Endocrine Journal 2007, 54 (4), 571–576

Pharmacokinetics and Pharmacodynamics of Glimepiride in

Type 2 Diabetic Patients: Compared Effects of Once- versus
Twice-daily Dosing
MICHIHIRO MATSUKI, MASAFUMI MATSUDA, KENJI KOHARA, MASASHI SHIMODA, YUKIKO KANDA,
KAZUHITO TAWARAMOTO, MAKOTO SHIGETOH, FUMIKO KAWASAKI, KOU KOTANI AND KOHEI KAKU

Division of Diabetes and Endocrinology, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki,
Okayama 701-0192, Japan

Abstract. To compare the pharmacokinetic and pharmacodynamic effects of glimepiride between once- and twice-daily
dosing in type 2 diabetic patients. Eight Japanese type 2 diabetic patients, who had been treated with 2 mg glimepiride
alone over 4 weeks (age 40–70, body mass index ≤25 kg/m2, hemoglobin A1C<8.0%), were randomly assigned to the
crossover study with glimepiride 2 mg once-daily and 1 mg twice-daily for 4 weeks for each regime. Serum concentra-
tions of glimepiride, plasma glucose, insulin and C-peptide were measured over 24 h at the fixed time intervals on the last
day of each crossover period, and HbA1C was measured at the same day. Pharmacokinetic profiles in two regimens were
different to each others; a single peak of serum glimepiride concentration was observed in once-daily, and double peaks in
twice-daily dosing. Drug concentration increased immediately, and peaked at 2 h after administration irrespective of
dosage. Cmax value in once-daily dose was higher than those in twice-daily doses. AUC values were not different
between two regimens. Pharmacodynamic profiles for plasma glucoses, serum insulin and C-peptide showed no statisti-
cally significant differences between two regimens, and parameters were not different each other. Analyses of adverse
events and laboratory data demonstrated a favorable safety profile of glimepiride. The present results suggest that
glimepiride may be suitable for once-daily dosing with respect to clinical usefulness.

Key words: Glimepiride, Type 2 diabetes, Pharmacokinetics, Pharmacodynamics

(Endocrine Journal 54: 571–576, 2007)

