PHARMACODYNAMICS AND

DRUG ACTION
Pharmacolunetic and ~harmacodvnamic I

interactions during multiple-dosd

administration of nisoldipine
and propranolol
Objectives: The pharmacokinetic and pharmacodynamic interactions after 7 days of oral treatment with
nisoldipine (10 mg twice daily) and propranolol (80 mg twice daily) were investigated in a partially ran-
domized, placebo-controlled crossover study of 12 healthy volunteers.
Methoh: At the end of each treatment period, pharmacokinetic parameters were measured, along with
blood pressure, heart rate, cardiac function, systemic hemodynamics, plasma catecholamines, forearm
blood flow, and apparent hepatic blood flow (estimated by the clearance of indocyanine green dye).
Results: After 7 days of treatment with nisoldipine and propranolol, neither drug altered the other's bio-
availability or elimination parameters, and propranolol did not change the area under the plasma con-
centration- time curve of nisoldipine's metabolite, N-9425. Nisoldipine alone increased apparent hepatic
blood flow and forearm blood flow compared with the other treatment groups but, with the addition of
propranolol, both of these parameters were similar to those in the placebo group. Changes in the other
hemodynamic parameters were consistent with the known effects of these drugs, and no differences in
plasma catecholamine levels were detected.
Cimclmions: In contrast to the findings with single-dose treatment, administration of the combination of
nisoldipine and propranolol for 7 days is not associated with any measurable kinetic interactions, al-
though significant hemodynamic interactions do occur. (CLINPHARMACOL THER1994;55:661-9.)

Thomas A. Shaw-Stiffel, MD, CM, FRCPC, FACP, Scott E. Walker, MScPharm,

Richard I. Ogilvie, MD, FRCPC, and Frans H. Leenen, MD, PhD, FRCPCa
Bridgeport, Conn., and Toronto, Ontario, Canada

From the Yale University-Affiliated G.I. Program, Bridgeport
Hospital, Bridgeport, and the Sunnybrook Health Science Centre
and Hypertension Unit, Toronto Western Hospital, University of
Toronto.
Supported by a grant from Miles Canada Inc
Presented in part at the World Congresses of Gastroenterology,
August 28-31, 1990, Sydney, Australia.
Received for publication July 8, 1993; accepted Dec. 9 , 1993
Reprint requests: Thomas A. Shaw-Stiffel, MD, Chief of Gastroen-
terology, Yale-Affiliated G.I. Program, Bridgeport Hospital, 267
Grant St., PO Box 5000, Bridgeport, CT 06610.
Calcium antagonists and P-receptor blockers are of-
ten used in combination to treat angina pectoris and
hypertension. However, both types of drugs have vari-
able effects on hepatic blood flow and oxidative me-
"Dr. Leenen is a career investigator of the Heart and Stroke Foun-
dation of Ontario. His current address is: Hypertension Unit, Uni-
versity of Ottawa Heart Institute, Ottawa Civic Hospital, 1053
Carling Ave. Ottawa, Ontario KlY 4E9, Canada.
Copyright O 1994 by Mosby-Year Book, Inc.
0009-9236194/$3.00 + 0 13/1/53581

