Abstract
G004 is a novel sulfonylurea hypoglycemic drug which aimed at reducing macro- and micro-vascular complications as well as controlling glucose excursion in type 2 diabetes mellitus. The pharmacokinetics of G004 in rats was sex- and dose-dependent over the dose range of 1–10 mg kg−1. The mean AUC values in the female rats were fivefold higher than those in males. Drug blood and tissue levels in female rats were higher than the most counterparts of males. Compared with male rats, G004 was eliminated slowly from female rats in the bile, urine and feces. Consistent with the in vivo observations, marked sex-related difference of the metabolizing activity between the male and female liver microsomes (RLM) was observed. The intrinsic clearance (V max/K m) of G004 was 3.1-fold larger in the RLM from male than female rats. Seventeen oxidative metabolites were identified in rat liver microsomes. The amount of three metabolites of G004 showed relatively sex-related difference in RLM incubations. CYP2C11 was demonstrated mainly contributing to the sex-related differences in the pharmacokinetics and disposition of G004 in rats.
Similar content being viewed by others
References
Audoly LP, Rocca B, Fabre JE, Koller BH, Thomas D, Loeb AL, Coffman TM, FitzGerald GA (2000) Cardiovascular responses to the isoprostanes iPF(2alpha)-III and iPE(2)-III are mediated via the thromboxane A(2) receptor in vivo. Circulation 101:2833–2840
Bandiera S (1990) Expression and catalysis of sex-specific cytochrome P450 isozymes in rat liver. Can J Physiol Pharmacol 68:762–768
Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R, Marinopoulos SS, Puhan MA, Ranasinghe P, Block L, Nicholson WK, Hutfless S, Bass EB, Bolen S (2011) Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med 154:602–613
Cimetiere B, Dubuffet T, Landras C, Descombes JJ, Simonet S, Verbeuren TJ, Lavielle G (1998) New tetrahydronaphthalene derivatives as combined thromboxane receptor antagonists and thromboxane synthase inhibitors. Bioorg Med Chem Lett 8:1381–1386
Davis SN, Cherrington AD (1993) The hormonal and metabolic responses to prolonged hypoglycemia. J Lab Clin Med 121:21–31
Gerstein HC (2002) Reduction of cardiovascular events and microvascular complications in diabetes with ACE inhibitor treatment: HOPE and MICRO-HOPE. Diabetes Metab Res Rev 18(Suppl 3):S82–S85
Gochfeld M (2007) Framework for gender differences in human and animal toxicology. Environ Res 104:4–21
Kamataki T, Maeda K, Yamazoe Y, Nagai T, Kato R (1982) Evidence for the involvement of multiple forms of cytochrome P-450 in the occurrence of sex-related differences of drug metabolism in the rat. Life Sci 31:2603–2610
Kato R (1974) Sex-related differences in drug metabolism. Drug Metab Rev 3:1–32
Kato R, Yamazoe Y (1992) Sex-specific cytochrome P450 as a cause of sex- and species-related differences in drug toxicity. Toxicol Lett 64–65(Spec No): 661–667
Kobliakov V, Popova N, Rossi L (1991) Regulation of the expression of the sex-specific isoforms of cytochrome P-450 in rat liver. Eur J Biochem 195:585–591
Komura H, Iwaki M (2005a) Nonlinear pharmacokinetics of propafenone in rats and humans: application of a substrate depletion assay using hepatocytes for assessment of nonlinearity. Drug Metab Dispos 33:726–732
Komura H, Iwaki M (2005b) Pharmacokinetics and metabolism of metoprolol and propranolol in the female DA and female Wistar rat: the female DA rat is not always an animal model for poor metabolizers of CYP2D6. J Pharm Sci 94:397–408
Laakso M (1999a) Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes 48:937–942
Laakso M (1999b) Hyperglycemia as a risk factor for cardiovascular disease in type 2 diabetes. Prim Care 26:829–839
Legraverend C, Mode A, Wells T, Robinson I, Gustafsson JA (1992) Hepatic steroid hydroxylating enzymes are controlled by the sexually dimorphic pattern of growth hormone secretion in normal and dwarf rats. FASEB J 6:711–718
Liu XQ, Wu GZ, Gao C, Zhang WP, Ma Y, Su X (2007) Glycometabolism of sulfonylurea compound G004 in vitro and in vivo. Chin J New Drug 16:1581–1584
