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Eur J Clin Pharmacol (1987) 32:315-318
European Journal of
Clinical Pharmacology
© Springer-Verlag 1987
Propranolol Pharmaeokinetics and Pharmaeodynamies After Single
Doses and at Steady-State*
R. L. Lalonde, J. A. Pieper, R.J. Straka, M. B. Bottorff, and D. M. Mirvis
Departments of Clinical Pharmacy and Medicine, University of Tennessee, Memphis, Tennessee, USA
Summary. The duration and extent of cardiac beta-
blockade and their relationship to propranolol
pharmacokinetics were assessed in nine healthy vol-
unteers. Each subject received 160 mg of regular
propranolol (R), 160 mg of sustained-release pro-
pranolol (SR) and no drug (control), both as single
doses and once daily for 7 days.
After single doses and at steady-state, both
products caused a decrease in exercise heart rate for
at least 24 h, compared to control. The time course
of effect was similar to the time course of serum
propranolol concentration. The oral clearance of
propranolol decreased from single doses to steady-
state for both R and SR; however, the difference
achieved statistical significance only for R. These
changes were reflected in mean accumulation ratios
(AUC steady-state 0-24 h/AUC single dose 0-infin-
ity) of 1.49 and 1.68 for R and SR, respectively.
The pharmacokinetic data are consistent with a
decrease in intrinsic hepatic clearance of proprano-
lol, leading to an increase in bioavailability at
steady-state. Despite a two-fold difference in the
bioavailability of R and SIL there was no difference
in the area under the effect-time curve at steady-
state.
Key words:
propranolol; pharmacodynamics, phar-
macokinetics, beta-blockade, sustained-release pro-
pranolol
Propranolol has been shown to accumulate upon
chronic dosing to an extent greater than that expect-
ed based on single dose pharmacokinetics (Wood et
* Presented in part at the III World Conference on Clinical
Pharmacology and Therapeutics, Stockholm, Sweden, July 1986
al. 1978). Also, Silber et al. (1983) have demon-
strated a 56% reduction in propranolol's intrinsic
clearance measured at steady-state as the dose was
increased from 40 to 320 mg per day. This change in
intrinsic clearance coupled with metabolite urinary
excretion data, suggests the elimination of propran-
olol is nonlinear over this dosage range. Using these
data, Wagner (1985) has shown that propranolol in-
put rate profoundly affects its bioavailability. The
consequences of propranolol's nonlinear pharmaco-
kinetics and its implications upon cardiac beta-
blockade have yet to be fully investigated. The pur-
pose of this study is to investigate the effects of
acute and chronic once daily oral administration of
regular or sustained-release propranolol and the re-
lationship between the pharmacokinetics, and the
duration and extent of cardiac beta-blockade.
Methods
Nine healthy male volunteers ranging in age from
23 to 39 years (mean age 27 years) and ranging in
weight from 66 to 82 kg (mean weight 75 kg), partic-
ipated in the study. The subjects had no evidence
of previous or current cardiac, respiratory, renal or
hepatic dysfunction. All were nonsmokers and ab-
stained from taking caffeine containing products,
other drugs and alcohol for the duration of the
study. The study was a randomized cross-over com-
parison of three regimens. During Phase I (single
dose phase), each subject received one sustained-re-
lease propranolol (SR) 160 mg capsule (Inderal LA,
Ayerst Laboratories Inc., New York, NY), regular
propranolol (R) 160 mg (two 80 mg Inderal tablets)
and no drug at all (control period).
The doses were administered at approximately
8:00 a.m. and the subjects fasted for 8 h before and
316
4 h after drug administration. At least 7 days passed
before proceeding to the next regimen. After com-
pletion of Phase I, all subjects entered a multiple
dose study (Phase II) using the same randomized
cross-over design. During Phase II, each drug was
taken once daily for 7 days with at least one drug-
free week between each regimen. On the last day of
each regimen during Phase II and on the test days
of Phase I, subjects underwent repeated treadmill
exercise tests. Each test was performed on a motor
driven treadmill at 6 mph, 10% grade for 2.5 min,
immediately before drug administration (time 0 for
control period) and then at 2, 4, 8, 12, 24, 32 and
48 h. Arterial blood pressure and an electrocardio-
gram were recorded immediately after each exercise
and heart rate (HR) was determined over 15 consec-
utive R-R intervals. Percentage reduction in HR was
calculated as the difference between post exercise
control HR and that measured after propranolol in-
gestion divided by the control HR then multiplied
by 100. After the single doses in Phase I and the last
doses in Phase II, blood was collected by direct ven-
ipuncture at 0, I, 2, 4, 6, 8, 12, 24, 32 and 48 h. No
heparin was used in the sample collection. The se-
rum was separated and frozen at -20 °C until anal-
ysis.