662 Shaw-StzJ31 et al.
tabolism that may lead to clinically important pharma-
cokinetic intera~tions.',~ Propranolol and nisoldipine,
a second-generation 1,bdihydropyridine, are likely to
interact in a complex manner because both are high-
clearance drugs with major "first-pass" removal,3x4
and each may itself alter hepatic blood In ad-
dition, propranolol and several calcium antagonists
other than nisoldipine inhibit hepatic enzyme activ-
ity.778
In a previous single-dose study by our group, nisol-
dipine was found to increase the area under the plasma
concentration-time curve (AUC) and maximum
plasma concentration (C,,,) of propranolol, and pro-
pranolol did the same for n i s ~ l d i ~ i nThe
e . ~ sensitivity
to isoproteronol infusions was decreased when nisol-
dipine was added to propranolol, suggesting enhanced
P-blockade during combined therapy. In addition, the
effects of propranolol on heart rate and total peripheral
resistance were abolished by adding nisoldipine,
whereas the increase in cardiac output seen with nisol-
dipine was attenuated by propranolol.
Other single-dose studies combining nisoldipine
with atenolol or sotalol have documented similar phar-
macokinetic effeck4 Nicardipine, another dihydropy-
ridine calcium antagonist, has been shown to increase
the bioavailability of propranolol1° but not that of
atenolol." The only study to date using long-term
doses of nisoldipine has shown that it significantly in-
creases the C,, and AUC of propranolol and the
C, of atenolol, but it was added to the P-receptor
blocker only after 1 week.I2
Therefore the purposes of this study were to docu-
ment for the first time the kinetic and hemodynamic
interactions during multiple-dose oral administration
of nisoldipine and propranolol begun concomitantly
and at the usual therapeutic doses, as well as to ex-
plore the mechanisms by which these interactions may
occur.
METHODS
Subjects. Twelve nonsmoking white male volun-
teers (mean age, 28 + 2 years; range, 18 to 45 years;
*
mean weight, 72 3 kg; range, 54 to 92 kg) took part
in this study, which was approved by the Human Eth-
ics Committee of the Toronto Western Hospital. Re-
cruits were obtained by means of advertisements on
the University of Toronto campus. All subjects were
normal as determined by history, physical exam-
ination, blood work, urinalysis, urine drug screens,
electrocardiogram, and echocardiogram. All subjects
denied abusing alcohol or other drugs, taking medica-
tions within l month of the study, or having any aller-
CLINICAL PHARMACOLOGY & THERAPEUTICS
JUNE 1994
gies to nisoldipine, propranolol , indocy anine green
(ICG) dye or other drugs (sulfonamides, penicillins,
or iodides) that may predispose a subject to ICG hy-
persensitivity. Before the study, the protocol, equip-
ment, and possible side effects were discussed, and
written informed consent was obtained. Smoking, al-
cohol, and other drugs were prohibited, and urine
drug screens were checked at random. No significant
adverse events occurred.
Protocol. Each subject participated in four 7-day
treatment periods. At the end of each treatment period
the tests described below were conducted, with 10-day
washout periods between. During the first period, all
subjects received placebo plus placebo, whereas for
the remaining periods they were randomly assigned
(Latin-square method) to receive the following: (1) 10
mg nisoldipine plus placebo, (2) 80 mg propranolol
plus placebo, or (3) 10 mg nisoldipine plus 80 mg
propranolol, all taken twice daily.
For the first 2 days of each period, propranolol (or
its placebo) was started as a half-tablet, whereas nisol-
dipine (or its placebo) was always administered as a
single tablet. Each drug was identical in appearance to
its corresponding placebo, and both were kept in sim-
ilar light-excluding containers to prevent nisoldipine
degradation. Drug compliance was checked by pill
counts and baseline drug concentrations at the end of
each period, and no subject had to be excluded for this