GLIMEPIRIDE, a new generation sulfonylurea, has
been widely used in the world including Japan. In
comparison with conventional sulfonylurea drugs,
glimepiride has several benefits: rapid and complete
absorption after oral administration, a lower dose, long
duration of action, and possible insulin-sensitizing
effect [1–3]. In addition, the previous clinical studies
demonstrated that glimepiride once-daily dose, which
is a common usage of this agent in Europe and the US,
Received: March 20, 2006
Accepted: March 2, 2007
Correspondence to: Michihiro MATSUKI, M.D., Ph.D., Division
of Diabetes and Endocrinology, Department of Internal Medicine,
Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama
701-0192, Japan
Abbreviations: AUC: area under the curve, BID: twice a day
provided a good glycemic control of type 2 diabetes as
well as twice-daily doses [4]. Sulfonylurea drugs are
preferred as the first choice rather than other oral
antidiabetic agents to treat type 2 diabetic patients in
Japan, probably due to the lower potency of insulin
release from the pancreas in Japanese subjects com-
pared with Caucasian. On the other hand, the usual
daily dosage of conventional sulfonylurea drugs in
Japanese patients is much less than that in Caucasian
patients. These facts strongly suggest that the patho-
physiology of type 2 diabetes mellitus and the sensitiv-
ity to sulfonylurea drugs are different between the two
populations. It is of interest, however, that the usual
daily dose range of glimepiride (~1–4 mg) is not differ-
ent between Japan and Europe/US, and that an average
daily dose is ~2–3 mg in Japan (unpublished data). In
Japan a twice-daily dosing of sulfonylureas including
572 MATSUKI et al.
glimepiride is more common than once-daily dose
without any significant evidence.
In the present study, we attempted to investigate the
pharmacokinetic and pharmacodynamic properties of
once- or twice- daily dose of glimepiride in random-
ized, 2-phase crossover study in Japanese type 2 dia-
betic patients. This is the first report to demonstrate
the correlation between pharmacokinetics and pharma-
codynamics of glimepiride in type 2 diabetic patients
using the crossover-study protocol.
Research design and Methods
The study was conducted as a single center, random-
ized, two-period, crossover trial in Kawasaki Medical
School Hospital. The study protocol was approved by
the institutional review boards at the Ethics Committee
of Kawasaki Medical School Hospital, and the study
was carried out according to the principles of Decla-
ration of Helsinki. Written informed consent was ob-
tained from all patients.
Subjects
Outpatients with type 2 diabetes mellitus were re-
cruited according to the following inclusion criteria:
treated with 2 mg glimepiride alone over 4 weeks dura-
tion, age 40–70 years, weighing less than 25 kg/m2 of
body mass index, and HbA1C less than 8.0%. All sub-
jects were free of concomitant illness such as heart dis-
ease, hepatic (serum alanine aminotransferase more
than the upper limit of normal) or renal (serum creati-
nine more than the upper limit of normal) dysfunction.
None of the patients had a history of severe hypoglyce-
mia, active proliferative retinopathy or clinically sig-
nificant neuropathy. Concomitant medications without
hypoglycemic agents were permitted if the dose was
stabilized for one month and during the study.
Study design
Prior to the randomized 2-period crossover study,
patients were treated with once-daily 2 mg of glime-
piride in order to stabilize metabolic control over 3 to
5 weeks as a screening period. After screening period,
subjects were randomly allocated to once-daily dose
regimen with 2 mg of glimepiride before breakfast or
twice-daily with 1 mg before breakfast and dinner, and
were treated for 4 weeks (the first-period of crossover).
Then, the regimen was reversed from that used in the
first-period. Patients were treated by the new regimen
for 4 weeks (the second-period of crossover). During
the study period, they were asked to maintain a fixed
calorie diet, which was calculated individually based
on the ideal body weight and physical activity of each
patient. They were also asked to fix meal times at 8 am
for breakfast, midday for lunch and 6 pm for dinner.
Subjects were admitted one day before the final day
of each period of the study. On the next day, 24-h
profiles for serum glimepiride concentration, plasma
glucose, serum insulin and C-peptide levels were
analyzed. For the determination of HbA1C and other
biochemical parameters, blood was drawn before
breakfast. For the pharmacokinetic experiment, serum
glimepiride concentrations were measured 14 times
over 24 hours. For pharmacodynamic experiment,
plasma glucose levels 19 times, and serum insulin and
C-peptide levels were also measured 15 times. During
experiments, each subject was fed an individually
fixed-calorie diet three times, which they were asked to
maintain before admission. Except for the fixed meals,
no food or drink other than water was permitted until
completion of studies.
Analytical procedures
Plasma glucose and HbA1C were measured by stan-
dard laboratory methods. Insulin and C-peptide levels
were measured by enzyme immunoassay method and
glimepiride concentrations were analyzed by liquid
chromatography-tandem mass spectrometry method
(SRL, Inc., Tokyo, Japan), using of the Hitachi L-
Series (Hitachi, Tokyo, Japan). Glimepiride from 1 ml
plasma with internal standard was extracted by same
volume of diethyl ether and 1-fluoro 2,4-dinitro-
benzene, and was dried. Standards of glimepiride and
patient samples were separated using Spherisorb ODS
2 column (5 µm, 4.6 mm i.d. × 125 mm, Waters,
Milford, MA, USA) and a mobile phase consisting of
acetonitrile and perchlorate (1 : 1) were used. Blood
concentration of glimepiride was calculated by mea-
suring peak area. The quantification limit was 12.5
to 200 ng/mL. Interday coefficients of variation for
glimepiride were 9.0% at 12.5 ng/mL, 3.7% at 50.0 ng/
mL, and 5.0% at 200.0 ng/mL (n = 15). Intraday coef-
ficients of variation for glimepiride were 2.3% at 12.5
ng/mL, 2.6% at 50.0 ng/mL, and 1.6% at 200.0 ng/mL
 PHARMACOKINETICS AND PHARMACODYNAMICS OF GLIMEPIRIDE 573

