Pharmacology & Pharmacy, 2011, 2, 332-337
doi:10.4236/pp.2011.24042 Published Online October 2011 (
Copyright © 2011 SciRes. PP
Association between Sex Differences and the
Pharmacokinetics of Repaglinide among a
Malaysian Population
Ruzilawati Abu Bakar1*, Mohd Suhaimi Ab Wahab1, Imran Ahmad2, Gan Siew Hua3
1Department of Pharmacology, Universiti Sains Malaysia, Kota Bharu, Malaysia; 2Department of Family Medicine , Universiti Sains
Malaysia, Kota Bharu, Malaysia; 3Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Ma-
Email: *
Received April 28th, 2011; revised May 20th, 2011; accepted June 25th, 2011.
This study was conducted to evaluate the effect of sex differences on the pharmacokinetics of repaglinide in healthy
subjects. One hundred twenty one healthy volunteers (61 ma le and 60 female; aged 18 - 50 years) were included in the
study. Subjects were administered a single 4-mg repaglinide oral dose. Blood samples were taken at 0, 30, 60, 120, 180
and 240 min. Serum repaglinide levels were determined by a high-performance liquid chromatography (HPLC) method.
Subjects were also genotyped by polymerase chain reactions-restriction fragment length polymorphisms (PCR-RFLP)
for CYP3A4*4, *5 and *18 alleles and by an allele-specific multiplex PCR for CYP2C8*2, *3, *4 and *5 alleles. The
pharmacokinetics of repaglinide were comparable between male and female subjects. The mean clearance (CL) of re-
paglinide was 16.0% lower (p = 0.03), the mean area under the serum concentration-time curve (AUC) was 12.8%
higher (p = 0.04) and the peak serum concentration (Cmax) was 13.2% higher (p = 0.03) in females compared to male
subjects. The mean rate of elimination (kel) and mean CL of repaglinide were 47.6 7% (p = 0.03) higher and 29.25% (p
= 0.03) higher, respectively, in male subjects having CYP2C8*5 allele compared to female subjects. We also found that
the mean half-life (t1/2) of repaglinide was 42.43% h igher (p = 0.03), and the mean AUC was 35.83% higher (p = 0.03)
in female subjects when compared to the male subjects ha ving CYP2C8*5 allele. Sex differen ces significantly influence
the pharmacokinetics of repag linide.
Keywords: Sex Differences, CYP2C8, CYP3A4, Polymorphisms, Repaglinide
1. Introduction
Repaglinide was the first meglitinid e analogu e to become
available. It is used in type 2 diabetic patients to normal-
ise postprandial hyperglycaemia [1,2]. Like the sulfony-
lureas, repaglinide reduced blood glucose by stimulating
insulin release from pancreatic
-cells [3]. It has a fast
onset and short duration of action. Repaglinide is rapidly
absorbed from the gastrointestinal tract after oral admini-
stration and eliminated in the bile. Only a very small
fraction of the administered dose is excreted through the
urine. It differs from other antidiabetic agents in its
structure, bind ing profile, duratio n of action an d mode of
excretion [3]. Cytochrome P4502C8 (CYP2C8) and cy-
tochrome P4503A4 (CYP3A4) are the principal enzymes
that participate in its oxidative biotransformation [4].
CYP2C8 is the major human hepatic P450, constitut-
ing about 12% of total microsomal CYP content in the
liver [5] in which it conducts oxidative metabolism of at
least 5% of drugs cleared by phase I metabolism. Drugs
for which CYP2C8 contributes significantly to their bio-
transformation include the anticancer drug paclitaxel [6 ],
the antidiabetic drugs rosiglitazone and troglitazone [7]
and repaglinide [4], the antimalarial amodiaquine [6] and
the hydroxymethylglutaryl co-enzyme A reductase in-
hibitors such as cerivastatin and fluvastatin [8].
CYP3A4 is involved in the metabolism of more than
60% of all drugs used in humans [5]. It is found in hu-
man livers, gastrointestinal tracts, kidneys, lungs, brains,
endotheliums, placentas, lymphocytes and intestines [9].
It plays important roles in the metabolism of drugs used
in humans including antidiabetics, antiarrhythmics, anti-
histamines, synthetic oestrogens, cancer chemotherapeu-
tic drugs, human immunodeficiency virus protease in-
Association between Sex Differences and the Pharmacokinetics of Repaglinide among a Malaysian Population333
hibitors, calcium channel antagonists, immunosuppres-
sants and cholestero l-lowering drugs [10].
Numerous studies have examined the influence of sex
differences on drug metabolism. Physiological factors
such as differences in body weigh t and composition, me-
tabolizing enzymes or hormone concentrations may dif-
ferentially affect the pharmacokinetics and pharmacody-
namics of many drugs between women and men [11].
