BIOPHARMACEUTICS/PHARMACOKINETICS/HEMODYNAMICS

Pharmacokinetic and Biopharmaceutic

Aspects of Once Daily Treatment with
Metoprolol CR/ZOK: A Review Article
Anders Sandberg, MSc, Berth Abrahamsson, MSc, Carl-Gunnar Regcfrdh, PhD,
Ingrid Wieselgren, MSc, and Robert Bergstrand, MD, PhD

In the development of a new controlled release preparation and its subsequent assess-
ment there are a number of factors that need to be considered both related to the drug
itself and to the pharmaceutical preparation. This review describes the biopharmaceuti-
cal and pharmacokinetic properties of metoprolol CR/ZOK, a recently introduced for-
mulation of a widely used beta,-selective adrenoceptor antagonist intended for once
daily usage.
The metoprolol CR/ZOK preparation provides reproducible dissolution and absorption
properties resulting in stable plasma concentrations with minimum fluctuations over a
24-hour dosage interval. This has been shown in extensive studies comprising over 200
healthy volunteers. Considerations for a new drug preparation such as bioavailability
and variability in relation too standard treatment and the clinical significance of taking
the drug with food and in increasing doses, are potential concerns that do not seem to be
a problem for the therapeutic use of metoprolol CR/ZOK. Furthermore, the pharmacoki-
netic data achieved in young healthy subjects appear to be relevant for the treatment of
patients, as shown by the consistent plasma concentration profiles obtained in elderly
and in hypertensive patients.

R ecent advances in formulation technology have need to be considered. Finally, the effects of taking
enabled the development of well designed con- the drug with food, taking the drug chronically, ad-
trolled release (CR) dosage forms of both new chemi- ministering increasing doses and prescribing the
cal entities and already established drugs. The aim is preparation for patients as opposed to healthy sub-
to reach the full therapeutic potential of each drug jects all need to be investigated. In this review these
as regards efficacy, safety, and patient compliance. aspects will be considered for metoprolol CR/ZOK,
Before initiating such a development it is important, a product which is designed to provide essentially
however, to be familiar with nature of the drug itself constant plasma concentrations in the therapeutic
such as its physicochemical and pharmacokinetic range after once daily administration.
properties and to consider the biopharmaceutical
characteristics of the new preparation. It is also im- BASIC PHYSICOCHEMISTRY AND CLINICAL
portant to consider problems which may arise from PHARMACOKINETICS
the drug being absorbed along the whole length of
Like other beta1-adrenoceptor antagonists, metopro-
the gastrointestinal tract. For a drug like metoprolol
lol is a weak base with a pKa of about 9.5. The parti-
which is extensively metabolized and undergoes
tion coefficient (K0) between octanol and phosphate
relatively high first-pass metabolism, these aspects
buffer (pH 7.4 and 25#{176}C)is 0.53.1 Metoprolol thus
belongs to the group of lipid soluble beta-blockers,
From Pharmaceutical Research and Development, (Sandberg and
although it is much less lipophilic than for example
Abrahamsson), Cardiovascular Research, AB Hassle, MOlndal, Sweden
propranolol (K0 = 15.8). Since metoprolol has an
(Dr. Reg#{225}rdhand Ms. Wieseigren), and Gothenburg University, Depart- asymmetric carbon, it exists as two enantiomers; the
ment of Medicine, Ostra Hospital, Gothenburg, Sweden (Dr. Berg- pharmacologically active S-form and the consider-
strand). Address for reprints: Anders Sandberg, Pharmaceutical Re- ably less active R-form.2 The racemic mixture of the
search and Development, AB Hassle, S-431 83 M#{246}lndal. two enantiomers is used clinically. Because of low

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 PHARMACOKINETIC REVIEW OF METOPROLOL CR/ZOK

aqueous solubility of the base, metoprolol is used as olize metoprolol. No significant effect on the mean
a salt in pharmaceutical preparations. Conventional total body clearance or elimination half life was ob-
tablet products, Seloken,#{174} Betaloc,#{174} Beloc,#{174} (Astra, tained, however, in patients with liver cirrhosis
AB Hassle, M#{246}lndal, Sweden), and Lopressor,#{174} when compared with a group of healthy volun-
(Ciba-Geigy, Summit, NJ), thus contain the very sol- teers.14 A possible explanation is that some of the
uble tartrate salt (>700 mg/mi in water at 37#{176}C) patients were treated with enzyme-inducing drugs
whereas the present formulation, metoprolol CR/ which compensated for a disease induced decrease
ZOK, contains the succinate salt (270 mg/ml) in- in the capability to metabolize metoprolol.
stead. The succinate salt is better suited for a con- The plasma concentration-effect relationship for
trolled release formulation than the tartrate which is metoprolol appears to be related to the hemody-
too soluble to provide constant drug delivery over an namic and pharmacologic effects involved. As first
extended time period. For the same reason, the fu- shown by Johnsson et al.’5 and thereafter verified in
marate salt is used in the metoproiol Oros#{174}formula- several other studies, there is a linear relationship
tion3 (Ciba Geigy, Summit, NJ). between log plasma concentration of metoprolol and
The pharmacokinetic properties of metoprolol the beta,-blocking effect, registered as the reduction
have been reviewed in several articles, the most re- of exercise-induced tachycardia. In contrast, no sim-
cent one by Benfield et al.4 The gastrointestinal (GI) ple relationship has been established between the
absorption of metoprolol is rapid and complete after plasma concentration and the antihypertensive ef-
presentation in a fast dissolving dosage form and fect, either on systolic or diastolic blood pressures.
maximum plasma concentration is reached after 1-2 The concentration-response curve can be regarded
hours.5 The systemic availability after oral adminis- as relatively flat irrespective of the effect being stud-
tration is, however, reduced by about 50% due to ied and the therapeutic concentration range for
hepatic first-pass metabolism. The magnitude of metoprolol is, as for other beta blockers, broad com-
presystemic elimination differs between individuals pared with for example vasodilating drugs. Too high
primarily because the oxidation to the major metab- plasma concentrations may, however, lead to un-
olites, H 117/04 and H 119/66, is under genetic in- wanted effects due to excessive beta,-blockade or by
fluence.6 Furthermore, factors that may change the involvement of beta2-receptors.
liver blood flow or the hepatic enzyme activity From its physicochemical, pharmacokinetic and
could influence the systemic availability. Concomi- clinical pharmacological properties described above,
tant food intake has thus been shown to increase the it is obvious that metoprolol is suitable for presenta-
bioavailability by up to 40%. After having reached tion in a controlled release formulation and that
the systemic circulation, metoprolol is extensively clinical benefits could be gained from such a devel-
and rapidly distributed in a volume of distribution of opment. A prerequisite is, however, that the deliv-
about 5.6 L/kg. The time course of the plasma con- ery system is safe, reproducible and does not cause
centration is described biexponentially with a short greater intersubject variation than a conventional
distribution half life of 5-15 minutes followed by the dosage form of the drug.
elimination phase with an average half-life of 3-4
DESCRIPTION OF PRODUCT AND
hours. Metoprolol is extensively metabolized in the
STUDY PROTOCOLS
liver by enzymes belonging to the cytochrome P-450
system. Oxidative deamination, 0-dealkylation The pharmaceutical development of metoprolol
with subsequent oxidation and aliphatic hydroxyla- CR/ZOK, including formulation considerations as
tion are the three main pathways and the formed well as different biopharmaceutical aspects, has
metabolites are almost exclusively excreted in been previously described.1617 Several years of de-
urine.8 One of the metabolites, a-hydroxymetopro- velopment resulted in a multiple-unit formulation
lol, possesses some beta1-blocking activity, although containing metoprolol succinate in the form of indi-
its potency is only about one tenth of the parent drug vidual drug delivery units (pellets). The reasons for
and is of no clinical importance in patients with choosing the succinate salt have been discussed by
normal liver and renal function.9 Ragnarsson et al.16 Spherical cores of the drug are
The pharmacokinetics of metoprolol are essen- coated with a polymeric membrane of mainly ethyl-
tially unaltered in the elderly10-1112 and in patients cellulose which controls the drug release from the
with renal insufficiency,13 as compared to young pellets. Each pellet acts as a diffusion cell and is
healthy subjects. However, since the drug is sub- designed to deliver metoprolol at a near constant
jected to extensive hepatic metabolism, patients rate for about 20 hours, independently of pH and
with severe liver disease may require a lower thera- other physiological variations. The pellets are incor-
peutic dose because of impaired capability to metab- porated in a divisible tablet which breaks up after

