Article

b-Blocker Dialyzability in Maintenance Hemodialysis Patients

A Randomized Clinical Trial

Alvin Tieu,1 Thomas J. Velenosi,1 Andrew S. Kucey,1 Matthew A. Weir,2,3 and Bradley L. Urquhart1,2,4

Abstract
Background and objectives There is a paucity of data available to describe drug dialyzability. Of the available
information, most was obtained before implementation of modern hemodialysis membranes. Our study charac- 1
Departments of
terized dialyzability of the most commonly prescribed b-blockers in patients undergoing high-flux hemodialysis. Physiology and
Pharmacology and
2
Design, setting, participants, & measurements Patients on hemodialysis (n=8) were recruited to an open label, Division of
Nephrology, and
pharmacokinetic, four-way crossover trial. Single doses of atenolol, metoprolol, bisoprolol, and carvedilol were 3
Epidemiology and
administered on separate days in random order to each patient. Plasma and dialysate drug concentrations were Biostatistics,
measured, and dialyzability was determined by the recovery clearance and arterial venous difference methods. Department of
Medicine, Schulich
Results Using the recovery clearance method, the dialytic clearance values for atenolol, metoprolol, bisoprolol, and School of Medicine
and Dentistry, The
carvedilol were 72, 87, 44, and 0.2 ml/min, respectively (P,0.001). Applying the arterial venous difference University of Western
method, the dialytic clearance values of atenolol, metoprolol, bisoprolol, and carvedilol were 167, 114, 96, and Ontario, London,
24 ml/min, respectively (P,0.001). Ontario, Canada; and
4
Lawson Health
Research Institute,
Conclusions Atenolol and metoprolol are extensively cleared by hemodialysis compared with the negligible London, Ontario,
dialytic clearance of carvedilol. Contrary to estimates of dialyzability on the basis of previous literature, our data Canada
indicate that bisoprolol is also dialyzable. This finding highlights the importance of conducting dialyzability
studies to definitively characterize drug dialytic clearance. Correspondence:
Clin J Am Soc Nephrol 13: 604–611, 2018. doi: https://doi.org/10.2215/CJN.07470717 Dr. Bradley L.
Urquhart, 1151
Richmond Street,
Medical Sciences
Introduction elimination, and kidney-mediated drug clearance. The Building Room 216,
The importance of cardiovascular disease among majority of drugs are not tested in patients on dialysis London, ON, Canada
N6A 5C1. Email: Brad.
patients with CKD cannot be overstated. It accounts during the drug development process, which results
Urquhart@schulich.
for nearly 45% of deaths among patients on hemodi- in a lack of appropriate dosage recommendations (12– uwo.ca
alysis, an incidence 10–20 times greater than in the 15). Drug disposition is an especially important con-
general population (1–3). Over the past four decades, sideration in patients on hemodialysis because there is
b-adrenergic receptor antagonists (b-blockers) have minimal to no residual kidney function for drug
emerged as a fundamental component of treating excretion. Despite requirements to characterize kidney-
cardiovascular disease. b-Blockers decrease BP, heart mediated elimination during drug development, there
rate, myocardial oxygen demand, arrhythmia, and are very minimal data on drug clearance in patients on
oxidative stress, and they improve left ventricular hemodialysis. Specifically, drug dialyzability—the effi-
function (4). More importantly, their ability to reduce ciency of drug removal by dialysis—is likely to vary
mortality has been shown in numerous randomized among b-blockers, which should be considered when
clinical trials (5–8). Although b-blockers are widely they are prescribed to patients. The use of drugs that are
prescribed in patients on hemodialysis, this is on the highly dialyzed can result in subtherapeutic plasma
basis of their proven efficacy in patients with normal concentrations during and after hemodialysis and in-
kidney function. Extrapolating findings from the general crease the risk for adverse clinical outcomes (16). Currently,
population to patients with CKD has a number of caveats. definitive data on drug dialyzability are only available
The pharmacokinetics of many drugs are altered in CKD, for 10% of medications.
including both kidney- and nonkidney-mediated elim- The dialyzability of b-blockers is presumed largely
ination (9–11). Expectations that b-blockers will deliver on the basis of physicochemical characteristics and not
similar therapeutic efficacy in patients on hemodialysis experimental evidence (17). Of the available informa-
compared with the general population are based on very tion, most data were obtained before implementation
little evidence. of modern high-flux dialysis membranes, rendering
For drugs to be approved for use in patients, detailed many of the older studies irrelevant (18). Therefore,
pharmacokinetic analysis must be undertaken to char- this study was conducted to define the modern
acterize parameters, such as bioavailability, metabolic dialyzability of the most commonly used b-blockers.