Ignoring these sex differences during drug development
may lead to side-effects or toxicity as well as inadequate
response during drug treatment due to these differences
in drug metabolism [11].
Several investigators also have attempted to determine
potential sex differences in the metabolic activity of cy-
tochrome P450 (CYP) enzymes including CYP3A and
CYP2C. Some studies suggest higher CYP enzymes ac-
tivities in women than men [12], there are also reports of
no sex differences [13] or even lower in activities in
women [14]. Thus, these findings have been largely in-
consistent or inconclusive.
This study was designed to investigate the influence of
sex differences on the pharmacokinetics of repaglinide.
The secondary objective was to investigate whether sex
differences exist in CYP3A4 and CYP2C8 activities by
use of population pharmacokinetic modelling methods.
2. Materials and Methods
The study was conducted following approval by the Re-
search and Ethics Committee, School of Medical Sci-
ences, Universiti Sains Malaysia. All the subjects gave
their written informed consent prior to study enrolment.
One hundred twenty one healthy volunteers were re-
cruited, including 61 men and 60 women. All subjects
aged 18 to 50 years with a normal body mass index
(BMI). These volunteers were students and staff of Uni-
versiti Sains Malaysia, Health Campus, Kelantan, Ma-
laysia. They were ascertained to be healthy by a medical
history, physical examination and routine laboratory
Subjects were asked to fast overnight before the study.
On the day of repaglinide administration, 5 ml of blood
were collected in plain vacutainer tubes to determine
repaglinide’s concentration at 0 min (baseline). Subjects
then administered a single 4-mg repaglinide [Novo
Nordisk, Denmark] oral dose with 100 ml of water. On
each study day subjects were allowed to have a light
breakfast, precisely 10 min after repaglinide administra-
tion. The breakfast was eaten within 10 min. The break-
fast consisted of one sandwich (two pieces of bread with
eggs, tomato and margarine) and contained approxi-
mately 1550 kJ energy, 70 g carbohydrates, 8 g protein
and 6 g fat. Blood samples (5 mL into vacutainer for
pharmacokinetic study) were drawn from a cannulated
forearm vein at five designated times: 30, 60, 120, 180
and 240 min. Serum were separated within 30 min after
blood sampling.
During the day of repaglinide administration, the sub-
jects were under direct medical supervision and blood
glucose levels were monitored throughout the day. Addi-
tional glucose solution for intravenous use and glucagons
for intramuscular use were available in case of severe
hypoglycaemia but they were not needed.
The reversed-phase high performance liquid chroma-
tographic (HPLC) methods described by Ruzilawati et al.
[15] were used to measure serum repaglinide concentra-
tions. In brief, samples were processed after addition of
the internal standard (indomethacin, Sigma-Aldrich, St.
Louis, MO, USA). A calibration curve was analysed in
the concentratio n range of 20 - 200 ng /ml. Samples were
extracted with ethyl acetate and injected into the chro-
matographic system composed of an automatic sampler
(Waters, Mildford, MA, USA). Reversed-phase chroma-
tographic separation was achieved on Purospher STAR
C-18 analytical column (4.8 mm × 150 mm; 5 m parti-
cle size). The mobile phase consisted of 60:40 v/v ace-
tonitrile - ammonium formate (pH 2.7; 0.01 M) and was
run at 1 ml/min. The reten tion times of indomethacin and
repaglinide were approximately 5.3 and 6.2 min, respec-
For genetic analysis, a 5 mL ethylenediaminetetraace-
tic acid (EDTA) blood sample was drawn from each
subject and stored at –20˚C until deoxyribonucleic acid
(DNA) extraction. DNA was extracted with standard
methods (QIAamp DNA Blood Mini Kit, Qiagen, Hilden,
Germany). All subjects were genotyped for CYP3A4*4,
*5 and *18 alleles by the polymerase chain reaction- re-
striction fragment length polymorphism (PCR-RFLP)
method as described by Ruzilawati et al. [16]. Subjects
were also genotyped for CYP2C8*2, *3 and *4 alleles.
The method of allele-sp ecific PCR based on a previously
published protocol described by Muthiah et al. [17] was
The population pharmacokinetic parameters of repag-
linide was characterized by the Nonparametric Adaptive
Grid (NPAG) programme, a module of USC*PACK®
(version 12. 0) [ 1 8].
Mann-Whitney tests were used to compare the effect
of sex on repaglinide pharmacokinetic parameters using
the SPSS package (ver. 12, SPSS, Chicago, IL). Data
were presented as mean ± SD. A p value of < 0.05 was
considered to be statistically significant.