SUPPLEMENT S3
 SANDBERG ET AL

ingestion and allows a rapid dispersion in the gastro- slightly modified using mass spectrometric detec-
intestinal tract. Each 100 mg metoprolol CR/ZOK tion.19 The assay methods were validated in each
tablet contains 95 mg metoprolol succinate in ap- study with respect to specificity, sensitivity, linear-
proximately 1600-1800 pellets. Three tablet ity and precision. The lowest determinable concen-
strengths containing the same type of drug pellets, tration with a standard deviation of 10% was set to
50 mg, 100 mg and 200 mg, have been developed to 5-20 nmol/L. The metoprolol metabolites H 117/04
provide flexibility in the treatment of the individual (aliphatic carboxylic acid) and H 119/66 (cs-hy-
patients. A schematic illustration of the metoprolol droxymetoprolol) were determined by liquid chro-
CR/ZOK tablet is shown in Figure 1. matography and fluorimetric detection.2#{176}
In the development of a new controlled release
product, it is important to show that the final for- GASTROINTESTINAL TRANSIT
mulation has reproducible biopharmaceutical prop- AND ABSORPTION
erties and provides consistent results in different
studies. The following pages describe these proper- For a once daily preparation designed to release the
ties for metoprolol CR/ZOK in detail, using data drug over a long period of time, absorption becomes
from earlier published studies as well as hitherto the rate-limiting pharmacokinetic process unless
unpublished results. Most of the findings have been the elimination half-life of the drug is very long. It is
obtained from studies in different groups of healthy a prerequisite for a controlled release preparation
young male subjects, but a limited amount of data that the drug substance should be adequately ab-
from other groups are also presented. All studies sorbed over most of the gastrointestinal tract. Stud-
were randomized, blinded and of cross-over design. ies of the absorption in different parts of the GI tract
Most of them were comparisons between metoprolol are therefore fundamental for selecting an optimal
CR/ZOK administered once daily and conventional release profile of the product. In addition, it is im-
metoprolol tablets, Seloken,#{174} Beloc,#{174}Betaloc, (Astra, portant to identify such physiological and biophar-
AB Hassle, M#{246}lndal, Sweden) or Lopressor,#{174} Lopre- maceutical factors that may be of significance for the
sor#{174},(Ciba-Geigy, Summit, NJ) given in different clinical effect by influencing drug delivery and ab-
dosage regimens. Table I summarizes study design sorption in the GI tract.
and demographic data for the major studies in- One important factor in this respect is the reten-
cluded in this review. tion of the drug preparation in different regions of
The metoprolol concentrations in plasma were the GI tract after intake. It has been shown in studies
determined by gas chromatography and electron- by means of gammascintigraphy, that 50% of the
capture detection.’8 In one study, the method was administered pellets are emptied from the stomach
in about 0.5-3 hours.23 For pellets having a diameter
of less than about 2 mm, which is the case with
metoprolol CR/ZOK, gastric emptying appears to be
fairly reproducible and not appreciably affected by
Coating layer
the presence of food. This is in contrast to larger
particles, such as nondisintegrating single-unit prep-
Metoprolol arations, for which prolonged retention times in the
succinate core stomach greater than 10 hours can be seen after con-
comitant intake of food.24 On the other hand, the
small intestinal transit time, which is approximately
.Tablet forming 3 hours, seems independent of size and type of dos-
excipients age form as well as of food.25
Most of the pellets from a metoprolol CR/ZOK
dose can therefore be expected to have reached
cecum by about 3.5-6 hours after intake and thereaf-
ter further contribution of a given dose will have to
rely on absorption from the colon. Having reached
th-e ileocecal region there is evidence that pellets
may be gathered together before being further trans-
ported into the ascending colon.26 The transit of ma-
Figure 1. Schematic drawing of a metoprolol CH/ZOK tablet. The
coated pellets are liberated after ingestion and act as individual terial through the entire colon is often a slow process
delivery units with controlled release of metoprolol succinate. resulting in a total average GI-transit time of 24

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 PHARMACOKINETIC REVIEW OF METOPROLOL CR/ZOK

TABLE I

Summary of Study Design and Demographic Data for Eight Studies with Metop rolol CR/ZOK in Healthy Subjects

Mean (range) Subject Data

Day(s) ofNumber of
Study Treatments Measurement Subjects Age Weight

Metoprolol CR/ZOK 7-8 15 26 (21-3 1) 74 (59-94)

100 mg od
Lopressor#{174}100 mg od
ii Metoprolol CR/ZOK 7-8 18 27 (19-33) 71(59-86)
200 mg od
Lopressor#{174}100 mg bid
III Metoproioi CR/ZOK 7-8 18 26 (21-31) 74 (63-84)
300 mg od
Lopressor#{174}100 mg tid
IV Metoprolol CR/ZOK 7-8 18 23 (20-32) 76 (67-86)
400 mg od
Lopressor#{174}100 mg qid
V Metoprolol CR/ZOK 5-6 12 25 (20-30) 78 (66-85)
50mg od
Seloken#{174}50 mg od
VI Metoprolol CR/ZOK 6-8 18 25 (21-31) 77 (66-86)
100 mg od
Lopressor#{174}100 mg od
VII Metoprolol CR/ZOK od 7-8 12 23 (21-26) 75 (69-80)
100 mg, 200 mg, 400 mg
600 mg
VIII Metoprolol CR/ZOK 1 18 26 (20-32) 73 (63-98)
400 mg (2 x 200 mg)
Fasting-Nonfasting

