Eur J Clin Pharmacol (1997) 53: 141143
PHARMACOKINETICS AND DISPOSITION
J. Armstrong V. F. Challenor B. S. Macklin
A. G. Renwick D. G. Waller
The inuence of two types of meal on the pharmacokinetics
of a modied-release formulation of nifedipine (Adalat Retard)
Received: 12 August 1996 / Accepted in revised form: 10 February 1997
Abstract Objective: The eect of two dierent types of
meal on the absorption of a modied-release formula-
tion of nifedipine (Adalat Retard) was studied.
Results: A light breakfast produced a delay in gastric
emptying (indicated by the rate of paracetamol absorp-
tion) compared with the fasting state, but did not alter
the tmax or Cmax for nifedipine signicantly. After a
cooked breakfast, there was less delay in gastric emp-
tying and again no delay in tmax for nifedipine. However,
the Cmax for nifedipine was signicantly higher than in
the fasting state. Neither meal inuenced the bioavail-
ability of nifedipine.
Conclusion: The results suggest that the nature of the
meal has an important inuence on the absorption
prole of this formulation of nifedipine, probably by an
eect on its dissolution. This study illustrates the im-
portance of considering the eects of dierent types of
meal before concluding that food does not aect the
pattern of drug absorption.
Key words Nifedipine; drug absorption, food
Introduction
There are many ways in which food can inuence the
rate and extent of absorption of drugs from the gas-
trointestinal tract [13]. With some drugs, the absolute
bioavailability can be aected, while for others the rate
of absorption is changed. Several previous studies have
examined the eects of food on the absorption of dif-
ferent formulations of nifedipine.
J. Armstrong V.F. Challenor B.S. Macklin A.G. Renwick
D.G. Waller (&)
Clinical Pharmacology/Medicine Group,
C Level West Wing,
Southampton General Hospital,
Tremona Road,
Southampton SO16 6YE, United Kingdom
Tel +44 1703 794626
Springer-Verlag 1997
Using the immediate-release capsule formulation,
Reitberg et al. [7] found that food produced a signicant
reduction in the maximum observed plasma nifedipine
concentration (Cmax). Interestingly, this reduction showed
a tendency to be larger with a light meal than with a
cooked meal, although these dierences did not reach
statistical signicance.
Ueno et al. [10] studied the absorption of the modi-
ed-release Adalat Retard (Bayer) formulation of
nifedipine after a light meal. They found a higher Cmax,
but an unchanged time to maximum concentration
(tmax) compared with the fasting state. They reported an
increased bioavailability after food, but this might have
been because the area under the plasma nifedipine
concentrationtime curve (AUC) was calculated only
over the rst 12 h. Also, it is unclear whether the chro-
matographic assay [9], used for measuring nifedipine in
that study, was able to separate the parent drug from its
nitropyridine metabolite.
We have shown that the pattern of absorption of a
20-mg biphasic-release formulation of nifedipine was
altered after a typical `English' cooked breakfast [3]. This
formulation contains a crystalline preparation of nifedi-
pine, similar to that in Adalat Retard, which is designed
to dissolve slowly and release 15 mg of nifedipine over a
prolonged period. A second 5-mg microcrystalline com-
ponent dissolves more quickly to produce a more rapid
increase in drug concentration. The eect of the meal, in
this study, was to delay the onset of absorption, after
which the plasma concentration rose steeply to produce a
signicantly higher Cmax than in the fasting state. After
food, the apparent plasma half-life of nifedipine was
shorter. These ndings are consistent with a delay in
gastric emptying due to the meal, allowing greater
dissolution of the crystals in the stomach. Subsequent
delivery of dissolved drug to the small intestine would
then explain the delayed onset of absorption, followed by
a more rapid increase in plasma drug concentration.