604 Copyright © 2018 by the American Society of Nephrology www.cjasn.org Vol 13 April, 2018
Clin J Am Soc Nephrol 13: 604–611, April, 2018
We hypothesized, on the basis of physicochemical charac-
teristics and previous literature (Table 1), that atenolol and
metoprolol would be highly dialyzed, whereas bisoprolol
and carvedilol would be minimally removed during hemo-
dialysis (19–22).
Materials and Methods
Study Design and Participant Eligibility
We conducted an open label, four-way crossover trial of the
four most commonly prescribed b-blockers in Ontario,
Canada—atenolol (50 mg), metoprolol (50 mg) bisoprolol
(5 mg), and carvedilol (6.25 mg)—among eight patients
receiving maintenance hemodialysis at the London Health
Sciences Centre hemodialysis units. The sample size was de-
termined by a power calculation using preliminary data and
assuming an a of 0.05 and power of 0.8. Patients were at least
18 years of age and receiving thrice weekly hemodialysis for
at least 90 days before the study. We excluded patients with
significant gastrointestinal/liver disease, patients with body
mass index .40 kg/m2, and those who could not safely
receive a study b-blocker (treatment with contraindicated
medications, prior adverse drug reactions to b-blockers,
severe reactive airway disease, or hemodynamic instability
during dialysis). Patients who met the eligibility criteria
provided informed written consent in accordance with the
Declaration of Helsinki. This study was approved by the
Health Sciences Research Ethics Board at Western University
(104909; registered at clinicaltrials.gov: NCT03361280).
Clinical Data Collection, Interventions, and Follow-Up
We randomly administered a single oral dose of one of
the study b-blockers 4 hours before hemodialysis initiation.
To achieve randomization, each b-blocker was assigned a
number between one and four, and a random number
generator was used to determine treatment order. A
research assistant generated the randomization sequence,
and the patient’s nephrologist or nurse provided the
b-blocker on the study day. Because this was an open
label study, there was no concealment of treatment. This
process was repeated with each of the three remaining
b-blockers during separate dialysis sessions, which were a
minimum of 48 hours apart. During each hemodialysis
treatment, blood samples were collected from the arterial and
venous ports at six time points. During 4-hour dialysis
treatments, we collected blood at 0, 0.5, 1, 2, 3, and 4 hours.
During 3.5-hour dialysis treatments, we collected blood at
hours 0, 0.5, 1, 1.5, 2.5, and 3.5. For 3-hour dialysis treatments,
we collected blood at hours 0, 0.5, 1.5, 2, 2.5, and 3. Arterial
blood samples were used to determine hematocrit. For all
treatments, we also collected the total spent dialysate into a
200-L food-grade plastic barrel. We collected demographic
information, health status, and dialysis prescription details at
the time of study enrolment. The study period was from
February 2015 to March 2016.
b-Blocker Extraction Analyses with Mass Spectrometry
b-Blockers were extracted from plasma and dialysate
samples using solid-phase extraction cartridges (Phenomenex,
Torrance, CA) conditioned according to the manufacturer’s
instructions. b-Blocker concentrations in plasma (free
plus protein bound) and dialysate were determined by
b-Blocker Dialyzability, Tieu et al. 605
ultraperformance liquid chromatography coupled to quad-
rupole time-of-flight mass spectrometry (Waters, Milford,
MA). Methodologic details can be found in Supplemental
Material.
Determining Dialytic Clearance
The two main methods to evaluate the clearance of med-
ications during hemodialysis are (1) the arterial venous (A-V)
difference method and (2) the recovery clearance method, and
they are described by the following equations (18,23–25):
CLA-V ¼ QP ½ðAconc 2 Vconc Þ=Aconc  þ QUF ½Vconc =Aconc 
; (1)
QP ¼ QB ð1 2 HctÞ
where CLA-V is A-V difference clearance, QP is mean plasma
flow rate, QB is mean blood flow rate, QUF is mean ultra-
filtration rate, Hct is hematocrit, Aconc is arterial plasma
drug concentration, and Vconc is venous plasma drug con-
centration. Also,