Abbreviations: od = once daily, bid = twice daily, tid = three times daily, qid = four times daily.
Note: Study No. V and Nos I-tV are presented in this supplement in’ and,22 respectively.

hours or more.27 This is illustrated for metoprolol

CR/ZOK in Figure 2, showing a gammascintigraphic
image of the preparation in a young healthy subject
28 hours after dosing. In this example, the pellets
reached the colon about 5 hours after intake under
fasting conditions, but had not moved further than
to the area around the hepatic flexure during the
next 23 hours. For this individual it is obvious that
the total residence time in the gastrointestinal tract
is sufficiently long for a continuous drug release
over a 20-hour period. However, the transit process
may be quite variable between individuals and con-
ditions such as constipation and diarrhea may signif-
icantly change the retention time of a pharmaceuti-
cal preparation within the same individual. Exam-
ples of total transit times shorter than 12 hours in
Figure 2. Gammascintigraphic image showing the gastrointestinal
some subjects have been reported by John et al.28
position of 51Cr labeled metoprolol CR/ZOK pellets 28 hours after and Davis et al.29 for the Oros#{174}delivery system. In
administration in a young healthy subject. such cases, the dose unit may be expelled before its

SUPPLEMENT S5
 SANDBERG ET AL

drug content has been completely released. This absorption-time profiles after once daily dosage of
could of course lead to reduced bioavailability29 and metoprolol CR/ZOK 100 mg in 12 healthy subjects
impaired response to the drug treatment. Although are shown in Figure 3. As can be seen, absorption
it seems that pellets are generally transported more was similar and appeared to continue for at least 24
slowly in the colon than a large nondisintegrating hours in 11 of the 12 subjects. In one subject, how-
unit (capsule 25 x 9 mm),3#{176}
the potential differences ever, the absorption process seemed to be completed
between single-unit preparations and pellets with after 12 hours as indicated by his deviating profile.
respect to colon transit time remain to be fully ex- Comparing the individual absorption curves with
plored. the in vitro dissolution profiles when simulating dif-
As previously indicated, the conditions in the dif- ferent physiological factors (Figure 4), it is obvious
ferent parts of the GI tract will influence the absorp- that drug delivery from the dosage form is indepen-
tion of a drug from that site and may have an impact dent of the environmental conditions in the GI tract.
on the overall bioavailability. The suitability of the Thus there is a good in vitro/in vivo correlation over
large bowel as an effective and reproducible site for the entire time interval, which is important for the
absorption of metoprolol has been shown in several prediction of the product’s performance in vivo and
studies using different techniques.31-32 These studies can serve as a tool when establishing the limits for
have demonstrated that the extent and rate of meto- in vitro dissolution in the quality control of the
prolol absorption from the entire colon is compara- product.
ble to that in the duodenum and other parts of the
BIOAVAILABILITY ISSUES
small intestine. The effective distal uptake of meto-
prolol has also been confirmed in bioavailability Impact on Plasma Concentration Profile
studies with metoprolol CR/ZOK, by calculating the
fraction absorbed from plasma concentration-time The continuous drug release and prolonged absorp-
data using the Wagner-Nelson method.33 Individual tion provided by metoprolol CR/ZOK result in a

Fraction absorbed

0 4 8 12 20 24 28
Time (hours)

Figure 3. Fraction absorbed drug during 30 hours after single dose administration of metoprolol CR/ZOK 100 mg in 12 healthy subjects.
Calculated from individual plasma concentration-time data by the Wagner-Nelson method.

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 PHARMACOKINETIC REVIEW OF METOPROLOL CR/ZOK

stable plasma concentration profile, without any Whereas metoprolol CR/ZOK showed a consistent
marked peak concentration and with minimum and low fluctuation over the entire dosage range, the
fluctuations over the 24-hour dosage interval. This is peak to trough relationship was highly dependent of
illustrated in Figure 5, showing the mean plasma the number of daily doses for the conventional met-
concentration profiles after once daily administra- oprolol treatment. The conventional tablet thus has
tion of metoprolol CR/ZOK, 200 mg, and twice daily to be given three to four times a day in order to
administration of conventional Lopressor#{174} tablets, provide the same low fluctuation of the plasma
100 mg, in a group of 18 healthy male volunteers levels as achieved with metoprolol CR/ZOK once
(study No II, Table I). It is apparent that the con- daily.
trolled release rate has significantly changed the
properties related to rate of bioavailability, for ex- Reduced Extent of Bioavailability
ample, maximum plasma concentration, time to
reach the plasma peak and mean residence time in It is known that the extent of systemic availability
the body. for drugs having substantial first-pass loss is in-
The variation between peak and trough plasma versely related to the rate at which the drug is pre-
concentration over the dosage interval is also con- sented to the eliminating organ, in this case the
siderably less pronounced for the controlled release liver. For example sustained release propranolol
preparation than for the twice daily conventional (Inderal LA, ICI Pharmaceuticals, Macclesfield, UK)
tablet regimen. This parameter can be measured as has a relative bioavailability of about 50-60% com-
the percentage fluctuation of plasma levels over the pared with conventional propranolol tablets.35’36
dosage interval as described by Skelly et al.34 The Similarly, other cardiovascular drugs like nifedipine
equation and the results obtained in steady-state and furosemide have also been reported to have a
studies with metoprolol CR/ZOK are shown in Fig- reduced bioavailability when given in preparations
ure 6, comparing once daily treatment of the con- having extended release of the drug.37-38 Metoprolol
trolled release preparation with conventional meto- has also shown reduced bioavailability properties
prolol tablets given once a day up to four times a day. when administered in a sustained release prepara-

Fraction released dose

1.0-

0.8-

0.6-

sim. gastric juice pH 1.2

0.4-
USP buffer pH 5.5
USP buffer pH 5.5 + surf actant
USP buffer pH 6.8
0.2-
USP buffer pH 6.8, 50 RPM

0 4 12 16 24
Time (hours)

Figure 4. In vitro dissolution profiles of a commercial batch of metoprolol CR/ZOI( 100 mg (No NC 217). Mean data from six tablets
determined under different test conditions using the following method: 500 ml test medium at 37#{176}C,USPII apparatus (rotating paddle) at a
rotation speed of 100 RPM (in one experiment 50 RPM was used). Metoprolol was detected by t]V-spectrophotometry at 274 mm.

