Association between Sex Differences and the Pharmacokinetics of Repaglinide among a Malaysian Population
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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 (C<sub>max</sub>) 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 (t<sub>1/2</sub>) 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.
- Dornhorst A. Insulinotropic meglitinide analogues. Lancet. 2001; 358: 1709-1716.
- Hatorp V. Clinical pharmacokinetics and pharmacodynamics of repaglinide. Clin Pharmacokinet. 2002; 41(7): 471-483.
- Culy CR, Jarvis B. Repaglinide: a review of its therapeutic use in treatment of type 2 diabetes mellitus. Drugs. 2001; 61(11): 1625-1660.
- 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.
- 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.
- 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.
- 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.
- Muck W. Clinical pharmacokinetics of cerivastatin. Clin Pharmacokinet. 2000; 39: 99-116.
- 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.
- Watkins PB. Non-invasive tests of CYP3A4 enzymes. Pharmacogenetics. 1994; 4: 171-184.
- 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.
- Yee GC, Lennon TP, Gmur DJ. Age-dependent cyclosporine: pharmacokinetics in marrow transplant recipients. Clin Pharmacol Therap. 1986; 40: 438-443.
- 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.
- 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.