Association between Sex Differences and the Pharmacokinetics of Repaglinide among a Malaysian Population

doi:10.4236/pp.2011.24042

Paper Menu >>

Journal Menu >>

Pharmacology & Pharmacy, 2011, 2, 332-337

doi:10.4236/pp.2011.24042 Published Online October 2011 (http://www.SciRP.org/journal/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-

laysia.

Email: *[email protected]

Received April 28th, 2011; revised May 20th, 2011; accepted June 25th, 2011.

ABSTRACT

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

tests.

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-

tively.

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

used.

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

Association between Sex Differences and the Pharmacokinetics of Repaglinide among a Malaysian Population

334

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-

jects.

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

subjects.

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

subjects.

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

repaglinide.

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

subjects.

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-

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

females.

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

repaglinide.

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.

304/PPSP/6131450).

REFERENCES

[1] A. Dornhorst, “Insulinotropic Meglitinide Analogues,”

Lancet, Vol. 358, No. 9294, 2001, pp. 1709-1716.

doi:10.1016/S0140-6736(01)06715-0

[2] V. Hatorp, “Clinical Pharmacokinetics and Pharmacody-

namics of Repaglinide,” Clinical Pharmacokinetics, Vol.

41, No. 7, 2002, pp. 471-483 .

Association between Sex Differences and the Pharmacokinetics of Repaglinide among a Malaysian Population

336

doi:10.2165/00003088-200241070-00002

[3] C. R. Culy and B. Jarvis, “Repaglinide: A Review of Its

Therapeutic Use in Treatment of Type 2 Diabetes Melli-

tus,” Drugs, Vol. 61, No. 11, 2001, pp. 1625-1660.

doi:10.2165/00003495-200161110-00008

[4] T. B. Bidstrup, I. Bjornsdottir, U. G. Sidelmann, M. S.

Thamsen and K. T. Hansen, “CYP2C8 and CYP3A4 Are

the Principal Enzymes Involved in the Human in Vitro

Biotransformation of the Insulin Secretagogue Repag-

linide,” British Journal of Clinical Pharmacology, Vol.

56, No. 3, 2003, pp. 301-314.

doi:10.1046/j.0306-5251.2003.01862.x

[5] S. Rendic and F. J. Carlo, “Human Cytochrome P450

Enzyme: A Status Report Summarizing Their Reaction,

Substrates, Inducers and Inhibitors,” Drug Metabolism

Reviews, Vol. 29, No. 1-2, 1997, pp. 413-580.

doi:10.3109/03602539709037591

[6] D. Dai, C. Darryl, D. C. Zeldin, J. A. Blasidell, B. Chanas,

S. J. Coulter, et al., ”Polymorphisms in Human CYP2C8

Decrease Metabolism of the Anticancer Drug Paclitaxel

and Arachidonic Acid,” Pharmacogenetics, Vol. 11, No.

7, 2001, pp. 597-607.

doi:10.1097/00008571-200110000-00006

[7] H. Yamazaki, A. Shibata, M. Suzuki, M. Nakajima, N.

Shimada and F. P. Guengerich, “Oxidation of Troglita-

zone to a Quinine-Type Metabolite Catalyzed by Cyto-

crome P450 2C8 and P450 3A4 in Human Liver Micro-

somes,” Drug Metabolism and Disposition, Vol. 27, No.

11, 1999, pp. 1260-1266.

[8] W. Muck, “Clinical Pharmacokinetics of Cerivastatin,”

Clinical Pharmacokinetics, Vol. 39, No. 2, 2000, pp.

99-116. doi:10.2165/00003088-200039020-00002

[9] T. Shimada, H. Yamazaki, M. Mimura, Y. Inui and F. P.

Guengerich, “Interindividual Variations in Human Liver

Cytochrome P450 Enzymes Involved in the Oxidation of

Drugs, Carcinogens and Toxic Chemicals,” Journal of

Pharmacology and Experimental Therapeutics, Vol. 270,

No. 1, 1994, pp. 414-423.