SUPPLEMENT $7
 SANDBERG El AL

Plasma conc. (nmol/l)

1000-

#{149}
metoprolol CR/ZOK 200 mg once daily
#{149}
metoprolol CT 100 mg twice daily
800-

600-

400-

200-

I I 11111 I I - I I I --

Days 234567 4h 8h 12h 16h 20h 24 h

Time after dose day 7

Figure 5. Mean plasma concentrations of metoprolol in 18 healthy subjects, measured at 24 hours on treatment days 2 to 7 and frequently
on the final day of 7 days of treatment with metoprolol CR/ZOK 200 mg once daily and conventional tablets (Lopressor#{174}) 100 mg twice
daily.

tion of the matrix type,39 although not to the same garded as negligible as discussed previously41 and
extent as propranolol. Having a slower and more elsewhere in this supplement, the reason(s) why less
constant delivery rate than the matrix based prod- drug enters the systemic circulation when adminis-
ucts, metoprolol in the 14/190 Oros#{174}system has tered in a controlled release preparation should be
been reported to have a mean bioavailability of 62% investigated. It is likely that a slow drug release rate
at steady state relative to conventional metoprolol will result in a reduced bioavailability, partly be-
tablets 100 mg given twice daily.40 The correspond- cause it allows maximal first-pass metabolism since
ing value obtained with metoprolol CR/ZOK in the hepatic extraction is a saturable process and partly
study illustrated in Figure 5 was 68%, confirming because drug still may be left in the preparation at
that the drug release rate influences the fraction of the time it is passed through the GI tract. On the
the metoprolol dose reaching the systemic circula- other hand, speeding up the release rate will result
tion. A summary of relevant bioavailability parame- in a greater AUG but at the same time lead to greater
ters obtained in five steady state studies with meto- fluctuations of plasma concentrations over the dos-
prolol CR/ZOK is given in Table II. The average age interval with higher peak and lower trough
value for the mean relative bioavailability of meto- values.’6
prolol CR/ZOK in these studies, covering the dosage
range from 50 to 400 mg, was 82% (68-102%) com- Metabolites in Urine
pared to conventional metoprolol tablets.
Although the clinical implications of the reduced An attempt to clarify the reduced bioavailability for
bioavailability for metoprolol CR/ZOK can be re- metoprolol CR/ZOK was done in a steady-state

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 PHARMACOKINETIC REVIEW OF METOPROLOL CR/ZOK

% fluctuation
600 -

#{149}
metoprolol CR!ZOK once daily
500- #{149}
metoprolol CT; different regimens

400-

300-

200 -

100-
I I

i#{224}o 200 300 40

Dose (mg)

Figure 6. Mean (SEM) percentage fluctuation of plasma concentrations at steady state after treatment with metoprolol CR/ZOK 50-400mg
once daily and conventional metoprolol tablets (CT) 50-100 mg once daily, 100 mg twice daily, 100 mg three times daily and 100 mg four
times daily. The percentage fluctuation was calculated by the following equation ‘:

Cmax - Cm,0
100 where r = dose interval.
ALJC/r

TABLE II

Mean (SD) Pharmacokinetic Results at Steady State After Once Daily Dosing of Metoprolol CR/ZOK 50-400
mg and Conventional Metoprolol Tablets (CT) Given Once Daily or in More Frequent Daily Doses
Parameter
Cm,, Cn AUC
Study No Dose Level Treatment (nmol/L) (nmol/L) (nmoi . h/L) MRT (h)

I 100 mg CR/ZOK 145 (68) 70 (41) 2433 (1317) 15.4 (4.4)

CTod* 606(254) 3(13) 2934(1391) 4.6(1.0)
II 200 mg CR/ZOK 404 (264) 116 (148) 5843 (5032) 12.2 (2.7)
CTbd 959(361) 87(103) 7876(4723) 11.2(2.2)
III 300 mg CR/ZOK 665 (328) 343 (240) 12368 (6876) 17.2 (2.1)
CT tid 1287 (495) 396 (277) 16860 (8355) 14.9 (1.8)
IV 400 mg CR/ZOK 837 (204) 278 (100) 12920 (3635) 13.7 (1.0)
CTqid 1111 (268) 469(156) 15481 (4294) 14.1 (1.9)
V 50 mg CR/ZOK 71(78) 39 (50) 1312 (1548)
CTod 221(157) 6(16) 1364(1571)

* For conventi onal tablet (CT) treatme nts see also Table I.

SUPPLEMENT $9
 SANDBERG FT AL

pared with conventional Seloken#{174} tablets 100 mg

TABLE Ill once daily and 50 mg twice daily. The plasma con-
Mean (SD) Percentage Urinary Excretion of centrations and pharmacodynamic effects achieved
Metoprolol and Two Major Metabolites, H 117/04 in this study have already been presented.4’ Table III
gives the percentage excretion of the three com-
and H 119/66, After Treatment With Metoprolol
CR/ZOK 100 mg Once Daily and Conventional pounds in urine in relation to the given dose, during
Metoprolol Tablets (Seloken#{174})100 mg Once Daily one 24-hour interval at steady-state.
and 50 mg Twice Daily in 12 Healthy Subjects As expected, all three metoprolol treatments
showed the same metabolic pattern with the ali-
Percent Excret ed of the Given D ose (Mean SD) phatic carboxylic acid (H 117/04) recovered in larg-
Metoprolol Seloken Seloken#{174} est amounts. However, both metabolites and the par-
CR/ZOK Tablet Once Tablet Twice ent drug were excreted in urine to a significantly
Compound Once Daily Daily Daily less extent for metoprolol CR/ZOK as compared to
the two conventional metoprolol treatments. The
Metoprolol 8.7 (5.8) 11.0 (8.2) 12.2 (8.9)
H 117/04 45.8 (10.2) 66.6 (14.0) 60.2 (7.1) total excretion of all three compounds represented
H 119/66 5.9(3.4) 8.0(4.1) 8.2(5.1) approximately 60%, 86%, and 81% of the given dose
of metoprolol CR/ZOK and the two conventional
treatments, respectively. These results do not indi-
cate increased hepatic extraction of metoprolol by
study by investigating the urinary recovery of un- the liver for this relatively low dose, since the for-
changed metoprolol and its major metabolites, mation of metabolites was not increased after ad-
H 117/04 and H 119/66, in 12 healthy volunteers. ministration at a slow rate. In addition, the data sug-
Metoprolol CR/ZOK 100 mg once daily was corn- gest that the partially active metabolite, a-hydroxy-

Frequency
15-

#{149}
metoprolol CR!ZOK 100
metoprolol CT 100 mg

10-

5-

0 I I I U U I I I I I I
I U I I U I

1 2 3 4 5 6 7 8 9 10 12 14 16 AUC
(nmol h/I)
#{149} 1000
#{149}

Figure 7. Frequency distribution of individual AUC values on treatment day 7 in three bioavailability studies comparing metoprolol
CR/ZOK 100 mg once daily with conventional metoprolol tablets (CT) 100 mg once daily. The number of subjects included in the three
studies was 15, 18 and 12, respectively.