reason. Subjects and technicians were blinded to the
drug sequence. On each study day, the investigator
who obtained blood samples for pharmacokinetics and
recorded hemodynamic data (apart from echocardiog-
raphy), as described below, was not blinded. This was
necessary to minimize excessive blood letting of the
subject because serial blood samples were drawn only
for the drug(s) the subject had been taking during the
preceding 7-day period and on the morning of the
study day.
For 24 hours before each study day, subjects were
told to avoid caffeine and substances that alter cy-
tochromes P450 activity. They were asked to take the
last drug or placebo tablets at 9 PM the night before
each study day and then to fast. After arrival at the
Hypertension Unit, pill counts were checked and the
subjects were reexamined, weighed, and given a stan-
dardized liquid breakfast. This consisted of orange
juice (200 ml), one Instant Breakfast (Carnation, Tor-
onto, Ontario, Canada) mixed with 2% milk (250 ml)
and yogurt (175 gm), and 300 ml water. The subjects
remained supine for the next 4 hours in a quiet semi-
darkened room during the studies. For blood sam-
pling, an indwelling catheter was inserted into a fore-
CLINICAI. PHAKMACO1.OGY & THERAI'LUTICS
\'OLUME 55, NUMBER 6
1000 I I
0 5
Fig. 1. Propranolol plasma concentration (in nanograms per milliliter) versus time curves. Data
represent mean values & SEM for 12 subjects. Open circles, Propranolol alone; solid circles, pro-
pranolol plus nisoldipine.
arm vein and kept patent with heparin (5000 units in
30 ml). The remaining study equipment was set up
and baseline data obtained after 30 minutes of accli-
matization. Study tablets were then administered (t =
0), about 1 hour after breakfast.
Over the next 4 hours, the following were mea-
sured: blood pressure, heart rate, and blood samples
for appropriate drug concentrations at 0, V2, 1, 1V2, 2,
3, and 4 hours; echocardiography with carotid pres-
sure tracings at 0, 1, 2, 3, and 4 hours; plasma cate-
cholamines at 0 and 2 hours; forearm blood flow at 0,
2, and 4 hours and apparent hepatic blood flow by
ICG clearance once at 2 hours. The first study day
(placebo plus placebo) was completed at this point.
On subsequent study days, subjects were allowed to
sit up and eat a standardized lunch; blood samples for
drug concentrations were drawn at 5, 6, 7, 8, 10, and
12 hours; and a standardized supper was provided at 9
hours. After the 12-hour sample, the indwelling cath-
eter was removed and subjects went home. The sub-
jects returned the next morning for the 24-hour blood
sample and hemodynamic measurements.
Equipment and methods. Blood pressure was mea-
Shaw-StzJtel et al. 663
I I I
0 Pro. alone
Pro. + Nis.
10 15 20 25
(hours)
sured by use of a Roche Arteriosonde 1225 (Roche
Medical Electronics Inc., Cranbury, N.J.) and heart
rate monitored on a Tektronix 414 (Tektronix Inc.,
Beaverton, Ore.). The mean arterial pressure was cal-
culated as diastolic blood pressure plus one third of
the pulse pressure (systolic minus diastolic pressure).
With use of a Toshiba Sonolayer SSH-60A echocardi-
ography machine with a 3.75 MHz transducer, in con-
junction with a Toshiba Linescan Recorder LSR-20B
(Toshiba, Osaka, Japan), we measured or calculated
the following parameters: left-ventricular end-diastolic
and end-systolic dimensions, stroke volume, cardiac
index, pressure-volume ratio, circumferential fiber
shortening, ejection fraction, and total peripheral re-
sistance, as described previously. ''
Forearm blood
flow was measured by mercury-in-silicone rubber
plethysmography as described elsewhere,I4 and fore-
arm resistance calculated by dividing mean arterial
pressure by forearm blood flow. Apparent hepatic
blood flow was estimated by means of the clearance of
a 0.5 mglkg bolus of ICG (Hynson, Westcott & Dun-
ning, Baltimore, Md.) infused intravenously over 60
seconds.
 CLINICAL PHARMACOLOGY & THERAPEUTICS
664 Shaw-Stzfel et al. JUNE 1994