[10] P. B. Watkins, “Non-Invasive Tests of CYP3A4 Enzymes,”

Pharmacogenetics, Vol. 4, No. 4, 1994, pp. 171-184.

doi:10.1097/00008571-199408000-00001

[11] J. Hamilton and B. Parry, “Sex-Related Differences in

Clinical Drug Response: Implications for Women’s Heal-

th,” Journal of the American Medical Women’s Associa-

tion, Vol. 38, No. 5, 1983, pp. 126-132.

[12] G. C. Yee, T. P. Lennon and D. J. Gmur, “Age-Dependent

Cyclosporine: Pharmacokinetics in Marrow Transplant Re-

cipients,” Clinic al Pharmacology & Therapeutics, Vol. 40,

No. 4, 1986, pp. 438-443. doi:10.1038/clpt.1986.204

[13] D. J. Greenbalt, J. S. Harmatz and L. L. von Moltke, “Age

and Gender Effects on the Pharmacokinetics and Pharma-

codynamics of Triazolam, a Cytochrome P450 3A Sub-

strate,” Clinical Pharmacology & Therapeutics, Vol. 76,

No. 5, 2004, pp. 467-479. doi:10.1016/j.clpt.2004.07.009

[14] M. E. Krecic-Shepard, C. R. Barnas, J. Slimko and J. B.

Schwartz, “Faster Clearance of Sustained Release Vera-

pamil in Men versus Women: Continuing Observations

on Sex-Specific Defferencesafter Oral Administration of

Verapamil,” Clinical Pharmacology & Therapeutics, Vol.

68, No. 3, 2000, pp. 286-292.

doi:10.1067/mcp.2000.109356

[15] A. B. Ruzilawati, A. W. Suhaimi, A. Imran, Z. Ismail and S.

H. Gan, “Method Development and Validation of Repag-

linide in Human Plasma by HPLC and Its Application to

Pharmacokinetics Study,” Journal of Pharmaceutical and

Biomedical Analysis, Vol. 43, No. 5, 2007, pp. 1831-1835.

doi:10.1016/j.jpba.2006.12.010

[16] A. B. Ruzilawati, A. W. Mohd Suhaimi and S. H. Gan,

“Genetic Polymorphisms of CYP3A4: CYP3A4*18 Allele

Is Found in Five Healthy Malaysian Subjects,” Clinica

Chimica Acta, Vol. 383, No. 1-2, 2007, pp. 158-162.

doi:10.1016/j.cca.2007.05.004

[17] Y. D. Muthiah, W. L. Lee, L. K. Teh, C. E. Ong, M. Z.

Salleh and R. Ismail, “A Simple Multiplex PCR Method

for the Concurrent Detection of Three CYP2C8 Vari-

ants,” Clinica Chimica Acta, Vol. 349, No. 1-2, 2004, pp.

191-198. doi:10.1016/j.cccn.2004.06.024

[18] A. B. Ruzilawati, A. W. Mohd Suhaimi and S. H. Gan,

“Population Pharmacokinetic Modeling of Repaglinide in

Healthy Subjects by Using Nonparametric Adaptive Grid

(NPAG) Algorithm,” Journal of Clinical Pharmacy and

Therapeutics, Vol. 35, No. 1, 2010, pp. 105-112.

doi:10.1111/j.1365-2710.2009.01042.x

[19] B. Meibohm, I. Beierle and H. Derendorf, “How Important

Are Gender Differences in Pharmacokinetics?” Clinical

Pharmacokinetics, Vol. 41, No. 5, 2002, pp. 329-342.