CLR ¼ Rdrug AUC0-T ; (2)
where CLR is dialyzer clearance, Rdrug is total amount of
drug recovered in dialysate, and AUC0-T is the area under
the plasma concentration-time curve during dialysis. The
AUC0-T was calculated by the trapezoidal method using
GraphPad Prism (version 6.01 for Windows; GraphPad
Software, San Diego, CA).
Statistical Analyses
We performed all statistical analyses using GraphPad Prism
(version 6.01 for Windows; GraphPad Software). We conduc-
ted hypothesis testing of atenolol, metoprolol, bisoprolol, and
carvedilol clearance using one-way ANOVA. After rejection of
the null hypothesis, multiple comparisons were evaluated by
Tukey post hoc test. Results are presented as mean6SD. We
considered a P value ,0.05 statistically significant.
Results
Assay Validation and Performance
The recovery percentages of atenolol, metoprolol, bisopro-
lol, and carvedilol using solid-phase extraction were 101%,
112%, 93%, and 112%, respectively. The intraday accuracy
and precision were assessed using five analytical replicates of
the lowest concentration on the dialysate calibration curve.
Accuracy, expressed as a bias percentage, was determined
by comparing the mean measured concentration with the
nominal concentration. Precision was determined by calcu-
lating the coefficient of variation percentage of the five
replicates. Using a signal-to-noise ratio of at least 10:1, the
lower limit of quantification of the calibration curve dis-
played acceptable accuracy (,10%) and precision (,10%) for
all b-blockers, except for the precision of carvedilol, which
was slightly above this limit. Specifically, the biases and
coefficients of variation were 4.2% and 1.1% for atenolol, 1.9%
and 1.5% for metoprolol, 2.0% and 2.7% for bisoprolol, and
26.0% and 12.5% for carvedilol, respectively.
Clinical Characteristics of Subjects
All eight subjects completed the pharmacokinetic four-
way crossover trial, and baseline clinical information is
606 Clinical Journal of the American Society of Nephrology

Table 1. Physicochemical properties and dialyzability statements for study b-blockers

Industry Review
Statements Articles
Physicochemical Expected
b-Blocker
Properties Levin Chazot Chen Redon Dialyzability
Product Dialysis of
et al. and et al. et al.
Monographs Drugs 2013a
(21) Jean (19) (20) (22)

Atenolol Molecular mass: Moderately Conventional D D D D High

266 D dialyzable HD: yes; dialyzability
Water solubility: (20%–50%) modern
13,500 mg/L HD: likely
Proteinbinding:10%
VD: 4.2 L/kg
Metoprolol Molecular mass: No statement Conventional D D D ND High
267 D HD: yes; dialyzability
Water solubility: modern
16,900 mg/L HD: likely
Proteinbinding:10%
VD: 3.2 L/kg
Bisoprolol Molecular mass: Not Conventional ND ND ND ND Low
325 D dialyzable HD: yes; dialyzability
Water solubility: modern
2,240 mg/L HD: no
Proteinbinding:30% data
VD: 3.0 L/kg
Carvedilol Molecular mass: Not Conventional ND ND ND ND Low
406 D dialyzable HD: no; dialyzability
Water solubility: modern
0.583 mg/L HD:
Protein binding: unlikely
.98%
VD: 1.6 L/kg

