Gas Chromatographic/Mass 

Spectrometric Differentiation of 

Atenolol, Metoprolol, Propranolol, 

and an Interfering Metabolite 

Product of Metoprolol 

Mike K. Angier

Russell J. Lewis

Arvind K. Chaturvedi

Dennis V. Canfield

Civil Aerospace Medical Institute

Federal Aviation Administration

Oklahoma City, OK 73125

October 2004

Final Report

This document is available to the public

through the National Technical Information

Service, Springfield, Virginia 22161.

 

Office of Aerospace Medicine

Washington, DC 20591

DOT/FAA/AM-04/15
NOTICE

This document is disseminated under the sponsorship of

the U.S. Department of Transportation in the interest of

information exchange. The United States Government

assumes no liability for the contents thereof.
i

Technical Report Documentation Page 

1. Report No. 2. Government Accession No. 3. Recipient's Catalog No. 

DOT/FAA/AM-04/15 

4. Title and Subtitle 5. Report Date 

Gas Chromatographic/Mass Spectrometric Differentiation of Atenolol, October 2004 

Metoprolol, Propranolol, and an Interfering Metabolite Product of

Metoprolol 

6. Performing Organization Code 

7. Author(s) 8. Performing Organization Report No. 

Angier MK, Lewis RJ, Chaturvedi AK, and Canfield DV 

9. Performing Organization Name and Address 10. Work Unit No. (TRAIS) 

11. Contract or Grant No. 

FAA Civil Aerospace Medical Institute 

P.O. Box 25082 

Oklahoma City, OK 73125 

12. Sponsoring Agency Name and Address 13. Type of Report and Period Covered 

Office of Aerospace Medicine 

Federal Aviation Administration 

800 Independence Ave., S.W. 

Washington, DC 20591 14. Sponsoring Agency Code 

15. Supplemental Notes 

This work was accomplished under the approved task AM-B-04-TOX-204 

16. Abstract 

Pilots who successfully control their hypertension with medications, diet, and/or exercise can be medically certified to fly 

an aircraft. At the present time, approximately 8% of active pilots are designated as "hypertensive with medication" by the 

Federal Aviation Administration (FAA). One of the groups of antihypertensives is the beta-blocker. Of this group, 

atenolol, metoprolol, and propranolol are commonly prescribed, and they also have chemical and structural similarities. 

The FAA’s Civil Aerospace Medical Institute (CAMI) toxicologically evaluates postmortem biological samples collected 

from pilots involved in fatal civil aviation accidents. Over the 10-year period, 1993-2002, CAMI has identified 50 pilot 

fatalities wherein atenolol was found in 24 pilots, metoprolol in 19 pilots, and propranolol in 7 pilots, which is consistent 

with the fact that these drugs have been in the lists of the top 200 most-prescribed drugs in the United States. In a few of 

the 50 pilot fatality cases, initial analysis suggested the presence of atenolol and metoprolol. However, there was no 

medical history with these cases supporting the use of both of these drugs, and it is also unusual for a patient to be 

prescribed atenolol together with metoprolol and/or propranolol. Therefore, further examination of the cases, wherein 

atenolol and metoprolol were apparently present, was undertaken. Atenolol, metoprolol, and/or propranolol, with their 

possible metabolite(s), were extracted from the selected case specimens, derivatized with pentafluoropropionic anhydride 

(PFPA), and analyzed by gas chromatography/mass spectrometry (GC/MS). The MS spectra of the PFPA derivatives of 

these 3 antihypertensives and a metoprolol metabolite are nearly identical. All of the PFPA derivatives had baseline GC 

separation, with the exception of a metoprolol metabolite product, which co-eluted with atenolol. There were 4 primary 

mass fragments (408, 366, 202, and 176 m/z) found with all of the PFPA-beta-blockers and with the interfering 

metabolite product. Therefore, this metabolite product could be misidentified as atenolol. However, atenolol has 3 unique 

fragments (244, 172, and 132 m/z), metoprolol has 2 unique fragments (559 and 107 m/z), propranolol has 4 unique 