Table I. Pharmacokinetic parameters for propranolol, nisoldipine, and its metabolite N-9425 in 12 healthy males
given propranolol, nisoldipine, or both for 7 days*
Prouranolol Nisoldi~ine
Proprunolol Nisoldipinr r proprunolol Nisoldipine Nisoldipine r proprunolol
AUC (ng . hrlml) 591 t 72 602 t 72 7.1 *
1.1 7.3 t 1.0
Lax (ng/ml) 112 15* 117 2 13 1.6 t 0.3 1.8 t 0.3
Lax(hr) 2.3 t 0.3 1.7 t 0.2 2.1 t 0.3 2.3 t 0.4
t l / ~ P(hr) 0.28 t 0.02 0.28 t 0.01 0.35 t 0.03 0.30 -C 0.03
Data are mean values + SEM.
AUC, Area under the plasma concentration-time curve; C,,,, maximum concentration; t,,, time to reach C,,; ty2P. elimination half-life.
*Combined therapy failed to alter these parameters compared to when the drugs were given alone.

Table 11. Systemic hemodynamics and cardiac function in 12 healthy males given placebo, nisoldipine,
propranolol, or the latter two in combination for 7 days
Hour

Systolic blood pressure (mm Hg)

Plac
N
P*
N + P* I
Diastolic blood pressure (mm Hg)
Plac
N*
P*
N + P*
Heart rate (beatslmin)
Plac

*
N + P*
I]
Cardiac index (L/min/m2)
Plac

*
N + P
I]
Circumferential fiber shortening
velocity (mmlsec)
Plac

N+P
Stroke volume (ml)
Plac
N
P
N + P
Pressure/volume ratio (mm Hglml)
Plac

N + P*
I]
Total peripheral resistance (U)
Plac

*
N + P
I]
Data are mean values r SEM.
Plac, Placebo; N, nisoldipine; P, propranolol; N + P, nisoldipine plus propranolol.
*Signifies p < 0.05 for comparisons to placebo, whereas bars indicate p < 0.05 for between drug comparisons (significant differences over time [ANOVA]).
CLINICAL PHARMACOLOGY & THERAPEUTICS
VOLUME 55. NUMHER 6
Nisoldipine Nisoldipine + propranolol
Sample analysis. Nisoldipine samples were care-
fully protected from light at all times. The tech-
niques used to measure plasma levels of nisoldi-
pine, its metabolite N-9425, propranolol, epineph-
rine, norepinephrine, and ICG are described else-
Statistical analysis. The data are expressed as mean
values zk SEM. The pharmacokinetic data were gener-
ated by the use of a nonlinear regression model, tak-
ing multiple dosing into account. Statistical analysis
of the data was performed by ANOVA for repeated
measures. Differences were deemed to be significant
at the p < 0.05 level. We used 12 subjects on the ba-
sis of power calculations to detect a significant differ-
ence in AUC and elimination half-life (tR) derived
from our previous study.9 Type I1 error was also ex-
cluded by appropriate calculations derived from this
study.
RESULTS
Pharmacokinetic parameters (Table I; Figs. I and
2 ) . No significant differences occurred in the pharma-
cokinetic parameters of bioavailability (AUC, C,,,,
time to reach C,, [t,,,], or elimination t&) for
nisoldipine with versus without propranolol or for pro-
pranolol with versus without nisoldipine (Table I). In
addition, there were no significant changes in these
parameters for the nisoldipine metabolite N-9425
with versus without propranolol. Figs. 1 and 2 illus-
trate the plasma concentrations-time curves for each
drug.
Blood pressure and heart rate (Table 11). For sub-
jects receiving placebo, both systolic and diastolic
blood pressure showed small increases with time. Sys-
tolic blood pressure was lowered by nisoldipine plus
propranolol compared with placebo or nisoldipine
alone and by propranoiol alone compared with pla-
cebo. Diastolic blood pressure was lowered by nisol-
dipine, nisoldipine plus propranolol, or propranolol
alone compared with placebo. No between-drug com-
parisons for diastolic blood pressure reached statistical
significance. Heart rate was lowered by nisoldipine
Shaw-Stzfeel et al. 665
plus propranolol or propranolol alone compared with
placebo or nisoldipine alone, but nisoldipine alone did
not change heart rate.
Cardiac function and systemic hemodynamics
(Table 11). Cardiac index was lowered by propranolol
alone compared with placebo, whereas it was higher
with nisoldipine alone compared with the other treat-
ments but not versus placebo. Total peripheral resis-
tance was increased by nisoldipine plus propranolol or
propranolol alone compared with nisoldipine alone.
Propranolol alone increased total peripheral resistance
versus placebo. The velocity of circumferential fiber
shortening was decreased by nisoldipine plus propran-
olol or propranolol alone compared with nisoldipine
alone but was unchanged by nisoldipine alone. There
were only minor changes in stroke volume and pres-
sure/volume ratio (Table II), left-ventricular end-
diastolic and end-systolic dimensions, and ejection
fraction (data not shown).
Regional hemodynamics (Table Ill). Forearm
blood flow was decreased by nisoldipine plus propran-
0101 or propranolol alone compared with nisoldipine
alone, decreased by propranolol alone compared with
nisoldipine plus propranolol or placebo, but increased
by nisoldipine alone compared with placebo. Forearm
arterial resistance was higher with propranolol alone
than that with the other treatments or placebo. Nisol-
dipine alone increased apparent hepatic blood flow
compared with nisoldipine plus propranolol, proprano-
lo1 alone, or placebo. The increases in forearm blood
flow and apparent hepatic blood flow induced by
nisoldipine were modified by the addition of propran-
0101 so that the values for both parameters during
combined therapy were not different from those ob-
sewed during placebo.
Plasma catecholamines (Table IV). Plasma nor-
epinephrine and epinephrine concentrations were not
significantly different between treatment groups. Da-
ta was available in only 10 of the subjects because
of technical problems in obtaining samples in two
subjects.
DISCUSSION
Nisoldipine is a potent peripheral and coronary va-
sodi~ator,'~ similar in structure to nifedipine but with
less negative inotropy, that has shown considerable
promise in the treatment of angina, hypertension, and
congestive heart f a i ~ u r e . ~ OIt -has
~ ~ been used in com-
bination with P-b~ockers,~ but few studies have as-
sessed kinetic or hemodynamic interactions, particu-
larly during long-term therapy.
In this study, the hemodynamic effects of nisol-
dipine and propranolol when each was taken alone
were similar to those documented previously.9~'9~24