Yes indicates that dialysis was found to enhance drug clearance from previously published studies. No indicates that dialysis was not
found to enhance drug clearance from previously published studies. No data indicate that no data or assumptions from physicochemical
properties exist to describe drug dialyzability. Likely drug is likely to be cleared by HD on the basis of physicochemical parameters, but no
data exist. Unlikely drug is unlikely to be cleared by HD on the basis of physicochemical parameters, but no data exist. VD, volume of
distribution; HD, hemodialysis; D, drug is listed as dialyzable in corresponding review article; ND, drug is listed as not dialyzable in
corresponding review article.
a
Annual guidelines published by Renal Pharmacy Consultants, LLC (Saline, MI). Dialyzability is on the basis of scientific and industry
data.

presented in Table 2. The mean age was 58 years old (rang-
ing from 28 to 80 years old), mean height was 1.7 m, and
mean weight was 95 kg. The mean body mass index was
32.6 kg/m2. There were four different dialyzers used in this
study: FX600, FX800, FX1000, and Revaclear Max 400. The
higher-value FX hemodiafilters have minor increases in their
Kf and clearance of metabolites (e.g., urea and creatinine) (26).
The Revaclear Max 400 dialyzer has a similar Kf but an elevated
clearance of metabolites compared with the FX1000 (27).
Safety
b-Blocker treatments were well tolerated by all study
participants, and no serious adverse drug reactions occurred.
No abnormalities in heart rate and BP were observed during
the study.
Dialyzability of b-Blockers in Patients on Maintenance
Hemodialysis
Recovery Method. Collection and analysis of plasma
samples over the duration of the hemodialysis session
allowed us to create plasma concentration-time profiles
(Figure 1) and determine b-blocker exposure for each subject
(reported as AUC02T). For atenolol, metoprolol, bisoprolol,
and carvedilol, patient drug exposures were 827.9, 106.9,
180.7, and 150.5 ng∙h/ml. The amounts of b-blocker re-
covered in total spent dialysate were 3.7, 0.6, 0.5, and 0.0 mg,
respectively. Drug exposure values and the total amounts of
drug recovered in dialysate were applied to the recovery
clearance method (Equation 2) to calculate dialytic clearance.
The null hypothesis that there is no difference in clearance
between any of the b-blockers was rejected (P,0.001).
Atenolol was readily dialyzable with a dialytic clearance of
72621 ml/min, which was similar to metoprolol’s clearance
of 87628 ml/min (Figure 2). The clearances of atenolol and
metoprolol were considerably higher than that bisoprolol at
4469 ml/min (P=0.02 compared with atenolol and P,0.001
compared with metoprolol). Carvedilol had a substantially
lower clearance (0.260.6 ml/min; P,0.001) than all of the
other study b-blockers.
A-V Difference Method. The blood flow and predialysis
hematocrit for each subject are shown in Table 2. These two
variables along with the difference in b-blocker concentra-
tions between the arterial and venous ports were used to
calculate dialyzability values by applying the A-V differ-
ence equation (Equation 1). The null hypothesis that there is
no difference in clearance between any of the b blockers
Table 2. Clinical characteristics of participants in a crossover trial assessing the dialyzability of four b-blockers

Subject
BB002 BB003 BB004 BB005 BB006 BB007 BB008 BB009
Identification

Sex Man Man Man Woman Man Man Man Man

Ethnicity White White White White Aboriginal Black White White
Canadian
Age, yr 42 73 66 28 47 72 80 53
Clin J Am Soc Nephrol 13: 604–611, April, 2018

Weight, kg 94 129 54 82 118 90 90 106

Height, m 1.7 1.9 1.7 1.5 1.7 1.6 1.7 1.8
Body mass 32.2 35.6 19.2 37.7 38.7 33.8 30.3 33.6
index, kg/m2
Residual kidney 300 425 260 Anuric Anuric 500 300 300
output, ml/d
Cause of CKD RPGN DM and PCKD Renux DM and HTN DM and DM
HTN nephropath HTN HTN
Dialysis 4 4 3 3.5 4 4 3 4
duration, h
Dialysis 3 3 3 3 3 3 3 3
frequency,
sessions
per week
Dialyzer type FX800 FX1000 FX600 FX600 FX1000 FX800 FX600 Revaclear
Max 400
Mean blood 382 323 354 397 287 385 325 313
flow rate,
ml/mina
Dialysis 1.560.04 1.160.12 1.460.11 1.660.15 1.260.02 1.660.03 1.060.04 1.160.03
adequacy, Kt/Va
Vascular access Central Central Fistula Fistula Central Central Fistula Fistula
catheter catheter catheter catheter
Hematocrit, 0.2760.01 0.3060.01 0.3360.01 0.2960.01 0.2760.01 0.2860.01 0.2960.02 0.3560.01
predialysisa
Hematocrit, postdialysisa 0.2460.01 0.3460.02 0.3660.01 0.3360.01 0.2860.01 0.3060.01 0.3260.03 0.3760.01

