Ruzilawati Abu Bakar, Mohd Suhaimi Ab Wahab, Imran Ahmad, Gan Siew Hua

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 male 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 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 females compared to male subjects. The mean rate of elimination (kel) and mean CL of repaglinide were 47.67% (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% higher (p = 0.03), and the mean AUC was 35.83% higher (p = 0.03) in female subjects when compared to the male subjects having CYP2C8*5 allele. Sex differences significantly influence the pharmacokinetics of repaglinide.

Keywords: Sex Differences, CYP2C8, CYP3A4, Polymorphisms, Repaglinide

Cite this paper: nullR. Bakar, M. Wahab, I. Ahmad and G. Hua, "Association between Sex Differences and the Pharmacokinetics of Repaglinide among a Malaysian Population," Pharmacology & Pharmacy, Vol. 2 No. 4, 2011, pp. 332-337. doi: 10.4236/pp.2011.24042.

References

[1]   Dornhorst A. Insulinotropic meglitinide analogues. Lancet. 2001; 358: 1709-1716.

[2]   Hatorp V. Clinical pharmacokinetics and pharmacodynamics of repaglinide. Clin Pharmacokinet. 2002; 41(7): 471-483.

[3]   Culy CR, Jarvis B. Repaglinide: a review of its therapeutic use in treatment of type 2 diabetes mellitus. Drugs. 2001; 61(11): 1625-1660.

[4]   Bidstrup TB, Bjornsdottir I, Sidelmann UG, Thamsen MS, Hansen KT. CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide. British J Clin Pharmacol. 2003; 56(3): 301-314.

[5]   Rendic S, Carlo FJ. Human cytochrome P450 enzyme: a status report summarizing their reaction, substrates, inducers and inhibitors. Drug Met Rev. 1997; 29: 413-580.

[6]   Dai D, Darryl C, Zeldin DC, Blasidell JA, Chanas B, Coulter SJ, et al. Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics. 2001; 11(7): 597- 607.

[7]   Yamazaki H, Shibata A, Suzuki M, Nakajima M, Shimada N, Guengerich FP. Oxidation of troglitazone to a quinine-type metabolite catalyzed by cytocrome P450 2C8 and P450 3A4 in human liver microsomes. Drug Metab Dispos. 1999; 27: 1260-1266.

[8]   Muck W. Clinical pharmacokinetics of cerivastatin. Clin Pharmacokinet. 2000; 39: 99-116.

[9]   Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. Interindividual variations in human liver cytochrome P450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals. J Pharmacol Exp Therap. 1994; 270: 414-423.

[10]   Watkins PB. Non-invasive tests of CYP3A4 enzymes. Pharmacogenetics. 1994; 4: 171-184.

[11]   Hamilton J, Parry B. Sex-related differences in clinical drug response: Implications for women’s health. J American Med Womens Assoc. 1983; 38:126-132.

[12]   Yee GC, Lennon TP, Gmur DJ. Age-dependent cyclosporine: pharmacokinetics in marrow transplant recipients. Clin Pharmacol Therap. 1986; 40: 438-443.

[13]   Greenbalt DJ, Harmatz JS, von Moltke LL. Age and gender effects on the pharmacokinetics and pharmacodynamics of triazolam, a cytochrome P450 3A substrate. Clin Pharmacol Therap. 2004; 76: 467-479.

[14]   Krecic-Shepard ME, Barnas CR, Slimko J, Schwartz JB. Faster clearance of sustained release verapamil in men versus women: continuing observations on sex-specific defferencesafter oral administration of verapamil. Clin Pharmacol Therap. 2000; 68: 286-92.

[15]   Ruzilawati AB, Suhaimi AW, Imran A, Ismail Z, Gan SH. Method development and validation of repaglinide in human plasma by HPLC and its application to pharmacokinetics study. J Pharm Biomed Anal. 2007; 43(5): 1831-1835.

[16]   Ruzilawati AB, Mohd Suhaimi AW, Gan SH. Genetic polymorphisms of CYP3A4: CYP3A4*18 allele is found in five healthy Malaysian subjects, Clin Chim Acta. 2007; 383: 158-162.

[17]   Muthiah YD, Lee WL, Teh LK, Ong CE, Salleh MZ, Ismail R. A simple multiplex PCR method for the concurrent detection of three CYP2C8 variants. Clin Chim Acta. 2004; 349: 191-198.

[18]   Ruzilawati AB, Mohd Suhaimi AW, Gan SH. Population pharmacokinetic modeling of repaglinide in healthy subjects by using nonparametric adaptive grid (NPAG) algorithm. J Clin Pharm Therap. 2010; 35: 105-112.

[19]   Meibohm B, Beierle I, Derendorf H. How important are gender differences in pharmacokinetics? Clin Pharmacokinet. 2002; 41 (5): 329-342.

[20]   Haidar SH, Johnson SB, Fossler MJ, Hussain AS. Modeling the pharmacokinetics and pharmacodynamics of a unique oral hypoglycemic agent using neural networks. Pharm Res. 2002; 19(1): 87-91.

[21]   Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs. 1995; 50: 222-239.

[22]   Hutson WR, Roehrkasse RL, Wald A. Influence of gender and menopause on gastric emptying and motility. Gastroenterology. 1989; 96: 617-629.

[23]   Abad-Santos F, Novalbos J, Galvez-Mugica MA, Gallego-Sandin S, Almeida S, Vallee F. Assessment of sex differences in pharmacokinetics and pharmacodynamics of amlodipine in a bioequivalence study. Pharm Res. 2005; 51: 445-452.

[24]   Franconi F, Brunelleschi S, Steardo L et al. Gender differences in drug responses. Pharm Res. 2007; 55: 81-95.

[25]   Greenblatt DJ, Divoll M, Abernethy DR. Physiologic changes in old age: Relation to altered drug disposition. J Am Geriatr Soc. 1982; 30(Suppl): S6–S10.

[26]   Chen M, Ma L, Drunsano GL, Nafziger AN. Sex differences in CYP3A4 activity using intravenous and oral midazolam. Clin Pharmacol Therap. 2006; 80: 531-538.

[27]   Schmucker DL, Woodhouse KW, Wang RK, Wyne H, James OH, McManus M. Effects of age and gender on in vitro properties of human liver microsomal mono-oxygenase. Clin Pharmacol Therap. 1990; 48: 365-374.

[28]   He P, Court MH, Greenblatt DJ, von-Moltke LL. Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin Pharmacol Therap. 2005; 77: 373-387.

[29]   Wolbold R, Klein K, Burk O, Nussler AK, Neuhaus P, Eichelbaum M. Sex is a major determinant of CYP3A4 expression in human liver. Hepatology. 2003; 38: 978- 988.

[30]   Tanaka E. Gender-related differences in pharmacokinetics and their clinical significance. J Clini Pharm Therap. 1999; 24: 339-346.

[31]   Kivisto KT, Kroemer HK. Use of probe drugs as predictors of drug metabolism in humans. J Clin Pharmacol. 1997; 37 (Suppl.): 40S-48S.