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metoprolol, does not have any greater impact on the

pharmacological response after controlled release TABLE IV
administration than after treatment with a conven-
Summary of Pharmacokinetic Results After a Single
tional tablet.
Dose of Metoprolol CR/ZOK in 18 Fasting and
Nonfasting Healthy Subjects
VARIABILITY-GENETIC POLYMORPHISM
Metoproiol CR/ZOK 400 mg Mean (SD)
The usually large interindividual variation in meto-
Parameter Fasting Nonfasting
prolol plasma concentrations after oral administra-
tion in an unselected population is essentially due to Cmax (nmol/L) 351 (272) 399 (332)
environmental and genetic variations including tmax(h) 13.5(3.1) 11.0(3.9)
polymorphism.6 Individuals having impaired ability C24 (nmol/L) 225 (229) 261 (259)
to eliminate metoprolol leading to high plasma con- AU C10,
centrations are thus identified as poor metabolizers (nmol h/L). 8009 (7445) 9203 (8896)
AUCr01,o (%) 120 (60)
(PM). The frequency of PM seems to vary between
ethnic groups; for example 5-10% of whites have
been reported to be PM, whereas this phenotype
seems to be represented to a much lower extent in average patient, in fact there is no clinical evidence
Japanese42 and in black Africans.43 Thus the major- to support this assumption.
ity of people may be defined as intermediate or ex- The polymorphic oxidation is specifically related
tensive metabolizers (EM). In addition, the pharma- to the substance and is not under the influence of
cokinetics of the S- and R-enantiomers of metoprolol the dosage form or drug delivery rate. This is obvi-
have been reported to differ in PM and in EM.44 The ous in Figure 7 where the frequency distribution of
fact that EM eliminate the almost inactive R-form individual AUG values are plotted for metoprolol
more effectively than the pharmacologically active CR/ZOK and conventional tablets in three steady-
S-form, may partly explain why the beta,-blocking state studies on the 100 mg dose level comprising
effect after administration of racemic metoprolol is totally 45 subjects. The two histograms were similar,
less variable between individuals than would be ex- both showing a skewed distribution of AUGs and
pected from total metoprolol plasma concentra- thus indicating a similar intersubject variation in
tions.45 The clinical significance of genetic polymor- systemic availability for the two different rates of
phism has not yet been completely unraveled for administration. The coefficient of variation for the
metoprolol. Though it might be expected that the AUGs in the three studies were: 54%, 104%, and
PM generally will require a lower dose than the 75% for metoprolol CR/ZOK, and 47%, 96%, and
68% for the conventional tablet.
More important than the intersubject variation
which can be handled by individual dose adjust-
AUC ment, is the reproducibility of a treatment within a
(nmol hit)
#{149} 1000
#{149}

metoprolol CRIZOK 100 m9 mtoprotol CT 100 mg subject after repeated administration. In one study
(No VI, Table I), plasma concentrations were mea-
sured during two consecutive dosage intervals at
steady state in a group of 18 healthy volunteers. As
can be seen in Figure 8, the AUGs on days 6 and 7
8 were rather similar for each individual following ad-
6
ministration of both metoprolol CR/ZOK and the
conventional tablet. This consistency in plasma
4.
levels within individuals from day to day at steady
2
state indicates that both metoprolol treatments yield
day6 dayl day6 dyl reproducible absorption and disposition properties
during chronic administration.

Figure 8. Individual AUCs on treatment days 6 and 7 after once EFFECT OF FOOD
daily dosing with metoprolol CR/ZOK 100 mg and conventional
metoprolol tablets (CT) 100 mg (Study Number VI, Table 1). The
AUC:s for each individual are connected with a line and in some
Usually drugs are taken with food and fluids. There
cases also marked with a symbol to illustrate inter- and intrasub- are numerous examples that concomitant food in-
ject variation. take can have a significant effect on the rate and/or

SUPPLEMENT Sil
 SANDBERG ET AL

mainly of carbohydrates (bread, corn flakes).’7 The

x hit) relative AUG (food/fasting) was 84-141% (mean
60000 105%), suggesting a nonsignificant effect of food. To
elucidate further the influence of food on the bio-
50000 availability of metoprolol from the GR/ZOK prepa-
ration, a second study was performed on 400 mg
which is at the upper end of the therapeutic dose
range. A single dose was given to 18 healthy males
(study No VIII, Table I), once while fasting and once
30000
immediately after a high fat breakfast. The mean
(SD) results are presented in Table IV. As in the low
20000 dose study, there was a tendency to an increased
Cmax and AUG after concomitant intake of food.
10000 However, the differences did not reach statistical
significance between the two treatments and the
0
plasma concentrations were relatively similar at the
600 end of the dosage interval (C24).
Dose (mg)
From these two studies it can be concluded that
food does not significantly change the plasma con-
centration-time profile for metoprolol CR/ZOK.
Figure 9. Individual AUG values versus dose in 11 subjects, on the
final day of 7 days of treatment with metoprolol CR/ZOK once
From the literature it is also obvious that the bio-
doily in the following doses: 100 mg, 200 mg, 2 X 200 mg and 3 availability properties of a fast-dissolving dosage
X 200 mg. form of metoprolol can be expected to be substan-
tially more affected by concomitant food intake than
seen with metoprolol CR/ZOK.7 It should be pointed
extent of bioavailability of a drug substance or out, however, that this conclusion cannot be ex-
pharmaceutical preparation.4647 This effect is of tended to other controlled release dosage forms of
clinical relevance, however, only when the drug has metoprolol since they may possess completely dif-
a small therapeutic range so that subtherapeutic or ferent pharmaceutical as well as biopharmaceutical
potentially toxic plasma concentrations may be pro- characteristics.
duced. Although this is not the case for metoprolol,
it was still important to find out whether the ab-
INFLUENCE OF DIFFERENT DOSES
sorption from a new formulation with modified re-
lease properties would be affected by food differ-
ently than from a conventional dosage form. Since For a drug having saturable first-pass extraction, it
metoprolol GR/ZOK delivers the drug over a long can be assumed that the plasma concentrations will
period of time, the plasma concentration curve increase nonlinearly when increasing the dose. De-
would not be expected to be influenced by a tran- pending on the enzymatic capacity in the liver, each
sient post prandial increase in splanchnic blood flow individual may have a threshold value for an oral
to the same extent as an immediate release prepara- dose before saturation of the first-pass effect will
tion.48 On the other hand, food can affect absorption influence the bioavailability of the drug. Metoprolol
and elimination of a dosage form in several other probably belongs to this group of drugs as indicated
ways; for instance by changing gastric emptying and by Johnsson et al.,’5 who found that the ratio be-
GI transit time, by changing the environmental con- tween AUG for a 20 mg and 50 mg oral dose (fast-
ditions (pH, pancreatic enzymes, bile) and by chang- dissolving tablet) was 1:3.8 and the corresponding
ing the amount and content of fluids in the GI tract. ratio for a 50 mg and 100 mg dose was 1:2.1. The
In addition, the composition of a meal may be im- authors suggested that the proportion of drug pass-
portant and different effects can be achieved with ing through the liver will gradually increase with
high protein, high carbohydrate and high fat diets. the dose as an effect of the saturable hepatic extrac-
respectively. tion. This should also be applicable to metoprolol
It has been shown that the bioavailability of a low GR/ZOK, although the situation is somewhat more
dose (50 mg) of metoprolol CR/ZOK was essentially complicated because of the slow rate of drug presen-
unchanged after single dose administration in 12 tation to the eliminating organ.
healthy subjects under fasting conditions and to- From a biopharmaceutical point of view it is not
gether with a standardized breakfast consisting expected that the three dosage strengths of meto-