RPGN, rapidly progressive GN; DM, diabetes mellitus; HTN, hypertension; PCKD, polycystic kidney disease.
a
Mean over the four dialysis sessions 6SD.
b-Blocker Dialyzability, Tieu et al.
607
608 Clinical Journal of the American Society of Nephrology

Figure 1. | b-Blocker plasma concentration-time profiles of patients with ESKD during hemodialysis. Plasma concentration-time profiles of
atenolol (A), metoprolol (B), bisoprolol (C), and carvedilol (D) during hemodialysis in patients with ESKD. Each subject received a single oral dose
of a b-blocker 4 hours before dialysis onset. Plasma concentrations of b-blockers were determined using ultraperformance liquid chroma-
tography coupled to a quadrupole time-of-flight mass spectrometer. Dashed curves represent individual pharmacokinetic profiles, and mean
pharmacokinetic curves are displayed in color. Results are presented as mean6SD, with n=8 for all treatment groups.

was rejected (P,0.001). We found atenolol to be the most
highly dialyzed b-blocker, with a mean6SD dialytic
clearance of 167623 ml/min. The dialytic clearances for
metoprolol and bisoprolol were 114619 and 96617
ml/min, respectively (Figure 3), which were both signif-
icantly lower than atenolol (P,0.001). The dialytic clear-
ances of atenolol, metoprolol, and bisoprolol were all
significantly higher than carvedilol’s clearance of 24618
ml/min (P,0.001).
Discussion
We determined the dialyzability of four commonly
prescribed b-blockers in patients receiving maintenance
hemodialysis. We found atenolol and metoprolol to be
highly dialyzable (72621 and 87628 ml/min) compared
with bisoprolol (4469 ml/min). All three of these b-blockers
displayed dialytic clearance values markedly higher than
that of carvedilol, which was found to have nearly negligi-
ble dialyzability (0.260.6 ml/min). With only 10% of cur-
rently marketed medications having definitive dialyzability
information on the basis of experimental data (17), this is an
important step in establishing how hemodialysis affects drug
disposition.
Despite kidney excretion accounting for only 5% of
metoprolol clearance (28), both atenolol and metoprolol
have physicochemical properties that enable them to be
extensively dialyzed (28–30). To our knowledge, no pre-
vious studies have determined the dialyzability of meto-
prolol. Metoprolol’s dialytic clearance (87 ml/min) is only
9% of its reported total clearance in patients with ESKD
(31). Although this may not warrant a supplemental dose
postdialysis, dialytic clearance shows an additional route
of elimination for metoprolol that is not observed in
healthy patients or patients with CKD. As for atenolol,
the A-V difference method applied by Flouvat et al. (32)
produced a clearance of 43 ml/min for patients with ESKD
on a coil kidney dialysis with cuprophane membrane.
Using the same equation, high-flux polysulfone dialyzers
in our study revealed a substantially higher dialytic
clearance of 167 ml/min. When the recovery clearance
equation was applied, the dialyzability of atenolol at 72
Clin J Am Soc Nephrol 13: 604–611, April, 2018
Figure 2. | Applying the recovery clearance equation, the dialytic
clearance of atenolol and metoprolol are significantly elevated as
compared with bisoprolol, while carvedilol displayed negligible
dialyzability. Dialytic clearance values for the four b-blockers (atenolol,
metoprolol, bisoprolol, and carvedilol) during hemodialysis in patients
with ESKD. Plasma concentrations of b-blockers were determined using
ultraperformance liquid chromatography coupled to a quadrupole
time-of-flight mass spectrometer, and dialyzability was calculated
using the recovery clearance method. Results are presented as
mean6SD, with n=8 for each treatment group. *P,0.01 for carvedilol
relative to all other b-blockers; #P,0.05 relative to bisoprolol;
##
P,0.01 relative to bisoprolol.
ml/min was still higher than the value determined by
Flouvat et al. (32). Furthermore, atenolol’s dialytic clearance
(72 ml/min) is five- to nine-fold higher than its total
clearance (8–14 ml/min) in patients with ESKD (33,34).
Carvedilol’s larger volume of distribution, decreased water
solubility, and extensive protein binding (98%) suggested
minimal or low dialytic clearance (35,36). Similar to earlier
findings by Miki et al. (37), we found that carvedilol