Liu L, Jiang Z, Liu J, Huang X, Wang T, Zhang Y, Zhou Z, Guo J, Yang L, Chen Y, Zhang L (2010) Sex differences in subacute toxicity and hepatic microsomal metabolism of triptolide in rats. Toxicology 271:57–63
McCormack VA, Dowsett M, Folkerd E, Johnson N, Palles C, Coupland B, Holly JM, Vinnicombe SJ, Perry NM, dos Santos Silva I (2009) Sex steroids, growth factors and mammographic density: a cross-sectional study of UK postmenopausal Caucasian and Afro-Caribbean women. BCR 11:R38
Molitch ME, DeFronzo RA, Franz MJ, Keane WF, Mogensen CE, Parving HH (2003) Diabetic nephropathy. Diabetes Care 26(Suppl 1):S94–S98
Mugford CA, Kedderis GL (1998) Sex-dependent metabolism of xenobiotics. Drug Metab Rev 30:441–498
Obach RS, Reed-Hagen AE (2002) Measurement of Michaelis constants for cytochrome P450-mediated biotransformation reactions using a substrate depletion approach. Drug Metab Dispos 30:831–837
Pantalone KM, Kattan MW, Yu C, Wells BJ, Arrigain S, Jain A, Atreja A, Zimmerman RS (2012) Increase in overall mortality risk in patients with type 2 diabetes receiving glipizide, glyburide or glimepiride monotherapy versus metformin: a retrospective analysis. Diabetes Obes Metab 14:803–809
Rudorfer MV, Potter WZ (1999) Metabolism of tricyclic antidepressants. Cell Mol Neurobiol 19:373–409
Scott J, Poffenbarger PL (1979) Pharmacogenetics of tolbutamide metabolism in humans. Diabetes 28:41–51
Shang LN, Gao C, Wu GZ, Zhang WP (2011) Effect of G004 on glucose and lipid metabolism in type 2 diabetic kkay mice. Chin J New Drugs 20:2057–2068
Sun H, Scott DO (2011) Impact of genetic polymorphisms of cytochrome P450 2 C (CYP2C) enzymes on the drug metabolism and design of antidiabetics. Chem Biol Interact 194:159–167
Suryawanshi S, Wahajuddin, Gupta RC, Singh SK (2011) Preclinical pharmacokinetics, dose proportionality, gender difference and protein binding study of 16-dehydropregnenolone, an antihyperlipidemic agent, in rats. J Pharm Pharmacol 63:41–48
Waxman DJ (1992) Regulation of liver-specific steroid metabolizing cytochromes P450: cholesterol 7alpha-hydroxylase, bile acid 6beta-hydroxylase, and growth hormone-responsive steroid hormone hydroxylases. J Steroid Biochem Mol Biol 43:1055–1072
Waxman DJ, Dannan GA, Guengerich FP (1985) Regulation of rat hepatic cytochrome P-450: age-dependent expression, hormonal imprinting, and xenobiotic inducibility of sex-specific isoenzymes. Biochemistry 24:4409–4417
Wu GZ, Wang GJ (2005) The usage of sulfonylurea and thiourea derivatives in synthesis of hypoglycemic agents. China Patent Int Cl: A61K 31/17, 2004/12/29
Yamaoka K, Tanigawara Y, Nakagawa T, Uno T (1981) A pharmacokinetic analysis program (multi) for microcomputer. J Pharmacobiodyn 4:879–885
Yamazaki H, Tabata S (1993) Sex difference in pharmacokinetics of the novel sulfonylurea antidiabetic glimepiride in rats. Arzneimittel-Forschung 43:1317–1321
Yang HX, Wu GZ (2009) Effects of new sulfonylurea compound G004 on glycometabolism in insulin-resistance HepG2 cells. Chin J Modern Med 19:820–826
Zhang HB, Zhou JP, Huang WL, Wu GZ (2005) New sulfonylurea and thiourea derivatives, the preparations and the related drug. China Patent, Int Cl: C07C311/58, 2005/1/5
Zhang HB, Zhang YA, Wu GZ, Zhou JP, Huang WL, Hu XW (2009) Synthesis and biological evaluation of sulfonylurea and thiourea derivatives substituted with benzenesulfonamide groups as potential hypoglycemic agents. Bioorg Med Chem Lett 19:1740–1744
Acknowledgments
The work was supported by the Hi-tech Research and Development Program of China (No. 2003AA2Z3530) and the Innovation and Entrepreneurship Training Program for the College Students of Ministry of Education, China (No. SZ12110).
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Hu, L., Agbokponto, J.E., Li, X. et al. In vivo and in vitro evidence of the sex-dependent pharmacokinetics and disposition of G004, a potential hypoglycemic agent, in rats. Eur J Drug Metab Pharmacokinet 40, 187–202 (2015). https://doi.org/10.1007/s13318-014-0196-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13318-014-0196-7