S12 #{149}
J Clin Pharmacol 1990;30:S2-S16
 PHARMACOKINETIC REVIEW OF METOPROLOL CR/ZOK

absorbed independently of the given dose. This was

demonstrated in a single-dose bioavailability
Adjusted AUC (nmol * hfl)
10000
study,17 showing a proportional increase in AUG of
metoprolol GR/ZOK 50-200 mg. In another study,49
the ratio of AUG during a dosage interval at steady
8000
state (day 4) between metoprolol GR/ZOK 100 mg
and 200 mg was found to be 1:2.2 (range 1:1.9-1:3.3),
6000
which might indicate a tendency for a dispropor-
tional increase in bioavailability with the given
4000
dose.
To evaluate the impact of dose on the bioavailabil-
2000
Y-12.4X+2580 ity of metoprolol GR/ZOK over the maximum range
that reasonably could be used in therapy, a further
110 2i)0 300 400 500 600
steady-state study was performed in 12 healthy sub-
Dose (mg) jects (study No VII, Table I). The following doses
were administered once daily during a treatment
period of 7 days; 100 mg, 200 mg, 400 mg (2 X 200 mg)
Figure 10. Relationship between mean (SEM) adjusted AUG and and 600 mg (3 X 200 mg). The individual AUG re-
the given dose of metoprolol CR/ZOK in the dose range 100-600
sults on days 7 and 8 for 11 subjects (data from one
mg. The individual AUG values were adjusted to the 200 mg dose
level to illustrate the dose related increase of AUG. subject were not evaluable) are shown in Figure 9.
The majority of the subjects tended to have a dis-
proportional increase in AUC as the dose was in-
prolol GR/ZOK will produce different plasma con- creased which was most evident at higher dose
centration profiles. They all contain the same coated levels. Nevertheless, the systemic availability
pellets of the drug which should be released and showed a predictable and dose related increase over

Plasma conc. (nmol/l)

#{149}
young healthy subjects, n = 15, Day 7
150
#{149}
elderly healthy subjects, n = 20, Day 4
A hypertensive patients, n =5, after 4 weeks

100

50

6h 12h 18h 24h

Time after dose

Figure 11. Median plasma concentrations of metoprolol at steady state in three different groups of subjects/patients receiving metoprolol
CR/ZOI( 100 mg once daily. The length of each treatment is indicated in the Figure.

SUPPLEMENT $13
 SANDBERG ET AL

the entire investigated range. This is obvious from reported in different panels of healthy volun-
Figure 10 in which AUG values are plotted versus teers.4”4549 The uniformity of plasma levels after ad-
the dose after adjustment to the 200 mg dose level. In ministration of metoprolol CR/ZOK in these three
all subjects there was a strong correlation for the different groups is also illustrated in Figure 11. The
linear relationship with mean r2 = 0.91 (range median steady-state plasma concentrations are plot-
0.69-0.99). From this relationship it can be con- ted over one dosage interval in a group of five hy-
cluded that the AUG at steady state will increase by pertensive patients after 4 weeks of treatment, in 20
about 130-160% when doubling the dose of meto- elderly healthy subjects (62-73 years) and in 15
prolol CR/ZOK. Similar findings have been reported young healthy subjects (study No I, Table I), respec-
for the metoprolol Oros#{174}preparation,5#{176} which indi- tively. The plasma concentration profiles obtained
cates that this deviation from direct proportionality suggest that neither age nor hypertension materi-
is not related to the formulation but rather to the ally affects the pharmacokinetics of metoprolol
saturable first-pass metabolism of metoprolol. How- CR/ZOK.
ever, the linearity also shows that the increase in
bioavailability should be predictable and relatively SUMMARY AND CONCLUSION
constant over the entire dose range 100-600 mg. In
addition, the plasma concentration profiles were Metoprolol GR/ZOK is a once daily preparation
consistent with a prolonged drug absorption without which produces relatively constant plasma concen-
any indication of dose-dumping in any of the sub- trations with minimum fluctuations over a 24-hour
jects at any dose level. Although doses in the 50-200 period. The formulation consists of individually
mg range will be mainly used in clinical practice, it coated pellets of metoprolol succinate which pro-
seems that higher doses of metoprolol CR/ZOK may vides reproducible dissolution and absorption prop-
be safely prescribed without producing unpredict- erties after administration. Extensive studies in
ably high plasma concentrations. healthy subjects have shown that metoprolol GR/
ZOK produces consistent results over a wide dose
APPLICABILITY TO OTHER GROUPS THAN range and have not revealed any major pharmacoki-
YOUNG HEALTHY SUBJECTS netic or biopharmaceutic concerns related to the
formulation. Metoprolol CR/ZOK is about 80% as
The biopharmaceutical and pharmacokinetic prop- bioavailable as a conventional metoprolol tablet and
erties of a new drug product, defined during the de- the intersubject variation of plasma concentrations
velopment phase and thereafter documented, are in are similar for the two treatments.
many cases based solely on results from studies in Furthermore, the metoprolol GR/ZOK formula-
young healthy subjects. These may not always give tion is not significantly affected by food and shows a
good guidance to the properties of the product in the predictable, although not directly proportional, in-
clinical situation, because such factors as age and crease of AUG with dose. The plasma concentra-
disease could have a significant impact on, for in- tion-time profiles obtained in elderly and in hyper-
stance, the pharmacokinetics of the drug. Studies tensive patients are consistent with those in young
have shown that metoprolol is essentially unaffected healthy subjects which indicates that the results
by advancing age, declining renal function and in- achieved in the latter group are relevant for the pa-
flammatory disease.5’ It would therefore not be ex- tient. The therapeutic relevance of stable plasma
pected that the plasma drug concentrations levels of metoprolol is, however, addressed else-
achieved in patients given metoprolol GR/ZOK where in this supplement.
would appreciably differ from those in healthy sub-
jects, unless drug release and absorption have been
REFERENCES
changed due to an altered gastrointestinal function.
As with most other drug products, there is only
1. Reg#{227}rdh C-G: Pharmacokinetic aspects of some I-b1ocking
limited pharmacokinetic data on different patient
drugs. Acta Med Scand 1982:Suppl 665:49-60.
groups receiving metoprolol GR/ZOK. Available re- 2. Wahlund C. Nerme V. Abrahamsson T, Sjoquist P0: 3-adreno-
sults suggest, however, that the plasma concentra- ceptor affinity, cardiac a-blocking potency and depressive effects
tion profile is the same in the elderly and in patients of 5- and R-enantiomers of metoprolol. Acta Physiol Scand
with hypertension, as in young healthy subjects. 1988:Suppl 575:125.