666 Shaw-Stzfel et al.
7 -i
i3 5 10
Fig. 2. Nisoldipine plasma concentration (in nanograms per milliliter) versus time curves. Data
represent mean values 2 SEM for 12 subjects. Open circles, Nisoldipine alone; solid circles,
nisoldipine plus propranolol.
With combined treatment, cardiac P-blockade pre-
dominated, as shown by a persistent decrease in heart
rate and cardiac index, whereas individual effects of
each drug on total peripheral resistance were bal-
anced. These findings are consistent with previous
studies that indicate that nisoldipine acts primarily on
arteries, with a minor effect on cardiac function appar-
ently no greater than that with P-blockade
However, this does not exclude some chronotropic or
inotropic effects of nisoldipine. Changes in regional
blood flow were more pronounced. Nisoldipine in-
creased forearm blood flow and apparent hepatic
blood flow without a change in cardiac index, indicat-
ing selective vasodilation and redistribution of blood
flow, whereas propranolol blunted this effect. Similar
effects on forearm blood flow occurred in our previous
single-dose study.9
In terms of pharmacokinetic interactions, this study
showed that, with multiple doses of nisoldipine and
propranolol for 7 days, neither drug altered the other's
indexes of bioavailability (i.e., AUC and C,,,), rate
of absorption (t,,,), or elimination t&, in direct
CLINICAL PHARMACOLOGY & THERAPEUTICS
I I I
0 N i s . alone
0 Nis. + Pro.
15 20 25
(hours)
contrast to our single-dose study in which each drug
increased the other's AUC and c,,,.~ In a recent
study by Elliott et a1.12 multiple doses of nisoldipine
were also found to increase the C,, and AUC of
propranolol. However, nisoldipine was added to pro-
pranolol only after 1 week and both drugs were given
once daily, resulting in rather low plasma concentra-
tions at the end of each dosing interval. Thus Elliott's
study resembled more a single-dose than a steady-
state one.
Changes in drug absorption, the hepatic first-pass
effect, or both, related to single versus multiple drug
doses, may explain some of the differences in kinetic
data from our two studies. With respect to absorption,
no interactions have been reported between these
drugs in the gastrointestinal tract or between other
drugs of similar class.'32Because nisoldipine and pro-
pranolol are high-clearance drugs and first-pass re-
moval is the major determinant of their bioavailabil-
ity,334transient increases in hepatic blood flow during
absorption of these drugs may saturate hepatic drug-
binding sites or open attenuating presys-
CLINICAL PHARMACOLOGY & THERAI'EUTICS
VOLUME 55, NUMBER 6 Shaw-Stzfel et al. 667

Table 111. Forearm hemodynamics and apparent hepatic blood flow at baseline and at 2-hour intervals in 12
healthy males given placebo, nisoldipine, propranolol, or the latter two in combination for 7 days
Hour

Mean forearm blood flow (mllminldl)

Plac

P*
N +P ]
Mean forearm resistance (U)
Plac

P* I
N + P ]
Apparent hepatic blood flow (mllmin)
Plac
"*
P
N + P
I]
Date are mean values 2 SEM. Significant differences are as noted.
Plac, Placebo; N, nisoldipine, P, propranolol; N + P, nisoldipine plus propranolol.
*Signifies p < 0.05 for comparisons to placebo, whereas bars ind~catep < 0.05 for between-drug comparisons