displayed very minimal dialytic elimination. A low dialyz-
ability was similarly expected for bisoprolol after consulting
the dialysis of drugs guideline and peer-reviewed articles
(Table 1) (19–22). Our study indicates that bisoprolol is
cleared during hemodialysis, regardless of the calculation
method used. Kanegae et al. (38) found a comparable
dialytic clearance of 51 ml/min using the A-V method for
patients who were also prescribed polysulfone-based di-
alyzer membranes. This finding is contrary to previous
estimates of dialyzability for bisoprolol, but it is reflective
of its intermediate physicochemical properties compared
with carvedilol and atenolol (39,40). Although its total
clearance ranges from 70 to 84 ml/min in patients with
ESKD not on dialysis (38,41), the dialytic clearance of
bisoprolol (44 ml/min) is still over 1.5-fold higher than its
kidney-mediated excretion (28 ml/min) in these patients.
Only atenolol and metoprolol were expected to be
dialyzable; however, the results of our study allow us to
definitively state that bisoprolol is cleared during hemo-
dialysis. If dosing is not carefully monitored, patients
taking dialyzable drugs may have inadequate b-adrenergic
receptor blockade, resulting in suboptimal treatment.
Although the amounts of drugs that we recovered in
dialysate may seem unsubstantial relative to their initial
b-Blocker Dialyzability, Tieu et al. 609
Figure 3. | Applying the arterial venous difference equation, atenolol
was the most highly dialyzed b-blocker, while carvedilol displayed a
dialytic clearance value significantly lower as compared with the
other three b-blockers. Dialytic clearance values for the four
b-blockers (atenolol, metoprolol, bisoprolol, and carvedilol) during
hemodialysis in patients with ESKD. Plasma concentrations of
b-blockers were determined using ultraperformance liquid chroma-
tography coupled to a quadrupole time-of-flight mass spectrometer,
and dialyzability was calculated using the arterial venous difference
method. Results are presented as mean6SD, with n=8 for each treatment
group. *P,0.01 for carvedilol relative to all other b-blockers; #P,0.01
relative to atenolol.
dose, the bioavailability of these b-blockers is an important
consideration to determine the significance of hemodialysis
on drug clearance. For example, approximately 50% of
atenolol is absorbed systemically, with values as low as
12%–30% in patients with ESKD (33,34). Hence, the 3.7 mg
of atenolol recovered in dialysate (7.5% of the initial dose)
can be a significant amount and warrant changes for how
atenolol is prescribed to patients on dialysis. Accordingly,
atenolol, metoprolol, and bisoprolol may require postdial-
ysis dosing to ensure that adequate plasma concentrations
are maintained. Conversely, carvedilol removal by dialysis
is negligible. Because kidney-mediated excretion accounts
for ,2% of its elimination, plasma levels of carvedilol do
not accumulate in kidney impairment (42). These findings
suggest that no dosage adjustments are required for
carvedilol in patients on hemodialysis (37,43). Although
current clinical practice guidelines outlined by the National
Kidney Foundation make no recommendations on which
b-blocker should be prescribed to patients with CKD (44),
selection of carvedilol over other b-blockers may be
considered.
The strongest evidence in support of carvedilol as
opposed to other b-blockers is from its proven efficacy in
patients with ESKD. Carvedilol is the only b-blocker that
has been tested in prospective, randomized clinical trials in
patients on hemodialysis. Cice et al. (45) showed that year-
long administration of carvedilol reduces left ventricular
volumes and improves overall cardiac function for patients
on hemodialysis with dilated cardiomyopathy. This co-
hort was followed for another 12 months and showed a
significant reduction in all-cause mortality, cardiovascular
mortality, and all-cause hospitalizations compared with
610 Clinical Journal of the American Society of Nephrology
placebo-controlled patients (5). Additional analyses con-
ducted in this observational study indicated that carvedilol
use compared with placebo was associated with reductions
in fatal myocardial infarctions and strokes—two main
causes for cardiovascular death in patients with ESKD.