fragments (551, 183, 144, and 127 m/z), and the metoprolol metabolite product has 2 unique fragments (557 and 149

m/z). These distinctive fragments were further validated by (i) using a computer program that predicts logical mass 

fragments and (ii) performing GC/MS of deuterated PFPA-atenolol and PFPA-propranolol and of the PFPA-alphahydroxy metabolite of metoprolol. By using the unique mass fragments, none of the re-examined pilot fatality cases were 

found to contain more than 1 beta-blocker. Several unique mass fragments reported in this study can be used for the 

positive identification of the 3 commonly used and chemically/structurally similar beta-blockers and a co-eluting 

interfering metabolite product of metoprolol. Therefore, these mass ions can be used for differentiating and 

simultaneously analyzing these beta-blockers in biological samples. 

17. Key Words 18. Distribution Statement 

Forensic Science, Toxicology, Gas Chromatography/ Mass 

Spectrometery, Atenolol, Metoprolol, Propranolol, 

Interfering Metoprolol Metabolite Product 

Document is available to the public through the 

National Technical Information Service 

Springfield, Virginia 22161 

19. Security Classif. (of this report) 20. Security Classif. (of this page) 21. No. of Pages 22. Price 

Unclassified Unclassified 9 

Form DOT F 1700.7 (8-72) Reproduction of completed page is authorized 

1

GAS CHROMATOGRAPHIC/MASS SPECTROMETRIC DIFFERENTIATION

OF ATENOLOL, METOPROLOL, PROPRANOLOL, AND AN

INTERFERING METABOLITE PRODUCT OF METOPROLOL

INTRODUCTION 

Pilots who successfully control their hypertension with 

medication, diet, and/or exercise can be medically certified to fly aircraft. However, these pilots are considered 

hypertensive and are closely monitored by the Federal 

Aviation Administration (FAA) to ensure that their hypertension is properly controlled. Approximately 8% of 

the active pilots fall under the category of “hypertensive 

with medication.” During the investigation of fatal civil 

aviation accidents, postmortem samples obtained from 

pilots are submitted to the FAA’s Civil Aerospace Medical 

Institute (CAMI) for toxicological evaluation (1). During such evaluation, submitted samples are analyzed for 

prescription and nonprescription drugs (2), and it is 

common to find beta-blocker antihypertensives such as 

atenolol, metoprolol, and propranolol in the submitted 

biological samples. This observation is consistent with 

the fact that 28.7% of the U.S. general population have 

been diagnosed with hypertension (3), and these 3 antihypertensives have been in the lists of the top 200 drugs 

dispensed in the U.S. (4, 5).

During a 10-year period of 1993-2002, postmortem 

samples from 3290 civil aviation accident pilot fatalities 

(cases) were received by CAMI. Toxicological evaluation 

of these cases revealed that 50 of the 3290 fatalities had 

the commonly prescribed beta-blockers, atenolol, metoprolol, and propranolol. Out of the 50 fatalities, atenolol, 

metoprolol, and propranolol were found to be present in 

24, 19, and 7 fatalities, respectively, but the initial analysis 

indicated the presence of atenolol and metoprolol in 4 of 

these pilot fatalities. Since (i) the combined use of both 

drugs was not consistent with the history of the drug use 

by those pilots, (ii) it is uncommon to simultaneously 

prescribe 2 beta-blockers, and (iii) these commonly used 

antihypertensives have considerable amount of chemical 

and structural similarity (6), further examination was 

undertaken for those fatality cases wherein atenolol and 

metoprolol were initially detected. Such examination 

entailed selectively and simultaneously analyzing the 3 

commonly used beta-blockers in the submitted biological 

samples and rectifying any possible analytical interference 

with the antihypertensives.