Table IV. Plasma concentrations of norepinephrine amil, nifedipine, and isradipine may all increase
and epinephrine at baseline and at 2 hours in 10 '
hepatic blood flow, 3238328,29but the effect of nisol-
healthy males given placebo, nisoldipine, dipine is less clear. In one study, no change in appar-
propranolol, or the latter two in combination for ent hepatic blood flow was observed when nisoldipine
7 days was given as a continuous infusion for either 8 or 24
Norepinephrine Epinephrine hours nor when it was given at two different doses.6
Hour (pgw (pgw However, when ICG clearance is used as an estimate
of apparent hepatic blood flow, serial determinations
0 Placebo at such short time intervals are ina~curate.~" In an-
N other study, apparent hepatic blood flow increased sig-
P nificantly after a single oral dose of nisoldipine (20
N + P mg), but it returned to baseline when the same dose
2 Placebo
N was continued for another 3 days.31 Transient in-
P creases in hepatic blood flow have also been observed
N + P with verapami12' and nifedipine. 32
Few studies have assessed the combined effects of
Data are mean values t SEM. There were no significant differences calcium antagonists and P-blockers on hepatic blood
+
N, Nisoldipine; P, propranolol; N P, nisoldipine plus propranolol.
flow. In one study, no change in apparent hepatic
blood flow was detected with verapamil alone or when
it was added to propranolol.33 In another, both single
temic clearance and improving bioavailability. With and multiple doses of nisoldipine, when added to
sustained increases in hepatic blood flow, the flow- atenolol or propranolol, did increase apparent hepatic
dependent systemic clearance of these drugs will also blood flow compared with that on each drug alone,
increase, counteracting any initial effect on bioavail- but the effect on apparent hepatic blood flow of nisol-
ability thus with no overall change in AUC.~' dipine alone was not described, preventing a con-
Propranolol has also been shown to lower apparent trolled comparison. l 2
hepatic blood flow,5 although in this study no statisti- With these issues in mind, the differences in our ki-
cal difference in apparent hepatic blood flow was ob- netic data can be explained as follows. In the single-
served between propranolol alone and placebo. Verap- dose study, a single dose of nisoldipine (20 mg) was