Serum concentrations of propranolol and 4-hy-
droxypropranolol were measured by HPLC with
fluorescence detection (Lo et al. 1982). Intra- and
inter-day coefficients of variation for propranolol
and its metabolite ranged from 1.5% to 10.5%, over
the range of concentrations observed in this study,
with a limit of sensitivity of 1 ng/ml. Standard non-
compartmental equations were used to calculate the
area under the serum concentration-time curve
R. L. Lalonde et al.: Propranolol at Steady-State
(AUC), terminal elimination rate constant (k) and
apparent oral clearance (CL). AUC was calculated
to infinity after single doses and over 24 h at steady-
state.
The kinetic parameters were compared by Fried-
man's analysis of variance and the heart rate data
were compared by parametric ANOVA. Post-hoc
tests were done using nonparametric multiple com-
parison and Newman-Keuls tests, respectively
(Conover 1980). Paired comparisons were done us-
ing the Wilcoxon paired-sample test.
Results
The mean serum propranolol concentration-time
curves are shown in Fig. 1 and the individual phar-
macokinetic parameters are summarized in Table 1.
With each product, the AUC over one dosing inter-
val at steady-state was larger than the AUC after a
single dose. The above AUC increase was evident in
8 of 9 subjects with R (p < 0.05). A similar average
AUC increase was evident with SR; however, be-
cause it occurred in only 6 of 9 subjects, the differ-
ence did not achieve statistical significance. The av-
erage AUC increases were 49% and 68% for R and
SR, respectively (p >0.05 between products). The
bioavailability of SR relative to R did not change
significantly between single doses and at steady-
state (0.55+_0.30 vs 0.52+0.11, p >0.05). The k val-
ues were consistently smaller with SR compared to
R (p < 0.05), probably because of continued absorp-
tion with SR. However, there was no significant
change in k values between single dose and steady-
state. After administration of R, the molar ratios of
Table 1. Propranolol pharmacokinetic and pharmacodynamic parameters for the regular (R) and sustained-release (SR) products
Subjects AUC (ng.h.m1-1) k (h -1) CL (ml.min -1 .kg -a) AUC Effect
(% reduction
in HR)
Single dose Steady-state Single dose Steady-state Single dose Steady-state Steady-state
R SR R SR R SR R SR R SR R SR R SR
1 544 294 1516 671 0.205 0.069 0.165 0.063 68.0 125.6 24.4 55.1 479 392
2 990 280 1307 673 0.132 0.107 0.140 0.121 33.9 t19.6 25.6 49.8 467 402
3 317 251 504 245 0.190 0.085 0.178 0.025 102.7 129.7 64.5 132.7 402 192
4 1048 555 1071 454 0.160 0.065 0.149 0.063 30.9 58.3 30.2 71.3 456 356
5 1074 477 1346 1032 0.185 0.058 0.172 0.078 34.5 77.7 27.5 35.9 551 538
6 1296 1455 2204 1065 0.126 0.088 0.149 0.054 26.6 23.7 15.6 32.3 473 437
7 1004 284 1324 574 0.213 0.073 0.219 0.064 35.3 124.8 26.8 61.8 432 581
8 1105 210 1099 547 0.231 0.042 0.181 0.122 36.6 192.4 36.8 73.9 576 422
9 717 563 1026 634 0.152 0.069 0.205 0.092 49.5 63.1 34.6 56.0 265 590
Mean 900 a 486 b 1267 c 655 b 0.177 a 0.073 b 0.173 a 0.076 b 46.5 a 101.7 b 31,8 c 63.2 b 456 a 434 a
+SD (310) (388) (455) (259) (0.037) (0.019) (0.026) (0.032) 24.5) (50.6) (13.7) (32.4) (90) (125)
For each parameter, means with different letters differ at p < 0.05
317
200 -
100
E
~ ~0
Z
o
Z
0
160
"~ 120140 I
~ • w..
• *R<SR<C
Z .,
R =
SR
< C
tO0
I
,
I
'
•
' - • ' , . ' , ,
I
, , i , • , • . , , , ,
0 6 12 18 24 30 36 42 48
TIME
(h)
t :
160
E
,<
n-"
120
3=
i
' ' ' • " r ' f [ r r l i I [ , t l r , ~ T r r
6 12 t8 24- 30 .36 4.2 48
TIME
(h)
100
r . . , . . , , , • , , p , , ~ , • , - . i , , 1
0 6 12 18 24 30 36 42 48
TIME (h)
.,,. ***
SR < R < C
** ** SR < R = (3
r I , ' ' • " ' ' ' v , r [ i , [ , r i , $ r , [
0 6
12
18 24 50 36 42 48
TIME:
(n)
200
100
~ 30
Z
0
o
Z
0
L3
R. L. Lalonde et al. : Propranolol at Steady-State
Fig. t. Mean propranolol serum concentrations and exercise heart rates (_+ SE.~n = 9) after regular propranolol ([]), sustained-release
propranolol (A) and control (©). The upper panels refer to single dose and the lower panels to steady-state
4-hydroxypropranolol AUC to propranolol AUC
were 0.074+0.032 and 0.037_+0.030 with single
dose and at steady-state, respectively (p < 0.05). Se-
rum concentrations of 4-hydroxypropranolol were
very low or not measurable after administration of
SR.