MATERIALS AND METHODS

Materials

All chemicals, reagents, and solvents were purchased 

from commercial sources in the highest possible purity and 

were used without any further purification. Specifically, the 

beta-blockers atenolol, metoprolol, and propranolol were 

purchased from Sigma Chemical Company (St. Louis, 

MO); N-methyl-4-(4-bromophenyl)-1,2,3,4-tetrahydro1-naphthylamine (internal standard) was purchased from 

Pfizer, Inc. (Groton, CT); pentafluoropropionic anhydride (PFPA) was supplied by Pierce, Inc. (Rockford, IL); 

and atenolol-D7 and propranolol-D5 were obtained from 

Cerilliant Corporation (Round Rock, TX). The alphahydroxy metabolite of metoprolol was kindly provided 

as a gift by AstraZeneca Pharmaceuticals (Macclesfield, 

Cheshire, UK). Bovine whole blood was obtained from 

Mikkelson Beff, Inc. (Oklahoma City, OK).

All aqueous solutions of drugs, chemicals, and reagents 

were prepared in double deionized water (DDW) obtained from Milli-QTplus Ultra-Pure Reagent Water System 

(Millipore®, Continental Water Systems, El Paso, TX). 

A 500-ng/mL solution of the internal standard was also 

prepared in DDW. Positive controls of the beta-blockers 

at a concentration of 200 ng/mL were prepared in bovine

whole blood from their 1.0 mg/mL methanolic standards. 

These controls were prepared in pools large enough to 

provide replicates for the entire study. Bovine blood was 

also used for negative controls. All samples were stored 

at –20°C until analyzed.

Extraction 

Solid tissue specimens were homogenized in DDW (1:

2 w/w) by using a PRO250 post-mounted homogenizer 

(Pro Scientific, Oxford, CT), equipped with a generator 

(10 mm diameter) set at 22,000 rpm. Three-mL aliquots 

of controls and specimen fluids, and 3.0-g aliquots of tissue homogenates were transferred to individual 16 × 150 

mm screw top glass test tubes, and 1.0 mL (500 ng/mL) 

of the internal standard solution was added to each tube. 

Mixtures in the tubes were vortexed briefly and allowed 

to stand for 10 min. To each of the tubes, except those 

containing urine, was added 9.0 mL of ice-cold aceto-
2 

nitrile (4°C), and the contents in the tubes were mixed 

on a rotary mixer for 15 min. Subsequently, the tubes 

were centrifuged at 820 × g for 5 min to remove cellular 

particulate matter, including precipitated protein. The 

supernatants in the tubes were then transferred to 16 ×

100 mm culture tubes and evaporated to less than 1 mL 

in a 40°C-water bath under a stream of dry nitrogen. To 

all the tubes, including the tubes that contained urine 

samples, was then added 4.0 mL of 0.10 M phosphate 

buffer (pH 6.00). 

The buffered mixtures were transferred to solidphase extraction (SPE) columns (Bond Elute Certify®

Columns, Varian Co., Harbor City, CA), which were 

pre-conditioned with 2.0 mL methanol, followed by 2.0 

mL of the 0.10 M phosphate buffer. A column flow rate 

of 1–2 mL/min was maintained in each step by using a 

Varian 24 port positive pressure manifold (Varian Co., 

Harbor City, CA) with approximately 3 psi of nitrogen. 

Once the extracts had passed through, the columns were 

washed with 1.0 mL of 1.0 M acetic acid, followed by 

6.0 mL of methanol. The columns were dried after each 

wash for 5 min with 25-psi nitrogen. Analytes were eluted 

off the columns with 4.0 mL of the freshly prepared 2% 

ammonium hydroxide in ethyl acetate, and the eluants 

were collected in conical glass test tubes. 

The eluants collected in the test tubes were then 

evaporated to dryness in a water bath at 40°C under a 

stream of dry nitrogen, and subsequently, PFPA (50.0 

μL) and ethyl acetate (50.0 μL) were added to each tube. 

These tubes were then capped, vortexed briefly, and incubated in a heating block set to 70°C for 20 min for 

the PFPA-derivatization. After removing the tubes from 

the heating block and allowing them to cool to ambient 

temperature, the reaction mixtures were evaporated to 

dryness in the 40°C water bath. The residues were then 

reconstituted in 50.0 μL of ethyl acetate and transferred 

to autosampler vials for analyses. 