Bioavailability of nifedipine was unchanged, but the
altered time-course of absorption meant that the elimi-
nation was no longer absorption rate limited, leading to a
142

short duration of drug exposure. In contrast to these Table 1 Pharmacokinetic data for paracetamol in the fasting state,
results, when the biphasic formulation was given after a after a continental breakfast and after an English breakfast (n=8);
Cmax, maximum plasma concentration; tmax, time to maximum
light `continental'-style breakfast, there was no change in concentration; AUC, area under curve; t half-life; MRT, mean
pharmacokinetics compared with the fasting state [8]. residence time
The current study compared the eects of two types
of meal on the pharmacokinetics of the Adalat Retard Fasting Continental English
modied-release formulation of nifedipine and investi- Cmax(lg ml)1) 22.1 (8.3) 13.7 (3.8)* 12.6 (3.0)**
gated the contribution of food-induced changes in gas- tmax(h) 0.34 (0.13) 1.19 (0.62)** 0.81 (0.50)*#
tric emptying to the pharmacokinetic prole. AUC0(lg ml)1 h) 52 (19) 51 (12) 52 (20)
t(h) 2.4 (0.6) 2.4 (0.3) 2.5 (0.5)
MRT (h) 3.3 (0.8) 3.9 (0.4) 3.9 (0.7)
Methods *
P < 0.05 compared with fasting
**
P < 0.01 compared with fasting
#
The study was approved by the local ethics committee and the P < 0.05 compared with continental breakfast
volunteers gave written informed consent. Eight healthy male
volunteers, aged 2223 years, were studied on three occasions with
at least 1 week between each study. Subjects fasted overnight and, mulation was increased by food (Table 2). The tmax for
on the morning of the study, received nifedipine (Adalat Retard nifedipine was about 2 h later than the tmax of para-
20 mg) in random order under one of three conditions: (1) after a cetamol and was not signicantly altered by either meal.
cooked breakfast of bacon, eggs and tomato with toast and orange
juice (containing approximately 23 g protein, 42 g fat, 36 g car- After food, there was a trend to a shorter t (which
bohydrate: average 600 kcal), (2) after a light meal of two slices of would normally be absorption-rate limited), but this was
toast and orange juice (containing 4.4 g protein, 10 g fat, 30 g not statistically signicant. There was no dierence in
carbohydrate: average 224 kcal) or (3) without food. the MRT, which is a better reection of the dissolution
Nifedipine 20 mg was given 15 min after the meal with 1 g
soluble paracetamol as a marker of gastric emptying [5], and or absorption characteristics of the formulation. The
100 ml water. Subjects remained supine for 4 h. After this, a bioavailability of nifedipine (as indicated by AUC0)
standard lunch was given and normal activity was permitted. Blood was similar in the fasting and fed states.
samples were withdrawn through an indwelling venous catheter
prior to the dose and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3,
3.5, 4, 5, 6 and 8 h after the dose. Further samples were obtained by
direct venepuncture 10, 12, 22 and 30 h after dosing. Blood was Discussion
anticoagulated with lithium heparin and plasma was immediately
separated under sodium-lamp illumination. Samples were stored in Food can alter drug pharmacokinetics in a variety of
a light-proof container at )20 C until analysis. Nifedipine and its
major rst-pass nitropyridine metabolite were assayed by HPLC
ways. First, it can delay gastric emptying and, therefore,
[12]. Plasma paracetamol levels were also measured by HPLC [1]. produce a lag before absorption occurs if the drug is not
The plasma concentrationtime proles for nifedipine and pa- absorbed by the gastric mucosa. For nifedipine, in the
racetamol were analysed by model-independent pharmacokinetic modied-release tablet formulation used in this study,
analysis. The maximum plasma drug concentration (Cmax) and the such delay could allow time for dissolution of the crys-
time taken to reach Cmax (tmax) are the observed values. Results are
expressed as the mean with standard deviation. Statistical analysis talline nifedipine, presenting the drug in a more rapidly
was by analysis of variance, distinguishing the eects due to absorbable form when gastric emptying eventually oc-
treatment, subject and residue, with location of signicant dier- curs. Second, the composition of the meal could also
ences by the paired Student's t-test, corrected for multiple com- inuence the rate of dissolution of some formulations
parisons.