This was first indicated by Ryd#{233}n et al.,52 showing 3. Theeuwes F, Swanson DR. Guittard C, Ayer A. Khanna S:
Osmotic delivery systems for the #{216}-adrenoceptor antagonists
that the 24-hour plasma concentrations of metopro-
metoprolol and oxprenolol: design and evaluation of systems for
lol measured after 4 weeks of treatment in a group of once-daily administration. Br J Glin Pharmacol 1985:19(Suppl
13 hypertensive patients, were comparable to those 2):69S-76S.

S14 #{149}
.1 Clin Pharmacol 1990;30:S2-S16
 PHARMACOKINETIC REVIEW OF METOPROLOL CR/ZOK

4. Benfield P. Clissold SP, Brogden RN: Metoprolol-An updated R: Pharmacokinetic and pharmacodynamic evaluation of meto-
review of its pharmacodynamic and pharmacokinetic properties, prolol controlled release (CR/ZOK) 50 mg in young subjects. I
and therapeutic efficacy, in hypertension, ischaemic heart dis- Clin Pharmacol 1990:30(Suppl):S28-S32.
ease and related cardiovascular disorders. Drugs 1986;31:376- 22. Lucker PW, Moore C. Wieselgren I, Bergstrand R: Pharmaco-
429. kinetic and pharmacodynamic comparison between metoprolol
5. Reg#{225}rdh C-G, Borg KO, johansson R, Johnsson C, Palmer L: CR/ZOK once daily and conventional tablets once daily and in
Pharmacokinetic studies on the selective f3,-receptor antagonist divided doses. J Clin Pharmacol 1990:30(Suppl):S17-S27.
metoprolol in man. I Pharmacokinet Biopharm 1974:2:347-364. 23. Davis SS, Hardy IC, Fara JW: Transit of pharmaceutical dos-
6. Lennard MS. Tucker CT. Woods HF: The polymorphic oxida- age forms through the small intestine. Gut 1986:27:886-892.
tion of tI-adrenoceptor antagonists. Clinical pharmacokinetic con- 24. Davis SS. Hardy JG, Taylor MJ. Whalley DR. Wilson CC: The
siderations. Gun Pharmacokinet 1986:11:1-17. effect of food on the gastrointestinal transit of pellets and an os-
7. Melander A. Danielson K, Scherst#{233}n B, W#{233}hlin E: Enhance- motic device (Osmet). Int J Pharm 1984:21:331-340.
ment of the bioavailability of propranolol and metoprolol by food. 25. Davis SS: The design and evaluation of controlled release
Clin Pharmacol Ther 1977:22:108-112. systems for the gastrointestinal tract. I Contr Release 1985;2:27-
8. Borg KO, Carlsson E, Hoffmann K-J, Jonsson T-E, Thorin H, 38.
Wallin B: Metabolism of metoprolol-(’H) in man, the dog and the 26. Fischer W. Boertz A, Davis SS et al: Investigation of the gas-
rat. Acta Pharmacol Toxicol (Copenh) 1975;36(Suppl 5):125-135. trointestinal transit and In Vivo drug release of isosorbide-5-ni-
9. Reg#{225}rdh C-C, Johnsson C, Jordo L, Lundborg P. Persson B-A, trate pellets. Pharm Res 1987:4:480-485.
R#{228}nn0: Plasma concentrations and beta-blocking effects in nor- 27. Metcalf AM. Phillips SF, Zinsmeister AR. MacCarty RL, Beart
mal volunteers after intravenous doses of metoprolol and pro- RW. Wolff BC: Simplified assessment of segmental colonic transit.
pranolol. I Cardiovasc Pharmacol 1980;2:71 5-723. Gastroenterology 1987;92:40-47.
10. Briant RH. Dorrington RE, Ferry DG, Paxton JW: Bioavailabil- 28. John VA, Shotton PA. Moppert J, Theobald W: Castrointesti-
ity of metoprolol in young adults and the elderly, with additional nal transit of Oros drug delivery systems in healthy volunteers: a
studies on the effects of metoclopramide and probanthine. Eur short report. Br J Clin Pharmacol 1985:19(Suppl 2):203S-2o6S.
Clin Pharmacol 1983:25:353-356.
29. Davis SS. Washington N, Parr CD et al: Relationship between
11. Reg#{233}rdh C-G, Landahl S. Larsson M et al: Pharmacokinetics of the rate of appearance of oxprenolol in the systemic circulation
metoprolol and its metabolite a-OH-metoprolol in healthy, non- and the location of an oxprenolol Oros 16/260 drug delivery sys-
smoking, elderly individuals. Eur I Clin Pharmacol 1983:24:221- tem within the gastrointestinal tract as determined by scintig-
226. raphy. Br I Glin Pharmacol 1988:26:435-443.
12. Larsson M, Landahl S. Lundborg P. Reg#{227}rdh C-C: Pharmaco- 30. Hardy JC, Wilson CC, Wood E: Drug delivery to the proximal
kinetics of metoprolol in healthy, elderly, non-smoking individ- colon. J Pharm Pharmacol 1985:37:874-877.
uals after a single dose and two weeks of treatment. Eur I Clin
31. Jonsson UE, Sandberg A: Absorption study of metoprolol with
Pharmacol 1984;27:217-222.
positioned release capsule. Second International Conference on
13. Jordo L, Attman P0, Aurell M, Johansson L, Johnsson C, Drug Absorption. Edinburgh. 1983:68. (Abstract).
Reg#{227}rdh C-G: Pharmacokinetic and pharmacodynamic properties
32. Codbillon J, Evard D, Vidon N et al: Investigation of drug
of metoprolol in patients with impaired renal function. Clin
absorption from the gastrointestinal tract of man. III. Metoprolol
Pharmacokinet 1980:5:169-180.
in the colon. Br J Clin Pharmacol 1985;19(Suppl 2):113S-118S.
14. Reg#{233}rdh C-C, Jordo L, Ervik M, Lundborg P. Olsson R, R#{246}nn
33. Wagner JC, Nelson E: Per cent absarbed time plots derived
0: Pharmacokinetics of metoprolol in patients with hepatic cir-
from blood level and/or urinary excretion data. I Pharm Sci
rhosis. Clin Pharmacokinet 1981 ;6:375-388.
1963:52:610-611.
15. Johnsson G, Reg#{227}rdh C-G, S#{246}lvell L: Combined pharmacoki-
34. Skelly JP. Barr WH: Biopharmaceutic considerations in de-
netic and pharmacodynamic studies in man of the adrenergic
signing and evaluating novel drug delivery systems. Clin lies
p1-receptor antagonist metoprolol. Acta Pharmacol Toxicol (Go-
Pract Drug Beg Affairs 1985:3:501-539.
penh) 1975;36(Suppl 5):31-44.
35. McAinsh I. Baber NS, Smith R, Young J: Pharmacokinetic and
16. Ragnarsson C. Sandberg A, Jonsson UE, Sjogren j: Develop-
pharmacodynamic studies with long acting propranolol. Br I Gun
ment of a new controlled release metoprolol product. Drug Dev
Pharmacol 1978;6:115-121.
Ind Pharm 1987;13:1495-1509.
36. Ohashi K, Ebihara A, Kondo K, Usami M: Clinical pharmaco-
17. Sandberg A, Ragnarsson G, Jonsson UE, Sjogren J: Design of a kinetics and pharmacological actions of a long-acting formulation
new multiple-unit controlled-release formulation of metoprolol
of propranolol. Arzneimittelforschung 1984:34:507-512.
-Metoprolol CR. Eur I Gun Pharmacol 1988:33(Suppl):S3-S7.
37. Pabst C, Lutz D, Molz KH, Dahmen W, Jaeger H: Pharmacoki-
18. Ervik M, Kylberg-Hanssen K, Johansson L: Determination of
netics and bioavailability of three different galenic nifedipine
metoprolol in plasma and urine using high-resolution gas chro-
preparations. Arzneimittelforschung 1986;36:256-260.
matography and electron-capture detection. J Chromatogr
38. Hammarlund-Udenaes M, Benet LZ: Furosemide pharmaco-
1986:381:168-174.
kinetics and pharmacodynamics in health and disease-an up-
19. Ervik M. Hoffman K-J. Kylberg-Hanssen K: Selected ion mon- date. / Pharmacokinet Biopharm 1989:17:1-46.
itoring of metoprolol and two metabolites in plasma and urine
39. Kendall MJ, John VA, Quaterman CP, Welling PG: A single
using deuterated internal standards. Biomed Mass Spectrom
and multiple dose pharmacokinetic and pharmacodynamic com-
1981;8:322-326.
parison of conventional and slow release metoprolol. Eur I Clin
20. Balm#{233}r K, Zhang Y. Lagerstrom P.O. Persson B-A: Determina- Pharmacol 1980;17:87-92.
tion of metoprolol and two major metabolites in plasma and urine
40. Good W, Leeson U, Zak SL, Wagner WE, Meeker JB, Arnold
by column liquid chromatography and fluorimetric detection. J JD: Oros controlled-release formulations of metoprolol: an ap-
Chromatogr 1987:417:357-365.
proach to the development of a system for once daily administra-
21. Wieselgren I, Lundborg P. Sandberg A, Olofsson B, Bergstrand tion. Br I Clin Pharmacol 1985;19(Suppl 2):231S-238S.