Gas Chromatographic/Mass Spectrometric 

Conditions

Analyses were performed by using a bench-top gas 

chromatograph/mass spectrometer (GC/MS) system, 

consisting of a Hewlett Packard (HP) 6890 series GC, 

interfaced with a HP 5973 quadrupole MS (Agilent 

Technologies, Palo Alto, CA). The GC/MS system was 

operated with a transfer line temperature of 280°C and a 

source temperature of 230°C. The GC separation of the 

analytes was achieved by using a HP-ULTRA-1 crosslinked 

100% methyl siloxane capillary column (12 m × 0.2 

mm i.d., 0.33 μm film thickness; Agilent Technologies, 

Palo Alto, CA). Helium was employed as the carrier gas 

at a flow rate of 1.0 mL/min. A HP 6890 autosampler 

was used to inject 1.0 μL of PFPA-derivatized products 

in ethyl acetate onto the GC/MS system. The GC was 

equipped with a split/splitless injection port operated at 

250°C in the splitless mode with the purge time of 0.5 

min. The GC oven temperature profile was 70–290°C at 

30°C/min, with a final hold time of 2.67 min, resulting 

in a total run time of 10 min. Initially, PFPA-derivatized 

standards of each analyte (1.0 μL of a 100.0 ng/μL ethyl 

acetate solution) were injected individually and analyzed 

using the full MS scan mode of 40 to 800 atomic mass 

units. Subsequently, the MS was operated in selected ion 

monitoring mode with a dwell time of 30 msec. 

Analysis Acceptability Criteria

Mass ions used for the identification and confirmation 

of each analyte were selected based on their abundance, 

mass-to-charge ratio (m/z), and uniqueness (Table 1). Acceptability criteria employed for the analysis were (i) ion 

Table 1. Retention times and mass fragments of the beta-blockers and interfering metabolite 

product.

Analytes Retention 

Times (min) Common Ions (m/z) Unique Ions (m/z) 

Atenolol 5.74 244,172,132 

Metoprolol 5.50 559,107 

Propranolol 5.80 551,183,144,127 

Interfering metoprolol 

metabolite product 5.75

408, 366, 202, 176 

557,149
3

ratios for a given analyte, measured as the peak area of a 

qualifier ion divided by the peak area of the confirmation 

ion, were required to be within ± 20% of the average of 

the ion ratios for the respective controls analyzed during 

that analysis; (ii) each ion monitored was required to 

have a minimum signal-to-noise ratio of 5; and (iii) the 

analyte was required to have a retention time within ±

0.20 min of the average retention time for the respective 

controls analyzed during that analysis. Any analysis of a 

particular analyte not meeting the aforementioned criteria 

was considered as either being negative or inconclusive 

for the analyte.

Mass Fragment Prediction

The distinctive fragments chosen for each analyte were 

validated for their uniqueness by using a computer program that predicted logical mass fragments of chemical 

compounds (HighChem Mass FrontierTM, ThermoFinnigan Corp., San Jose, CA). The predicted mass fragments 

were also subsequently confirmed by using the mass 

fragment patterns of the PFPA-derivatized atenolol-D7, 

propranolol-D5, and alpha-hydroxymetoprolol.

RESULTS AND DISCUSSION

The re-examination of the full scan mass spectral data 

of those fatality cases, wherein atenolol and metoprolol were initially suspected, revealed that the apparent 

atenolol peak was not atenolol, but it was most likely a 

co-eluting metabolite product of metoprolol. Such near 

misidentification highlighted a need for the development 

of a selective analytical method that can differentiate commonly used, chemically/structurally similar beta-blockers 

(6) and their possible interfering metabolite(s)/ product(s). 

In the present study, a GC/MS method is described that 

selectively distinguishes the 3 beta-blockers from each 

other and from an interfering metabolite product of 

metoprolol.