(n = 5). Table 1. Baseline characteristics

Pharmacokinetic parameters of glimepiride were Number of patients (female/male) 8 (2/6)
characterized by peak concentration in serum (Cmax), Age (years) 63.5 ± 1.8
time to Cmax (Tmax), and elimination half-life (T1/2), Body mass index (kg/m2) 22.9 ± 1.1
and the area under glimepiride concentration versus Diabetic duration (years) 14.6 ± 1.8
time curve (AUC) was calculated for different time pe- HbA1C (%) 6.9 ± 0.2
riods under the individual profiles by means of the trap-
ezoidal rule. Pharmacodynamic measures for glucose,
insulin and C-peptide concentrations were also evalu-
ated as in the same manner as in the pharmacokinetic
analyses.

Statistical analysis

All data from the two study groups were expressed

as mean ± standard error of the mean (SEM). Statisti-
cal comparisons were performed between the two
groups was determined by Mann-Whitney U test. Sta-
tistical significance was accepted when P value was
less than 0.05. Fig. 1. A 24-hr profile of serum glimepiride concentrations at
the last day of each crossover period. 2 mg QD (black
circle) or 1 mg BID (white square) glimepiride. Results
are shown as mean ± SEM (n = 8).
Results

A total of seven patients were screened for prepara- Table 2. Pharmacokinetic parameters
tion in this study, and eight patients with written in-
Once-daily Twice-daily P
formed consent (2 female and 6 male) were enrolled
and randomly allocated to one of the 2 groups accord- Tmax (h) 1.88 ± 0.21 2.3 ± 0.5A 0.267
2.0 ± 0.4B not calculated
ing to the protocol; one half to once-daily dose the reg-
AUC (ng·h/mL) 706.2 ± 63.3 630.8 ± 93.6 not calculated
imen and the remaining 4 subjects to twice-daily doses. T1/2 (hr) 3.28 ± 0.21 N.D.
All subjects completed the study for the 8 weeks. The
Parameters at the last day of each crossover period in 8 patients.
baseline characteristics of the 8 subjects are shown in
Results are shown. A: Glimepiride administered in the morning.
Table 1. The age was 63.5 ± 1.8 years, and the dura- B: Glimepiride administered in the evening.
tion of diabetes was 14.6 ± 1.8 years. Baseline HbA1C
was 6.9 ± 0.2% and body mass index was 22.9 ±
1.1 kg/m2. second peak, Table 2). Cmax of the second peak of
glimepiride concentration in twice-daily dosing group
Pharmacokinetics observed in the evening appeared to be lower than that
of the first peak observed in the morning, but not sig-
As shown in Fig. 1, the pharmacokinetic profiles in nificant statistically (P = 0.215). AUC values were not
two groups were different each other; a single peak of different between two groups.
serum glimepiride concentrations was observed in
once-daily dose group, and double peaks in twice-daily Pharmacodynamics
dose group. Glimepiride concentrations increased im-
mediately, and peaked around 2 h after administration The 24-h glucose profiles were similar in once-daily
in both once-daily and twice-daily groups. Cmax value dose and twice-daily doses of glimepiride as shown in
in once-daily dose was significantly higher than those Fig. 2. Fasting plasma glucose concentration, post-
in twice-daily doses only for the second peak prandial glucose concentration, mean plasma glucose
(P = 0.055 for the first peak and P = 0.005 for the and AUC value for plasma glucose were not different
574 MATSUKI et al.

Fig. 2. A 24-hr profile of plasma glucose levels at the last day

of each crossover period. 2 mg QD (black circle) or
1 mg BID (white square) glimepiride. Results are
shown as mean ± SEM (n = 8).