3. Results
One hundred and twenty one subjects completed the
study. Demographic data for the 121 subjects are dis-
played in Table 1. The comparison between healthy male
Copyright © 2011 SciRes. PP
Association between Sex Differences and the Pharmacokinetics of Repaglinide among a Malaysian Population
and female subjects’ repaglinide pharmacokinetic is
shown in Tables 2-4 summarize CYP3A4 and CYP2C8
genetic polymorphisms by sex in our subjects, respec-
tively. The comparison between the pharmacokinetic
parameters of repaglinide after a single oral dose of 4 mg
in male and female subjects having CYP2C8*5 allele is
shown in Table 5.
4. Discussion
Gender may be an important variable in the processes of
absorption, distribution, metabolism, and excretion. There
are several factors that may contribute to sex-related dif-
ferences in pharmacokinetics. These factors are gastric
acid secretion, gastrointestinal blood flow, proportions of
muscular and adipose tissue, amount of drug binding
Table 1. Demographics of 121 subjects.
Male (n = 61) Female (n = 60)
Age (year) 29.54 7.37 25.00 5.76
Body weight (kg) 62.06 7.20 54.19 7.59
Height (m) 166.92 5.72 157.23 7.27
BMI (kg/m2) 22.17 1.92 21.73 2.00
Table 2. Mean SD pharmacokinetic parameters of repag-
linide after a single dose of 4 mg in male and female sub-
Variable Male (n = 61) Female (n = 60)p
Mean Vd (L) 23.48 ± 9.05 22.21 ± 9.64 0.31 (NS)
Mean kel (h–1) 0.58 ± 0.24 0.57 ± 0.29 0.34 (NS)
Mean CL (L/h) 12.91 ± 4.16 10.91 ± 3.51 0.03
Mean t1/2 (h) 1.37 ± 0.49 1.47 ± 0.59 0.34 (NS)
Mean Cmax (ng/ml) 79.45 ± 28.28 89.95 ± 26.530.03
Mean tmax (h) 0.65 ± 0.39 0.58 ± 0.37 0.26 (NS)
Mean AUC (ng/ml per h) 324.50 ± 109.82 366.03 ± 117.860.04
NS: not significant.
Table 3. CYP3A4 genetic polymorphisms by sex in healthy
Genotypes Male n (%) Female n (%)
CYP3A4*1 56 (91.8%) 60 (100%)
CYP3A4*4 0 0
CYP3A4*5 0 0
CYP3A4*18 5 (8.2%) 0
TOTAL 61 (100%) 60 (100%)
Table 4. CYP2C8 genetic polymorphisms by sex in healthy
Genotypes Male n (%) Female n (%)
CYP2C8*1 54 (88.54%) 54 (90%)
CYP2C8*2 1 (1.63%) 0
CYP2C8*3 1 (1.63%) 0
CYP2C8*4 0 0
CYP2C8*5 5 (8.2%) 6 (10%)
TOTAL 61 (100%) 60 (100%)
Table 5. Mean ± SD pharmacokinetic parameters of repag-
linide after a single oral dose of 4 mg in male and female
subjects having CYP2C8*5 allele.
Variable Male (n = 5) Female (n = 5)p
Mean Vd (L) 24.34 ± 10.08 30.34 ± 13.170.35 (NS)
Mean kel (h–1) 0.65 ± 0.25 0.34 ± 0.96 0.03
Mean CL (L/h) 13.91 ± 1.84 9.84 ± 3.12 0.03
Mean t1/2 (h) 1.22 ± 0.48 2.12 ± 0.48 0.03
Mean Cmax (ng/ml) 69.28 ± 23.5 80.21 ± 34.850.92 (NS)
Mean tmax (h) 0.73 ± 0.38 0.52 ± 0.27 0.35 (NS)
Mean AUC (ng/ml per h )269.12 ± 31.10 419.40 ± 130.890.03
NS: not significant.
proteins, sex-specific cytochrome P450 isozymes, physi-
ologic and hormonal changes during the menstrual cycle
as well as renal blood flow [19].
However, there has been little published work evalu-
ating potential sex differences in pharmacokinetics of
The present study indicates that sex difference is sig-
nificantly influences the ph armacokin etics of repaglinide.
We found that the mean clearance (CL) of repaglinide
was 16.0% lower (p = 0.03), the mean area under the
serum concentration-time curve (AUC) was 12.8% higher
(p = 0.04) and the peak serum concentration (Cmax) was
13.2% higher (p = 0.03) in female compared to male
Haidar et al. [20] reported that, on average, female pa-
tients had larger AUC for repaglinide when compared to
male patients. A higher bioavailability (higher AUC val-
ues) has also been reported for females than males by
Harris et al. [21]. Regarding pharmacokinetic parameters
of drugs administered by the oral route, gastrointestinal
motility has also been shown to be affected by sex hor-
mones, which is slower in females than in males [22].