Although carvedilol is typically reserved for patients with
symptomatic heart failure, it may be worth expanding its
use in patients on dialysis due to its pharmacokinetic
properties and previous evidence indicating its strength to
improve patient morbidity.
There are other important considerations generated from
our study. Atenolol overdose is effectively treated by
hemodialysis (46). To our knowledge, it is unknown
whether hemodialysis is effective for treating overdose of
other b-blockers. Our study suggests that hemodialysis
may be a consideration to treat metoprolol or bisoprolol
overdose. The last important consideration pertains to
factors that can contribute to interindividual variability in
clearance. Hepatic drug metabolizing enzymes involved in
clearance of metoprolol, bisoprolol, and carvedilol have
genetic polymorphisms. For example, individuals can be
categorized from poor to ultrarapid metabolizers of meto-
prolol on the basis of their CYP2D6 genotype (47). Hence,
poor metabolizers of metoprolol may have a larger com-
ponent of their dose available for removal by hemodialysis.
Our study has some limitations that should be consid-
ered. The recovery clearance method is accepted as the gold
standard for determining dialyzability. This method
requires a sensitive assay to measure low drug concentra-
tions in large volumes of dialysate. Despite concentrating
samples 100-fold, some dialysate samples from patients
taking carvedilol were below our limit of quantification.
However, the negligible dialytic clearance of carvedilol
likely resulted in virtually no drug for detection. The
precision of our carvedilol assay was slightly above our
acceptable range. At very low concentrations of carvedilol,
this will introduce a small amount of variability in the
calculation of clearance. In addition, it is unknown whether
b-blockers bind to dialysis membranes or the dialysate
collection barrel, which can result in an underestimated
recovery clearance value. When calculating AUC of b
blockers, we determined total concentration (free plus
protein bound). This may also result in an underestimated
dialytic clearance. Another limitation of our study design is
quantifying b-blockers after a single oral dose. Although a
drug that is dialyzable after a single dose is also expected to
be cleared when taken chronically, future studies should
examine dialytic clearance for patients at steady state.
Patients enrolled in our study used different dialyzers.
Although the dialyzers were all modern high-flux dia-
lyzers, the type of dialyzer may have introduced a small
amount of variability in our clearance calculation. Lastly,
our study did not investigate the interdialytic pharmaco-
kinetics of the four b-blockers. Previous studies have
shown that the t1/2 and kidney clearances of these drugs
on nondialysis days return to values that are compara-
ble with those of patients with ESKD not yet on RRT
(32,37,48–50).
In conclusion, we have experimentally determined the
dialytic clearance of the most commonly prescribed
b-blockers. Our data show that atenolol and metoprolol
are markedly dialyzed compared with carvedilol. Despite
previous literature suggesting that bisoprolol would have
little to no dialyzability, we show that it is, in fact, cleared
during hemodialysis in patients using modern high-flux
dialyzers. Definitive dialytic clearance data presented in
this study can help design prospective trials to determine
whether outcomes are superior with poorly dialyzable
b-blockers compared with highly dialyzable b-blockers.
Acknowledgments
The authors would like to thank the staff, nurses, and biomedical
technicians working at the London Health Sciences Centre dialysis
clinics for their generosity and help in conducting this study. Images
used to generate the graphic abstract were from Servier Medical Art
(http://smart.servier.com).
This study was supported by the Canadian Institutes of Health
Research, the Canadian Foundation for Innovation, and the Schulich
School of Medicine and Dentistry at Western University.
Funders had no role in study design, data collection, or
interpretation.
Disclosures
None.
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Received: July 15, 2017 Accepted: January 5, 2018
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