Table 3. Pharmacodynamic parameters

Once-daily Twice-daily
Body mass index (kg/m2) 23.0 ± 1.0 22.9 ± 1.0
24-hr mean PG (mg/dL) 199.8 ± 17.2 195.3 ± 15.0
PG AUC (mg h/dL) 4775 ± 400 4101 ± 269
HbA1C (%) 6.9 ± 0.2 7.1 ± 0.1
ΣIRI (µU/mL) 226.9 ± 25.9 200.1 ± 23.4
ΣCPR (ng/mL) 54.9 ± 2.1 51.8 ± 2.4
Parameters at the last day of each crossover period in 8 patients.
Results are shown as mean ± SEM.
between the two groups (Table 3). The 24-h insulin
profiles showed 3 peaks of serum insulin level associ-
ated with meals in both two groups (Fig. 3A). Peak
values of insulin in twice-daily doses seemed to be
lower than those in once-daily dose group, whereas
there were no statistically significant differences in
fasting or postprandial insulin levels in two groups.
When the C-peptide profiles between two groups were
compared, there were also no significant differences at
any points measured (Fig. 3B). The 24-h total insulin
and C-peptide values were not different between two
groups. HbA1C values at the end of the study also were
not different in both groups (Table 3).
Safety
All patients included in this study were evaluated
with regard to safety. No case with hypoglycemia was
observed, and no adverse events were related to the
treatment with glimepiride, suggesting a favorable
safety profile of this drug.
P
0.792
0.834
0.600
0.958
0.294
0.294
Fig. 3. A 24-hr profile of serum insulin (A) and C-peptide (B)
at the last day of each crossover period. 2 mg QD
(black circle) or 1 mg BID (white square) glimepiride.
Results are shown as mean ± SEM (n = 8).
Discussion
This crossover study was initiated to compare the
pharmacological effects of glimepiride between once-
and twice-daily dosing based on the comparative anal-
yses of both pharmacokinetics and pharmacodynamics
of these two regimens. Our study clearly demonstrated
that once- and twice-daily dosing of glimepiride pro-
vided different pharmacokinetic profiles each other,
but were equally effective in regulating plasma glu-
coses, serum insulin and C-peptide levels in patients
with type 2 diabetes. The Tmax values observed in this
study were not different from those in normal subjects
and in diabetic patients reported previously [5–7]. A
recommended daily dosage of glimepiride in Japanese
subjects is ~1–4 mg, and the majority of patients
treated with this drug receive ~2–3 mg daily. Thus the
dosage used is appropriate in the study using Japanese
subjects.
 PHARMACOKINETICS AND PHARMACODYNAMICS OF GLIMEPIRIDE
Several observations using relatively higher dosage
of glimepiride also concluded that pharmacodynamic
effects of this drug given in once- and twice-daily to
diabetic patients were comparable. Rosenstock et al.
reported the comparable effect of once-daily dose of
glimepiride (8 mg or 16 mg) with twice-daily doses
(4 mg BID or 8 mg BID) in a double-blind placebo-
controlled study of American (ethnicity unknown) type
2 diabetic patients [4]. They concluded that there were
no meaningful differences in glycemic variables such
as fasting plasma glucose, postprandial glucose, HbA1C
value, and serum insulin and C-peptide levels be-
tween once- and twice-daily dosing. Furthermore,
Sonnenberg et al. demonstrated that 24 h mean glucose
concentrations showed a slightly greater decrease for
6 mg twice-daily, compared with once-daily dose, but
that clinically both regimens were effective in promot-
ing glycemic control [8].
It is of interest that insulinotropic effects were not
different between once- and twice-daily doses of
glimepiride, whereas a distinct difference in 24-h
pharmacokinetic profiles was observed between the
two regimens. The relationship between pharmaco-
kinetic and pharmacodynamic actions for sulfonylurea
drugs has been investigated [9, 10]. When sulfonyl-
urea drugs were administered, the correlation between
drug concentration and its effect on insulin level was
only apparent with the first 3–5 h after drug adminis-
tration [10]. In the present study, the first peak of
glimepiride concentration in blood was consistent with
the peak of serum insulin level after breakfast, but the
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