofol in

the surgical environment provides a urinary PPFG profile

that is much different, and easily distinguishable, from

that of a person who has been administered the anesthetic

regardless of the route of administration. This suggests

that it should be easy to identify propofol abusers from

the general population of anesthesia professionals, and a

positive result cutoff of 200 ng/mL in urine specimens

should be sufficient to identify a person who is misusing

propofol for recreational purposes.

5. Conclusion

The results presented here demonstrate that PPFG has a

very long and robust disappearance profile in urine, and

has the potential to easily distinguish propofol abusers

from the greater population of healthcare professionals.

To our knowledge, this is the longest window of detec-

tion that has been demonstrated following propofol

ingestion of any sort. Propofol has a high potential for

abuse and is increasingly a cause for concern in the

healthcare community, and routine testing of healthcare

professionals with access to the compound may be

warranted. Lack of scheduling by the United States Drug

Enforcement Administration has resulted in easy and

under-regulated access to propofol in most hospitals

where no inventory control is present. Propofol itself has

a very short window of detection in blood and urine, and

the data presented here suggest that measuring PPFG in

urine samples is an efficient and reliable tool for routine

screening for propofol use and abuse.

Long-Term Detection of Propofol Glucuronide in Urine Following

Anesthetic Induction and Maintenance with Propofol

534

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