Under the adopted instrumental conditions, the retention times for metoprolol, atenolol, and propranolol 

were 5.50, 5.74, and 5.80 min, respectively (Table 1), 

suggesting a baseline separation (Fig. 1). However, a metoprolol metabolite product interfered with atenolol, as this 

product co-eluted with the beta-blocker. The mass spectra 

of these 4 PFPA-analytes were nearly identical, as there 

were 4 dominating common fragments (408, 366, 202, 

and 176 m/z) with the 3 beta-blockers and the interfering metabolite product (Figs. 2-5). Given the retention 

times and the 4 dominating mass fragments, the metoprolol metabolite product could easily be misidentified 

as atenolol. This limitation was the reason for initially 

suspecting both atenolol and metoprolol in the pilot fatality cases. However, further in-depth examination of the 

mass spectral characteristics and chemical fragments of 

the analytes revealed the presence of 3 unique fragments 

(244, 172, and 132 m/z) for atenolol, 2 unique fragments 

(559 and 107 m/z) for metoprolol, 4 unique fragments 

(551, 183, 144, and, 127 m/z) for propranolol, and 2 

unique fragments (557 and 149 m/z) for the interfering 

metoprolol metabolite product. The uniqueness of the 

mass ions was further confirmed by the ThermoFinnigan 

HighChem Mass FrontierTM computer program and by 

the PFPA-atenolol-D7, PFPA-propranolol-D5, and PFPAalpha-hydroxymetoprolol GC/MS analyses.

The 3 major urinary metabolites of metoprolol are 

O-demethylated and oxidized, oxidative-deaminated, 

and aliphatic hydroxylated products (7, 8). The first 

2 metabolites have a carboxyl group and a secondary 

Figure 1. Total ion chromatogram of the PFPA-derivatized atenolol, metoprolol, and propranolol. Propranolol Atenolol 

5.20 5.40 5.60 5.80 6.00 6.20 6.40 6.60 6.80 0

20000

40000

60000

80000

100000

120000

140000

160000

180000

200000

220000

240000

260000

280000

300000

320000

Time-->

Abundance

Metoprolol 
4 

Figure 2. PFPA-atenolol mass spectrum, showing unique mass fragments for atenolol and mass 

fragments shared by all 3 beta-blockers and by the interfering metoprolol metabolite product.

50 100 150 200 250 300 350 400 450 0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

7500

8000

8500

9000

9500

m/z-->

Abundance 366

408

43

202

176

119

82 244 146

 132 172

O N

F F

F F

F

N

F F

F F

F

OH

N

F F

O

N

O

O

F F

F F

F F

F

F F

F

HO NH

O

F F

F F

F

O

F F

F F

F

HO N

F F

F F

F

O NH

F F

F F

F

Atenolol•2PFPA

N O

NH2

O

O

F

F F

F

F

O

F

F F

F

F

O

Figure 3. The mass spectrum of the PFPA-derivatized metoprolol, along with the chemical 

structures of the derivatized beta-blocker and primary fragments. 

50 100 150 200 250 300 350 400 450 500 550

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

m/z-->

Abundance 366

408

43

202

176

107

82 246 147 559

O

N O

O

F

F F

F

F

O

F

F F

F

F

O

HO

O

N O

O

F

F F

F

F

O

F

F F

F

F

O

Metoprolol•2PFPA
5

Figure 4. The mass spectrum of the PFPA-derivatized propranolol, along with the chemical 

structures of the PFPA-propranolol and relevant mass fragments.

50 100 150 200 250 300 350 400 450 500 550

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

m/z-->

Abundance 366

43

408

115 202

176

144

82

246 268 551

 127

 183

N O

O

F

F F

F

F

O

F

F F

F

F

O

O

H2O

•

N O

O

F

F F

F

F

O

F

F F

F

F

O

Propranolol•2PFPA

Figure 5. The mass spectrum of the product generated from the PFPA-derivatized alphahydroxymetoprolol, along with the likely chemical structures and primary fragments. 