668 Shaw-Stzffel et al.
administered one hour before propranolol (40 mg).
This may have led to an initial increase in apparent
hepatic blood flow, which enhanced propranolol bio-
availability and resulted in a higher A U C . O~n ~the~ ~ ~
other hand, at steady state after 7 days of multiple
doses, the initial increase in apparent hepatic blood
flow related to nisoldipine alone returned to baseline
with combination therapy, and as a result, the bio-
availability (and AUC) of propranolol remained un-
changed. In addition, had there been a sustained ele-
vation in apparent hepatic blood flow with multiple
doses of nisoldipine despite propranolol administra-
tion, this could have increased the flow-dependent
systemic clearance of propranolol after its absorption,
leading to no overall change in its A U C . ' , ~ ,The ~~
elimination t ~ ,of~ propranolol was not altered by nisol-
dipine, and if its volume of distribution were to re-
main unchanged, this would suggest the absence of
any detectable enzyme inhibition by nisoldipine in
contrast to that seen with diltiazem and verapa-
mi1.2~.34Likewise, multiple doses of propranolol may
not inhibit the biotransformation of nisoldipine be-
cause both its elimination t ~ ,and
~ the AUC of its major
metabolite (N-9425) remained unchanged.
T o conclude, in contrast to our single-dose study
with nisoldipine and propranolol, we could not show
any measurable effects on bioavailability or elimina-
tion during multiple-dose administration of these
drugs, even though significant pharmacodynamic in-
teractions occurred, notably in regional hemodynam-
ics. It remains to be determined whether these find-
ings, which were derived in normal volunteers, also
apply to patients with angina, hypertension, and con-
gestive heart failure. Furthermore, because nisoldipine
is now known to b e optically active, with the (+)-
form having greater cardiovascular activity in ~ i t r o , ~ '
more studies will be necessary to determine whether
any interactions involving nisoldipine are stereoselec-
t i ~ e . ~ ~
We thank Ms. Fiona Browning, Ms. Donna Holliwell,
Ms. Margery Cruise, Dr. John Cobby, and Dr. David
Frankel for technical assistance.
References
Schlanz KD, Myre SA, Bottorff MB. Pharmacokinetic
interactions with calcium channel antagonists (Part I).
Clin Pharmacokinet 1991;2 1:344-56.
Schlanz KD, Myre SA, Bottorff MB. Pharmacokinetic
interactions with calcium channel antagonists (Part 11).
Clin Pharmacokinet 1991;21:448-60.
Shand DG. Pharmacokinetic properties of the beta-ad-
renergic receptor blocking drugs. Drugs 1974;7:39-47.
CLINICAL PHARMACOLOGY & THERAPEUTICS
JUNE 1994
4. Friedel HA, Sorkin EM. Nisoldipine: a preliminary re-
view of its pharmacokinetic properties, and therapeutic
efficacy in the treatment of andina pectoris, hyperten-
sion and related cardiovascular disorders. Drugs
1988;36:682-731.
5. Westaby D, Bihari DJ, Gimson AES, Crossley IR, Wil-
liams R. Selective and non-selective beta blockage in
the reduction of portal pressure in patients with cirrho-
sis and portal hypertension. Gut l985;25: 121-4.
6. Van Harten J, van Bruemmelen P, Zeegers RRECM,
Danhof M, Breimer DD. The influence of infusion rate
on the pharmacokinetics and hemodynamic effects of
nisoldipine in man. Br J Clin Pharmacol 1988;25:709-
17.
7. Tucker GT, Bax ND, Lennard MS, Al-Asady S, Baha-
raj HS, Woods HF. Effects of beta-adrenoreceptor an-
tagonists on the pharmacokinetics of lignocaine. Br J
Clin Pharmacol 1984;l7:2 1S-283.
8. Bauer LA, Stenwall M, Horn JR, Davis R, Opheim K,
Green L. Changes in antipyrine and indocyanine green
kinetics during nifedipine, verapamil, and diltiazem
therapy. CLINPHARMACOL THER1986;40:239-42.
9. Levine MAH, Ogilvie RI, Leenen FHH. Pharmacoki-
netic and pharmacodynamic interactions between nisol-
dipine and propranolol. CLINPHARMACOL THER1988;
43~39-48.
10. Schoors DF, Vercruysse I, Musch G , Massart DL, Du-
pont AG. Influence of nicardipine on the pharmacoki-
netics and pharmacodynamics of propranolol in healthy
volunteers. Br J Clin Pharmacol 1990;29:497-501.
11. Sorkin EM, Clissold SP. Nicardipine: a review of its
pharmacodynamic and pharmacokinetic properties, and
therapeutic efficacy, in the treatment of angina pectoris,
hypertension and related cardiovascular disorders.
Drugs 1987;33:296-345.
12. Elliott HL, Meredith PA, McNally C, Reid JL. The in-
teractlons between nisoldipine and two beta-adrenocep-
tor antagonists-atenolol and propranolol. Br J Clin