The heart rates after treadmill exercise are
shown in Fig. 1. During both control periods, the
mean HR were not statistically different between
any time points. After single doses, both proprano-
lol products caused a decrease in HR at each time
point for up to 32 h, compared to control (p < 0.05).
The effect of R was greater than SR at each time
point up to 8 h; then the converse was true at 24
and 32 h. After 48 h, HR were no longer signifi-
cantly different from control. At steady-state, the
time course of HR was quantitatively similar to the
single dose phase. The effects on the heart rate-
systolic pressure product closely paralleled those on
HR. Table 1 shows the area under the effect-time (%
reduction in HR) curve over one dosing interval at
steady-state. Interestingly, there was no statistical
difference in the total effect observed at steady-state
between R and SR.
Discussion
Recently, Wagner (1985) showed how Michaelis-
Menten elimination of propranolol can explain the
more avid first-pass extraction when the drug is ad-
ministered as a sustained-release formulation, there-
by leading to a decrease in bioavailability. We ob-
served an average relative bioavailability of 0.55
after single doses and 0.52 at steady-state, consistent
with the predictions of Wagner. However, it is un-
clear if decreased absorption from the gut may con-
tribute to the lower bioavailability of SR. Both pro-
pranolol products exhibited an increase in AUC
and decrease in CL at steady-state, compared to sin-
gle doses. These changes reflect a decrease in intrin-
sic hepatic clearance of total drug, provided that
propranolol is completely absorbed and totally
eliminated by hepatic metabolism. A decrease in in-
trinsic hepatic clearance would be expected to in-
crease bioavailability at steady-state with little or no
change in the systemic clearance. This is consistent
with the observed increase in peak concentration
(larger than expected based on the half-life and dos-
ing interval) and lack of change in k at steady-state,
compared to single doses. The decrease in AUC ra-
318 R. L. Lalonde et al.: Propranolol at Steady-State
tio of 4-hydroxypropranolol to parent drug further
suggests that at least part of the decrease in intrinsic
clearance is from a reduced clearance to 4-hydroxy-
propranolol. Our data also indicate that at the dos-
age used, R and SR accumulate to a similar degree,
although there was more variability with the SR.
As indicated by the decrease in exercise HR
compared to control, both propranolol formulations
produce cardiac beta-blockade for at least 24 h after
single doses and at steady-state. We were able to de-
scribe the full time course of pharmacologic effects
since the HR had returned to baseline by 48 h. The
time course of effect tended to follow the time
course of propranolol serum concentrations. We al-
so calculated the area under the effect curve, as a
measure of total cardiac beta-blockade over one
dosing interval at steady-state. Despite a two fold
difference in bioavailability between products, the
total effects observed were essentially the same. In
addition, the peak concentration of regular pro-
pranolol increased 25% between single doses and
steady-state without any appreciable change in the
corresponding pharmacodynamic effects. These
discrepancies are probably explained by the nonlin-
ear serum concentration-effect relationship. We
have shown that the Emax model can best describe
the relationship between propranolol concentration
and percentage reduction in exercise HR (Lalonde
et al. 1987). At the higher concentrations achieved
with R, the concentration-effect curve is more flat
leading to smaller increments in effect with increas-
ing concentrations. Therefore, it must be recognized
that differences in cardiac beta-blockade (duration
of action, total effect) between products will be de-
pendent on the dosage regimen, range of concentra-
tions achieved and the particular pharmacodynamic
parameters that describe the concentration-effect re-
lationship in each individual.
References
Conover WF (1980) Practical non-parametric statistics, 2nd edn.
John Wiley and Sons, New York, NY
Lalonde RL, Pieper JA, Straka RJ, Bottorff MB, Mirvis DM
(1987) Pharmacodynamic modeling of propranolol. Clin Phar-
macol Ther 41:156
Lo Man-Wa, Silber B, Riegelman S (1982) An automated HPLC
method for the assay of propranolol and its basic metabolites
in plasma and urine. J Chromatogr Sci 183 : 126-131
Silber BM, Holford NHG, Riegelman S (1983) Dose dependent
elimination of propranolol and its major metabolites in hu-
mans. J Pharm Sci 72:725-732
Wagner JG (1985) Propranolol: Pooled Michaelis-Menten pa-
rameters and the effect of input rate on bioavailability. Clin
Pharmacol Ther 37:481-487
Wood AJJ, Carr K, Vestal RE, Belcher S, Wilkinson GR, Shand
DG (1978) Direct measurement of propranolol bioavailability
during accumulation to steady-state. Br J Clin Pharmacol 6:
345-350
Received: January20, 1987
accepted in revised form: June 10, 1987
Richard L. Lalonde, Pharm. D.
26 South Dunlap Street, Suite 202
Department of Clinical Pharmacy
Memphis, Tennessee 38163, USA