doi:10.2165/00003088-200241050-00002

[20] S. H. Haidar, S. B. Johnson, M. J. Fossler and A. S. Hus-

sain, “Modeling the Pharmacokinetics and Pharmacody-

namics of a Unique Oral Hypoglycemic Agent Using

Neural Networks,” Pharmaceutical Research, Vol. 19,

No. 1, 2002, pp. 87-91. doi:10.1023/A:1013611617787

[21] R. Z. Harris, L. Z. Benet and J. B. Schwartz, “Gender Ef-

fects in Pharmacokinetics and Pharmacodynamics,” Drugs,

Vol. 50, No. 2, 1995, pp. 222-239.

doi:10.2165/00003495-199550020-00003

[22] W. R. Hutson, R. L. Roehrkasse and A. Wald, “Influence

of Gender and Menopause on Gastric Emptying and Motil-

ity,” Gastroenterology, Vol. 96, No. 1, 1989, pp. 617-629.

[23] F. Abad-Santos, J. Novalbos, M. A. Galvez-Mugica, S.

Gallego-Sandin, S. Almeida and F. Vallee, “Assessment

of Sex Differences in Pharmacokinetics and Pharmaco-

dynamics of Amlodipine in a Bioequivalence Study,”

Pharmaceutical Research, Vol. 51, No. 5, 2005, pp. 445-

452. doi:10.1016/j.phrs.2004.11.006

[24] F. Franconi, S. Brunelleschi, L. Steardo, et al., “Gender

Differences in Drug Respo nses,” Pharmaceutical Resea rch,

Vol. 55, No. 2, 2007, pp. 81-95.

doi:10.1016/j.phrs.2006.11.001

[25] D. J. Greenblatt, M. Divoll and D. R. Abernethy, “Physi-

ologic Changes in Old Age: Relation to Altered Drug

Disposition,” Journal of the American Geriatrics Society,

Vol. 30, Supplement 11, 1982, pp. S6-S10.

[26] M. Chen, L. Ma, G. L. Drunsano and A. N. Nafziger,

Association between Sex Differences and the Pharmacokinetics of Repaglinide among a Malaysian Population

337

“Sex Differences in CYP3A4 Activity Using Intravenous

and Oral Midazolam,” Clinical Pharmacology & Thera-

peutics, Vol. 80, No. 5, 2006, pp. 531-538.

doi:10.1016/j.clpt.2006.08.014

[27] D. L. Schmucker, K. W. Woodhouse, R. K. Wang, H.

Wyne, O. H. Ja mes and M. McManu s, “Effect s of A ge and

Gender on in Vitro Properties of Human Liver Microsomal

Mono-Oxygenase,” Clinical Pharmacology & Therapeu-

tics, Vol. 48, No. 4, 1990, pp. 365-374.

doi:10.1038/clpt.1990.164

[28] P. He, M. H. Court, D. J. Greenblatt and L. L. von-Moltke,

“Genotype-Phenotype Associations of Cytochrome P450

3A4 and 3A5 Poly morphism with Midazola m Clearance in

Vivo,” Clinical Pharmacology & Therapeutics, Vol. 77, No.

5, 2005, pp. 373-387.

doi:10.1016/j.clpt.2004.11.112

[29] R. Wolbold, K. Klein, O. Burk, A. K. Nussler, P. Neu-

haus and M. Eichelbaum, “Sex Is a Major Determinant of

CYP3A4 Expression in Human Liver,” Hepatology, Vol.

38, No. 4, 2003, pp. 978-988.

[30] E. Tanaka, “Gender-Related Differences in Pharmacoki-

netics and Their Clinical Significance,” Journal of Clini-

cal Pharmacy and Therapeutics, Vol. 24, No. 5, 1999, pp.

339-346. doi:10.1046/j.1365-2710.1999.00246.x

[31] K. T. Kivisto and H. K. Kroemer, “Use of Probe Drugs as

Predictors of Drug Metabolism in Humans,” The Journal

of Clinical Pharmacology, Vol. 37, Supplement 1, 1997,

pp. 40S-48S. doi:10.1177/009127009703700121