Pharmacol 1991;32:379-85.
13. Leenen FHH, Smith DL, DeLeve L. Non-selective
beta-receptor stimulation and blockade and left ventric-
ular function. CLINPHARMACOL THER1983;34:570-5.
14. Ogilvie RI, Nadeau JH, Lutterodt A. Vasodilator ca-
pacity of forearm vessels in hypertension. Clin Exp Hy-
pertens [A] 1982;4:1391-407.
15. Krol GJ, Lettieri JT, Mazzu AI, et al. Bioequivalence
of Bayer and Miles nitrendipine tablet formulations.
J Cardiovasc Pharmacol 1987;4:S 129-35.
16. DeLeve LD, Endrenyi L, Leenen FHH. Plasma concen-
tration-response relationships of two formulations of
propranolol. J Clin Pharmacol 1985;25: 182-6.
17. Sole MJ, Hussain MN. A simple and specific radioen-
zymatic assay for the simultaneous measurement of pi-
cogram quantities of norepinephrine, epinephrine and
dopamine in plasma and tissues. Biochem Med
1977;18:301-7.
18. Rappaport PL, Thiessen JJ. High pressure liquid chro-
CLINICAL PHARMACOLOGY & THEKAI'EUTICS
VOLUME 55. NUMBER 6
matographic analysis of indocyanine green. J Pharma-
col Sci 1982;7 1: 157-61.
19. Kiowski W, Pfistere M, Burkart F. Direct vascular and
myocardial effects of nisoldipine. Am J Cardiol
1990;65G-9G.
20. Yokota M, Miyahara T, Iwase M, et al. Hemodynamic
mechanisms of antianginal action of calcium channel
blocker nisoldipine in dynamic exercise-induced an-
gina. Circulation l99O;8 1:1887-98.
21. Laederach K, Wiedmann P, Lauener F, Gerber A, Zie-
gler WH. Comparative acute effects of the calcium
channel blockers tiapamil, nisoldipine, and nifedipine
on blood pressure and some regulatory factors in nor-
mal and hypertensive subjects. J Cardiovasc Pharmacol
1986;8:294-302.
22. Barjon JN, Rouleau JL, Bichet D, Juneau C, De Cham-
plain J. Chronic renal and neurohumoral effects of the
calcium entry blocker nisoldipine in patients with con-
gestive heart failure. J Am Coll Cardiol 1987;9:622-30.
23. van Harten J, Burggraaf J, Ligthart GJ, van Brummelen
P, Breimer DD. Single- and multiple-dose nisoldipine
kinetics and effects in the young, the middle-aged, and
the elderly. CLINPHARMACOL THER1989;45:600-7.
24. Silke B, Verma SP, Midtbo KA, et al. A haemody-
namic study of the effects of combined slow-calcium
channel blockade (nisoldipine) and beta-blockade (me-
toprolol) in coronary heart disease. Int J Cardiol
1986;13:231-41.
25. McLean AJ, Skews H, Bobik A, Dudley FJ. Interaction
between oral propranolol and hydralazine. CLINPHARMA-
COL THER1980;27:726-32.
26. Evans GH, Shand DG. Disposition of propranolol.
Drug accumulation and steady-state concentrations dur-
ing chronic oral administration in man. CLINPHARMACOL
THER1973;14:487-93.
27. Wilkinson GR, Shand DG. A physiological approach to
hepatic drug clearance. CLIN PHARMACOL THER
1975;18:377-90.
Shaw-Stzfel et al. 669
28. Meredith PA, Elliott HL, Pasanisi F, Kelman AW,
Sumner DJ, Reid JL. Verapamil pharmacokinetics and
apparent hepatic and renal blood flow. Br J Clin Phar-
macol 1985;20:101-6.
29. Klockowski PM, Lener ME, Sirgo MA, Rocci ML.
Comparative evaluation of the effects of isradipine and
diltiazem on antipyrine and indocyanine green clear-
ances in elderly volunteers. CLIN PHARMACOL THER
1990;48:375-80.
30. Burczynski FJ, Pushka KL, Sitar DS, Greenway CV.
Hepatic plasma flow: accuracy of estimation from bolus
injections of indocyanine green. Am J Physiol
1987;252:H953-62.
3 1 . Meredith PA, Pasanisi HL, Elliott HL, Reid JL. The ef-
fect of nisoldipine on apparent liver blood flow and ef-
fective renal plasma flow. Br J Clin Pharmacol
1985;20:235-7.
32. Reiss WG, Bauer LA, Horn JR, Zierler BK, Easterling
TR, Strandness DE. The effects of oral nifedipine on
hepatic blood flow in humans. CLINPHARMACOL THER
1991;50:379-84.
33. Murdoch DL, Thomson GD, Thompson GG, Murray
GD, Brodie MJ, McInnes GT. Evaluation of potential
pharmacodynamic and pharmacokinetic interactions be-
tween verapamil and propranolol in normal subjects. Br
J Clin Pharmacol 1991;3 1 :323-32.
34. Bach D, Blevins R, Rubenfire M, Edwards DJ. The ef-
fect of verapamil on antipyrine pharmacokinetics and
metabolism in man. Br J Clin Pharmacol 1986;
21:655-9.
35. Baksi AK, Edwards JS, Ahr G. A comparison of the
pharmacokinetics of nisoldipine in elderly and young
subjects. Br J Clin Pharmacol 1991;31:367-70.
36. Hunt BA, Borttorff MB, Herring VL, Self TH, Lalonde
RL. Effects of calcium channel blockers on the pharma-
cokinetics of propranolol stereoisomers. CLINPHARMA-
COL THER1990;47:584-91.