Repaglinide is metabolised by oxidation process. Clear-
Copyright © 2011 SciRes. PP
Association between Sex Differences and the Pharmacokinetics of Repaglinide among a Malaysian Population335
ances of drugs that are metabolised by conjugation or
oxidation tend to be slower in women [23,24]. In general,
clearance of some drugs also depends on the rate of
blood flow into the eliminating organ. Women have a
smaller liver and a lower liver blood flow. According to
Meibohm et al. [19], women have an approximately 10%
lower glomerular filtration rate than men when normal-
ized for body surface area. This might explain the ob-
served 16% lower repaglinide clearance in female sub-
jects relative to male subjects.
No significant differences were seen in other pharma-
cokinetic parameters such as rate of elimination (kel),
rate of absorbtion (ka), half-life (t1/2), volume of distribu-
tion (Vd) and time to reach Cmax (tmax) between male and
female subjects.
Drug concentrations are dependent on the volume of
distribution (Vd). The Vd of a drug can affect the amount
of drug that give their effects at the site of action. Body
composition between women and men are different. This
factor might affect the Vd of certain drugs. Women have
a higher percentage of adipose tissue than do men.
Therefore, as suggested by Greenblatt et al. [25], there
should be a much larger Vd in women for lipophilic
drugs. This can result in a prolonged half-life of those
drugs. However, this did not occur in repaglinide’s
pharmacokinetics when we compared between males and
Differences in pharmacokinetic parameters between
males and females could also be explained by differences
in sex hormones and the menstrual cycle. However, in
this study, the phase of the menstrual cycle was not con-
sidered upon enrolment. Therefore, a new study would
be necessary to evaluate if menstrual cycle affects repag-
linide’s pharmacokinetics.
The allele frequencies of the CYP3A4*4 and *5 alleles
were 0% respectively for both male and female subjects
(Table 3). All five subjects (8.2%) with CYP3A4*18
mutations were found to be male (Table 4).
Although some studies suggested higher CYP3A4 ac-
tivity in women [26], there are no reports of sex differ-
ences in CYP3A4’s expression and function [27]. One
study even reported a lower enzyme activity in women
[14]. Some drugs that are substrates of CYP3A4 showed
higher clearance rates in women than in men, even after
correction for physiologic factors such as body weight
[21]. Some evidence supports the hypothesis that either
higher CYP3A4 protein expression in women or female
sex steroid modulation of CYP3A4 function could con-
tribute to higher CYP3A4-mediated clearance in women
[28]. According to Chen et al. [26], women have more
CYP3A4. In vitro studies conducted by Wolbold et al.
[29] that examined human liver samples detected higher
CYP3A4 expression levels in female liver samples. Ta-
naka [30] also suggested that drugs that are metabolised
by CYP3A4 frequently appear to be eliminated faster by
women. To date, however, there are no reports on sex
differences in CYP3A4 activity using repaglinide and our
study is the first. We did not however find a significant
correlation between repaglinide pharmacokinetics and
the various genotype groups, perhaps due to the unequal
distribution of sexes in the various groups. Furthermore,
we were unable to correlate sex and the observed kel and
CL values of repaglinide because all of our subjects with
the CYP3A4*18 genotype were male.
For CYP2C8, both subjects with CYP2C8*2 and
CYP2C8*3 were male subjects. There were five males
(8.20%) and six (10.00%) female subjects are having
CYP2C8*5 allele. In our study we found that the mean
(SD) kel and mean (SD) CL of repaglinide were 47.67%
(p = 0.03) higher and 29.25% (p = 0.03) higher, respec-
tively, in male subjects having CYP2C8*5 allele com-
pared to female subjects (Table 5). We also found that
the mean (SD) t1/2 of repaglinide was 42.43% higher (p =
0.03), and the mean (SD) AUC was 35.83% higher (p =
0.03) in female subjects when compared to the male sub-
jects having CYP2C8*5 allele. However, there was no
statistically significan t change in th e mean (SD) Vd, Cmax
or tmax of repaglinide.
Potential sex differences in CYP isoenzymes are ex-
pected to be most appropriately characterized by quanti-
fying the metabolism of probe drugs that are indicative of
a specific CYP activity [31]. Sex differences in activity
of the CYP enzymes will result in differences in Cl.
However there is no prior study on CYP2C8 activity in
male and female subjects. There are still large gaps in our
knowledge of sex differences in CYP2C8 activity and
therefore, significantly more research is needed.
In conclusion, the current data suggest that the phar-
macokinetic of repaglinide can be different between
women and men. Based on these data, we conclude that
gender significantly influences the pharmacokinetics of
5. Acknowledgements
This study was financially supported by Universiti Sains
Malaysia IRPA grant (grant no. 305/PPSP/6112222) and
Universiti Sains Malaysia short-term grant (grant no.
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