•

O

O

O

N

O

O

F F

F F

F F

F

F F

F

HO

F F

F F

F

50 100 150 200 250 300 350 400 450 500 550 0

Abundance 366

408

557

202 43 149 176

119

1000

2000

3000

4000

5000

6000

7000

8000

9000

Metoprolol Metabolite

Product•2PFPA

O

N O

O

F

F F

F

F

O

F

F F

F

F

O

O

?

m/z-->

•

O

O

O

N

O

O

F F

F F

F F

F

F F

F

HO

F F

F F

F

50 100 150 200 250 300 350 400 450 500 550 0

Abundance 366

408

557

202 43 149 176

119

1000

2000

3000

4000

5000

6000

7000

8000

9000

Metoprolol Metabolite

Product•2PFPA

O

N O

O

F

F F

F

F

O

F

F F

F

F

O

O

?

m/z-->
6

aliphatic hydroxyl group, but 1 of these 2 metabolites 

also has a secondary amino group. The third metabolite 

has 2 aliphatic hydroxyl groups and 1 secondary amino 

group. Based on the extraction and GC procedures 

adopted in this study and the selected mass fragment 

pattern of the interfering peak, the 2 acid metabolites 

were ruled out as possible interfering substances with 

atenolol. The third hydroxyl and amino group containing 

metabolite (alpha-hydroxymetoprolol) has 3 sites that 

can react with PFPA and, thereby, can generate a product 

with 3 CF3CF2CO– moieties. Approximately 0.11 min 

prior to the atenolol-interfering peak, there was also a 

non-interfering peak that had a parent ion and a mass 

fragmentation pattern consistent with that expected for 

the (CF3CF2CO)3–hydroxyl/amino metoprolol metabolite, i.e., alpha-hydroxymetoprolol, but the analyte that 

co-eluted with atenolol had mass fragments similar to 

those of a (CF3CF2CO)2–hydroxyl/amino metoprolol 

product, having a keto group in place of the hydroxyl 

group of alpha-hydroxymetoprolol. The presence of the 

(CF3CF2CO)2–metoprolol product could not be explained by the non-derivatization of the alpha-hydroxyl 

site, since there is no apparent steric hindrance for the 

site in the molecule. However, it could be possible that 

the hydroxyl group would have been converted into the 

keto group because of a chemical rearrangement prior to, 

or during, the PFPA derivatization and/or the subsequent 

loss of 1 of the 3 CF3CF2CO– groups of the derivatized 

alpha-hydroxymetoprolol upon exposure to the high 

temperature at the GC injector port, thus also generating a product with only 2 CF3

CF2CO– groups and a keto 

group. The mass spectral characteristics of this interfering 

metabolite product (Fig. 5) were further confirmed by 

analyzing a standard of alpha-hydroxymetoprolol after 

its PFPA derivatization. During this analysis, the interfering metabolite product peak was present along with 

the peak of 3 PFPA-alpha-hydroxymetoprolol. These 

findings suggest that the alpha-hydroxy metabolite of 

metoprolol was partially converted to the interfering, 

possible keto product. 

While atenolol was initially identified in a few metoprolol-positive cases, it was not detected in all metoprolol 

cases. This finding is most likely because the formation 

of the interfering metabolite product seems to be dependent upon the concentration of alpha-hydroxymetoprolol. In cases where alpha-hydroxymetoprolol was 

present in small quantities, the interfering product was 

undetectable and, thus, was not found to contain the 

atenolol-interfering analyte. Because of this concentration-production relationship, atenolol was initially 

detected or suspected in only a few metoprolol-positive 

cases wherein alpha-hydroxymetoprolol was possibly 

present in large quantities.

Overall, several unique mass fragments reported 

herein can be used to positively identify the 3 common 

beta-blockers and the co-eluting metoprolol metabolite 

product. By monitoring the selected unique mass fragments and, thereby, taking the selective analytical approach, none of the mentioned pilot fatality cases were 

found to contain more than 1 beta-blocker. Therefore, the 

analytical method reported in this study can be suitably 

adopted for selectively differentiating and simultaneously analyzing these structurally similar beta-blockers 

in biological samples.

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