either directly, by inuencing the lipid environment of
the gastric contents, or indirectly, by aecting secretion
of digestive juices. Such an eect could be more pro-
Results nounced for a modied-release formulation. A third
eect of food is to increase liver blood ow, which can
All volunteers completed the 3 study days. The peak
plasma concentration of paracetamol occurred later and
was lower after both types of breakfast when compared
with the fasting state. tmax was delayed 3.5-fold after the Table 2 Pharmacokinetic data for nifedipine in the fasting state,
after a continental breakfast and after an English breakfast (n=8);
continental breakfast and 2.5-fold after the English Cmax, maximum plasma concentration; tmax, time to maximum
breakfast, indicating that both meals delayed gastric concentration; AUC, area under curve; t, half-life; MRT, mean
emptying signicantly. Unexpectedly, the tmax for pa- residence time
racetamol, after the continental breakfast, was signi-
cantly delayed compared with that after the cooked Fasting Continental English
breakfast. Bioavailability and clearance of paracetamol Cmax(lg ml)1) 36.8 (13.5) 42.6 (23.4) 58.9 (18.9)**
(reected by the AUC0, elimination half-life (t) and tmax(h) 2.8 (2.6) 2.9 (1.2) 3.7 (2.0)
mean residence time (MRT) were unaltered by food AUC0(lg ml)1 h) 317 (229) 331 (208) 374 (198)
(Table 1). t1/2(h) 7.6 (3.5) 6.6 (2.9) 6.1 (3.8)
MRT (h) 10.9 (4.2) 10.2 (3.4) 9.2 (4.4)
In contrast to paracetamol, the peak plasma con-
centration of nifedipine from this modied-release for- **
P < 0.01 compared with fasting

reduce the rst-pass metabolism of drugs that undergo
high extraction from the portal circulation. Nifedipine is
a high-extraction compound [2] and its bioavailability
might therefore be increased in the fed state. Previous
studies with the modied-release Adalat Retard formu-
lation of nifedipine suggested that food prolonged the
tmax, and increased the Cmax and apparent bioavail-
ability of the drug, but statistical analyses of the results
were not reported [6, 10].
In the current study, the delay in absorption of pa-
racetamol suggests that both types of meal had delayed
gastric emptying and that the continental breakfast
produced a greater delay than the cooked breakfast. The
reason for this is unclear, although it is known that the
composition of a meal, as well as its bulk, can aect
gastric emptying. Despite the greater delay in gastric
emptying after the continental breakfast, neither meal
signicantly delayed tmax for nifedipine. This occurred
about 2 h after the initial gastric emptying, as indicated
by the absorption of paracetamol. The Cmax for nifedi-
pine was only higher than in the fasting state after the
cooked meal, and food had no eect on the bioavail-
ability of nifedipine. However, if the AUC for nifedipine
is calculated over the rst 12 h, this would suggest an
increase in bioavailability, as reported previously [10].
The discrepancies among the eects of food on the
absorption characteristics of nifedipine in the Adalat
Retard formulation suggests that the nature of the meal
is an important factor. Ueno et al. [11] found that in vitro
dissolution of the Retard tablet was not pH-dependent,
but was aected by `wetability'. This might be more
relevant for lipid-soluble componds such as nifedipine.
A high fat content in a meal will produce greater se-
cretion of bile salts and pancreatic juices than a low-fat
meal. This might aect the dissolution of the tablet to a
greater degree than the prolonged time spent in the more
acid environment of the stomach and explain the higher
Cmax. The continental breakfast used in the current
study was similar to that used by Ueno et al. [10] but
with substitution of orange juice for a glass of milk,
which might explain the dierences in results between
the studies. We conclude that the pharmacokinetics of
the retard formulation of nifedipine might be inuenced
143
only by certain types of food. This study demonstrates
the importance of considering the eects of dierent
types of meal before concluding that food does not aect
the pattern of dissolution and absorption of certain drug
formulations.
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