SUPPLEMENT S15
 SANDBERG ET AL

41. Sandberg A, Blomqvist I, Jonsson UE. Lundborg P: Pharmaco- 47. Jonkman Jl-IC: Food interactions with sustained-release the-
kinetic and pharmacodynamic properties of a new controlled-re- ophylline preparations. A review. Clin Pharmacokinet 1989:
lease formulation of metoprolol: A comparison with conventional 16:162-179.
tablets. Eur I Clin Pharmacol 1988;33(Suppl):S9-S14. 48. McLean AJ, McNamara PJ, duSouich P. Gibaldi M, Lalka D:
42. Horai Y, Ishizaki T, Ishikawa K. Metoprolol oxidation in a Food, splanchnic blood flow, and bioavailability of drugs subject
Japanese population: evidence for only one poor metaboliser to first-pass metabolism. Clin Pharmacol Ther 1978:24:5-10.
among 262 subjects. Br I Clin Pharmacol 1988;26:807-808. 49. Blomqvist I, Westergren G, Sandberg A, Jonsson UE, Lund-
43. lyun A0. Lennard MS. Tucker CT, Woods HF: Metoprolol borg P: Pharmacokinetics and pharmacodynamics of controlled-
and debrisoquin metabolism in Nigerians: Lack of evidence for release metoprolol: A comparison with atenolol. Eur J Clin Phar-
polymorphic oxidation. Clin Pharmacol Ther 1986:40:387-394. macol 1988:33(Suppl):S19-S24.
44. Lennard MS. Tucker CT, Silas JH, Freestone S. Ramsay LE, 50. Chan K, Redalieu E, MacNab M, Bouvet A, Gastellana J, Fu
Woods HF: Differential stereoselective metabolism of metoprolol Ci: Steady-state dose proportionality of metoprolol fumarate Oros
in extensive and poor debrisoquin metabolizers. Clin Pharmacol tablets. Pharm lies 1988;5(Suppl):S59.
Ther 1983;34:732-737. 51. Schneider RE, Bishop H, Kendall MJ, Quaterman CP: Effect
45. Oosterhuis B, Jonkman JHC. Kerkhof FA: Pharmacokinetic on inflammatory disease on plasma concentrations of three beta
and pharmacodynamic comparison of a new controlled-release adrenoceptor blocking agents. mt I Clin Pharmacol Ther Toxicol
formulation of metoprolol with a traditional slow-release formu- 1981:19:158-162.
lation. Eur I Clin Pharmacol 1988:33(Suppl):S15-S18. 52. Ryd#{233}n L, Kristenssan BE, Westergren C: Effect of controlled-
46. Melander A, Lalka D, McLean A: Influence of food on the release metoprolol on blood pressure and exercise heart rate in
presystemic metabolism of drugs. Pharmacol Ther 1988;38:253- hypertension: A comparison with conventional tablets. Eur J Glin
267. Pharmacol 1988:33(Suppl):S33-S37.

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